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1
Kober, Daniel L., Shimeng Xu, Shili Li, Bilkish Bajaj, Guosheng Liang, Daniel M. Rosenbaum e Arun Radhakrishnan. "Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis". Proceedings of the National Academy of Sciences 117, n. 45 (26 ottobre 2020): 28080–91. http://dx.doi.org/10.1073/pnas.2018578117.
Testo completoAbstract (sommario):
Lipid homeostasis in animal cells is maintained by sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors whose proteolytic activation requires the cholesterol-sensing membrane protein Scap. In endoplasmic reticulum (ER) membranes, the carboxyl-terminal domain (CTD) of SREBPs binds to the CTD of Scap. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi, where the actions of two proteases release the amino-terminal domains of SREBPs that travel to the nucleus to up-regulate expression of lipogenic genes. The CTD of SREBP remains bound to Scap but must be eliminated so that Scap can be recycled to bind and transport additional SREBPs. Here, we provide insights into how this occurs by performing a detailed molecular dissection of the CTD of SREBP2, one of three SREBP isoforms expressed in mammals. We identify a degradation signal comprised of seven noncontiguous amino acids encoded in exon 19 that mediates SREBP2’s proteasomal degradation in the absence of Scap. When bound to the CTD of Scap, this signal is masked and SREBP2 is stabilized. Binding to Scap requires an arginine residue in exon 18 of SREBP2. After SREBP2 is cleaved in Golgi, its CTD remains bound to Scap and returns to the ER with Scap where it is eliminated by proteasomal degradation. The Scap-binding motif, but not the degradation signal, is conserved in SREBP1. SREBP1’s stability is determined by a degradation signal in a different region of its CTD. These findings highlight a previously unknown role for the CTD of SREBPs in regulating SREBP activity.
2
Zhang, Lijun, Chunyan Li, Fang Wang, Shenghua Zhou, Mingjun Shangguan, Lina Xue, Bianying Zhang et al. "Treatment with PPARαAgonist Clofibrate Inhibits the Transcription and Activation of SREBPs and Reduces Triglyceride and Cholesterol Levels in Liver of Broiler Chickens". PPAR Research 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/347245.
Testo completoAbstract (sommario):
PPARαagonist clofibrate reduces cholesterol and fatty acid concentrations in rodent liver by an inhibition of SREBP-dependent gene expression. In present study we investigated the regulation mechanisms of the triglyceride- and cholesterol-lowering effect of the PPARαagonist clofibrate in broiler chickens. We observed that PPARαagonist clofibrate decreases the mRNA and protein levels of LXRαand the mRNA and both precursor and nuclear protein levels of SREBP1 and SREBP2 as well as the mRNA levels of the SREBP1 (FASNandGPAM) and SREBP2 (HMGCRandLDLR) target genes in the liver of treated broiler chickens compared to control group, whereas the mRNA level ofINSIG2, which inhibits SREBP activation, was increased in the liver of treated broiler chickens compared to control group. Taken together, the effects of PPARαagonist clofibrate on lipid metabolism in liver of broiler chickens involve inhibiting transcription and activation of SREBPs and SREBP-dependent lipogenic and cholesterologenic gene expression, thereby resulting in a reduction of the triglyceride and cholesterol levels in liver of broiler chickens.
3
An, Hyun-Jin, Jung-Yeon Kim, Mi-Gyeong Gwon, Hyemin Gu, Hyun-Ju Kim, Jaechan Leem, Sung Won Youn e Kwan-Kyu Park. "Beneficial Effects of SREBP Decoy Oligodeoxynucleotide in an Animal Model of Hyperlipidemia". International Journal of Molecular Sciences 21, n. 2 (15 gennaio 2020): 552. http://dx.doi.org/10.3390/ijms21020552.
Testo completoAbstract (sommario):
Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1β, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.
4
Mahmud, Iqbal, Guimei Tian, Tarun Hutchison, Brandon Kim e Daiqing Liao. "Abstract LB138: DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer". Cancer Research 82, n. 12_Supplement (15 giugno 2022): LB138. http://dx.doi.org/10.1158/1538-7445.am2022-lb138.
Testo completoAbstract (sommario):
Abstract Elevated lipid metabolism including lipogenesis is a major metabolic feature in cancer cells. In breast and other cancer types, genes involved in lipogenesis are highly upregulated, but the mechanisms that control their expression remain poorly understood. DAXX modulates gene expression through binding to numerous transcription factors although the functional impact of these diverse interactions remains to be defined. Our recent analysis indicates that DAXX is overexpressed in diverse cancer types and metastases. However, mechanisms underlying DAXX’s oncogenic function remains elusive. Using global integrated transcriptomic and lipidomic analyses, we show that DAXX plays a key role in lipid metabolism in triple-negative breast cancer (TNBC) cells. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipid synthesis and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and a DAXX mutant unable to bind SREBPs are incapable of promoting lipogenesis and tumor growth. In TNBC patients, DAXX expression levels are increased in breast cancer brain metastasis and correlate with poor patient survival. Our results identify the DAXX-SREBP axis as an important pathway for tumorigenesis in TNBC. (This work is supported by Florida Department of Health Grants.) Citation Format: Iqbal Mahmud, Guimei Tian, Tarun Hutchison, Brandon Kim, Daiqing Liao. DAXX interacts with sterol regulatory element-binding proteins (SREBPs) to promote oncogenic lipogenesis and tumorigenesis in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB138.
5
Wang, Hang, Feng Liu, Clarke F. Millette e Daniel L. Kilpatrick. "Expression of a Novel, Sterol-Insensitive Form of Sterol Regulatory Element Binding Protein 2 (SREBP2) in Male Germ Cells Suggests Important Cell- and Stage-Specific Functions for SREBP Targets during Spermatogenesis". Molecular and Cellular Biology 22, n. 24 (15 dicembre 2002): 8478–90. http://dx.doi.org/10.1128/mcb.22.24.8478-8490.2002.
Testo completoAbstract (sommario):
ABSTRACT Cholesterol biosynthesis in somatic cells is controlled at the transcriptional level by a homeostatic feedback pathway involving sterol regulatory element binding proteins (SREBPs). These basic helix-loop-helix (bHLH)-Zip proteins are synthesized as membrane-bound precursors, which are cleaved to form a soluble, transcriptionally active mature SREBP that regulates the promoters for genes involved in lipid synthesis. Homeostasis is conferred by sterol feedback inhibition of this maturation process. Previous work has demonstrated the expression of SREBP target genes in the male germ line, several of which are highly up-regulated during specific developmental stages. However, the role of SREBPs in the control of sterol regulatory element-containing promoters during spermatogenesis has been unclear. In particular, expression of several of these genes in male germ cells appears to be insensitive to sterols, contrary to SREBP-dependent gene regulation in somatic cells. Here, we have characterized a novel isoform of the transcription factor SREBP2, which is highly enriched in rat and mouse spermatogenic cells. This protein, SREBP2gc, is expressed in a stage-dependent fashion as a soluble, constitutively active transcription factor that is not subject to feedback control by sterols. These findings likely explain the apparent sterol-insensitive expression of lipid synthesis genes during spermatogenesis. Expression of a sterol-independent, constitutively active SREBP2gc in the male germ line may have arisen as a means to regulate SREBP target genes in specific developmental stages. This may reflect unique roles for cholesterol synthesis and other functional targets of SREBPs during spermatogenesis.
6
Bien, Clara M., e Peter J. Espenshade. "Sterol Regulatory Element Binding Proteins in Fungi: Hypoxic Transcription Factors Linked to Pathogenesis". Eukaryotic Cell 9, n. 3 (29 gennaio 2010): 352–59. http://dx.doi.org/10.1128/ec.00358-09.
Testo completoAbstract (sommario):
ABSTRACT Sterol regulatory element binding proteins (SREBPs) are membrane-bound transcription factors whose proteolytic activation is controlled by the cellular sterol concentration. Mammalian SREBPs are activated in cholesterol-depleted cells and serve to regulate cellular lipid homeostasis. Recent work demonstrates that SREBP is functionally conserved in fungi. While the ability to respond to sterols is conserved, fungal SREBPs are hypoxic transcription factors required for adaptation to a low-oxygen environment. In the fission yeast Schizosaccharomyces pombe, oxygen regulates the SREBP homolog Sre1 by independently controlling both its proteolytic activation and its degradation. SREBP is also required for adaptation to hypoxia in the human pathogens Cryptococcus neoformans and Aspergillus fumigatus. In these organisms, SREBP is required for virulence and resistance to antifungal drugs, making the SREBP pathway a potential target for antifungal therapy.
7
RIDGWAY, Neale D., e Thomas A. LAGACE. "Regulation of the CDP-choline pathway by sterol regulatory element binding proteins involves transcriptional and post-transcriptional mechanisms". Biochemical Journal 372, n. 3 (15 giugno 2003): 811–19. http://dx.doi.org/10.1042/bj20030252.
Testo completoAbstract (sommario):
The synthesis of phosphatidylcholine (PtdCho) by the CDP-choline pathway is under the control of the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase (CCT). Sterol regulatory element binding proteins (SREBPs) have been proposed to regulate CCT at the transcriptional level, or via the synthesis of lipid activators or substrates of the CDP-choline pathway. To assess the contributions of these two mechanisms, we examined CCTα expression and PtdCho synthesis by the CDP-choline pathway in cholesterol and fatty acid auxotrophic CHO M19 cells inducibly expressing constitutively active nuclear forms of SREBP1a or SREBP2. Induction of either SREBP resulted in increased expression of mRNAs for sterol-regulated genes, elevated fatty acid and cholesterol synthesis (>10–50-fold) and increased PtdCho synthesis (2-fold). CCTα mRNA was increased 2-fold by enforced expression of SREBP1a or SREBP2. The resultant increase in CCTα protein and activity (2-fold) was restricted primarily to the soluble fraction of cells, and increased CCTα activity in vivo was not detected. Inhibition of the synthesis of fatty acids or their CoA esters by cerulenin or triacsin C respectively following SREBP induction effectively blocked the accompanying elevation in PtdCho synthesis. Thus PtdCho synthesis was driven by increased synthesis of fatty acids or a product thereof. These data show that transcriptional activation of CCTα is modest relative to that of other SREBP-regulated genes, and that stimulation of PtdCho synthesis by SREBPs in CHO cells is due primarily to increased fatty acid synthesis.
8
Zoumi, Aikaterini, Shrimati Datta, Lih-Huei L. Liaw, Cristen J. Wu, Gopi Manthripragada, Timothy F. Osborne e Vickie J. LaMorte. "Spatial Distribution and Function of Sterol Regulatory Element-Binding Protein 1a and 2 Homo- and Heterodimers by In Vivo Two-Photon Imaging and Spectroscopy Fluorescence Resonance Energy Transfer". Molecular and Cellular Biology 25, n. 8 (15 aprile 2005): 2946–56. http://dx.doi.org/10.1128/mcb.25.8.2946-2956.2005.
Testo completoAbstract (sommario):
ABSTRACT Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix-loop-helix-leucine zipper proteins that regulate lipid metabolism. We show novel evidence of the in vivo occurrence and subnuclear spatial localization of both exogenously expressed SREBP-1a and -2 homodimers and heterodimers obtained by two-photon imaging and spectroscopy fluorescence resonance energy transfer. SREBP-1a homodimers localize diffusely in the nucleus, whereas SREBP-2 homodimers and the SREBP-1a/SREBP-2 heterodimer localize predominantly to nuclear speckles or foci, with some cells showing a diffuse pattern. We also used tethered SREBP dimers to demonstrate that both homo- and heterodimeric SREBPs activate transcription in vivo. Ultrastructural analysis revealed that the punctate foci containing SREBP-2 are electron-dense nuclear bodies, similar or identical to structures containing the promyelocyte (PML) protein. Immunofluorescence studies suggest that a dynamic interplay exists between PML, as well as another component of the PML-containing nuclear body, SUMO-1, and SREBP-2 within these nuclear structures. These findings provide new insight into the overall process of transcriptional activation mediated by the SREBP family.
9
Amemiya-Kudo, Michiyo, Hitoshi Shimano, Alyssa H. Hasty, Naoya Yahagi, Tomohiro Yoshikawa, Takashi Matsuzaka, Hiroaki Okazaki et al. "Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes". Journal of Lipid Research 43, n. 8 (agosto 2002): 1220–35. http://dx.doi.org/10.1194/jlr.m100417-jlr200.
Testo completoAbstract (sommario):
Recent studies on the in vivo roles of the sterol regulatory element binding protein (SREBP) family indicate that SREBP-2 is more specific to cholesterogenic gene expression whereas SREBP-1 targets lipogenic genes. To define the molecular mechanism involved in this differential regulation, luciferase-reporter gene assays were performed in HepG2 cells to compare the transactivities of nuclear SREBP-1a, -1c, and -2 on a battery of SREBP-target promoters containing sterol regulatory element (SRE), SRE-like, or E-box sequences. The results show first that cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c. Second, an E-box containing reporter gene is much less efficiently activated by SREBP-1a and -1c, and SREBP-2 was inactive in spite of its ability to bind to the E-box. Third, promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2. Finally, substitution of the unique tyrosine residue within the basic helix-loop-helix (bHLH) portion of nuclear SREBPs with arginine, the conserved residue found in all other bHLH proteins, abolishes the transactivity of all SREBPs for SRE, and conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes.These data demonstrate the different specificity and affinity of nuclear SREBP-1 and -2 for different target DNAs, explaining a part of the mechanism behind the differential in vivo regulation of cholesterogenic and lipogenic enzymes by SREBP-1 and -2, respectively.
10
Inoue, Noriyuki, Hitoshi Shimano, Masanori Nakakuki, Takashi Matsuzaka, Yoshimi Nakagawa, Takashi Yamamoto, Ryuichiro Sato et al. "Lipid Synthetic Transcription Factor SREBP-1a Activates p21WAF1/CIP1, a Universal Cyclin-Dependent Kinase Inhibitor". Molecular and Cellular Biology 25, n. 20 (15 ottobre 2005): 8938–47. http://dx.doi.org/10.1128/mcb.25.20.8938-8947.2005.
Testo completoAbstract (sommario):
ABSTRACT Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate lipid synthetic genes. In contrast to SREBP-2, which regulates cellular cholesterol level in normal cells, SREBP-1a is highly expressed in actively growing cells and activates entire programs of genes involved in lipid synthesis such as cholesterol, fatty acids, triglycerides, and phospholipids. Previously, the physiological relevance of this potent activity of SREBP-1a has been thought to regulate the supply of membrane lipids in response to cell growth. Here we show that nuclear SREBP-1a and SREBP-2 bind directly to a novel SREBP binding site in the promoter of the p21WAF1/CIP1 gene, the major cyclin-dependent kinase inhibitor, and strongly activate its promoter activity. Only the SREBP-1a isoform consistently causes induction of p21 at both the mRNA and protein levels. Colony formation assays and polyploidy of livers from transgenic mice suggest that activation of p21 by SREBP-1a could inhibit cell growth. Activation of endogenous SREBPs in lipid deprivation conditions was associated with induction of p21 mRNA and protein. Expression of p21 was reduced in SREBP-1 null mice. These data suggest a physiological role of SREBP-1a in p21 regulation. Identification of p21 as a new SREBP target might implicate a new paradigm in the link between lipid synthesis and cell growth.
11
FIELD, F. Jeffrey, Ella BORN, Shubha MURTHY e Satya N. MATHUR. "Polyunsaturated fatty acids decrease the expression of sterol regulatory element-binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport". Biochemical Journal 368, n. 3 (15 dicembre 2002): 855–64. http://dx.doi.org/10.1042/bj20020731.
Testo completoAbstract (sommario):
Regulation of sterol regulatory element-binding proteins (SREBPs) by fatty acid flux was investigated in CaCo-2 cells. Cells were incubated with 1mM taurocholate with or without 250μM 18:0, 18:1, 18:2, 20:4, 20:5 or 22:6 fatty acids. Fatty acid synthase (FAS) and acetyl-CoA carboxylase mRNA levels and gene and protein expression of SREBPs were estimated. 18:2, 20:4, 20:5 and 22:6 fatty acids decreased the amount of mature SREBP-1 and mRNA levels of SREBP-1c, SREBP-1a, FAS and acetyl-CoA carboxylase. SREBP-2 gene or mature protein expression was not altered. Liver X receptor (LXR) activation by T0901317 increased gene expression of SREBP-1c, SREBP-1a, FAS and acetyl-CoA carboxylase without altering SREBP-2. 20:5, but not 18:1, prevented the full expression of SREBP-1c mRNA by T0901317. T0901317 increased SREBP-1 mass without altering the mass of mature SREBP-2. Although only 18:2, 20:4, 20:5 and 22:6 suppressed SREBP-1, acetyl-CoA carboxylase and FAS expression, all fatty acids decreased the rate of fatty acid synthesis. T0901317 increased endogenous fatty acid synthesis yet did not increase secretion of triacylglycerol-rich lipoproteins. In CaCo-2 cells, polyunsaturated fatty acids decrease gene and protein expression of SREBP-1 and FAS mRNA, probably through interference with LXR activity. Since all fatty acids decreased fatty acid synthesis, mechanisms other than changes in SREBP-1c expression must be entertained. Increased endogenous fatty acid synthesis does not promote triacylglycerol-rich lipoprotein secretion.
12
Liu, Fang-Hong, Jie-Yun Song, Xiao-Rui Shang, Xiang-Rui Meng, Jun Ma e Hai-Jun Wang. "The Gene-Gene Interaction of INSIG-SCAP-SREBP Pathway on the Risk of Obesity in Chinese Children". BioMed Research International 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/538564.
Testo completoAbstract (sommario):
Background.Childhood obesity has become a global public health problem in recent years. This study aimed to explore the association of genetic variants in INSIG-SCAP-SREBP pathway with obesity in Chinese children.Methods.A case-control study was conducted, including 705 obese cases and 1,325 nonobese controls. We genotyped 15 single nucleotide polymorphisms (SNPs) of five genes in INSIG-SCAP-SREBP pathway, including insulin induced gene 1 (INSIG1), insulin induced gene 2 (INSIG2), SREBP cleavage-activating protein gene (SCAP), sterol regulatory element binding protein gene 1 (SREBP1), and sterol regulatory element binding protein gene 2 (SREBP2). We used generalized multifactor dimensionality reduction (GMDR) and logistic regression to investigate gene-gene interactions.Results.Single polymorphism analyses showed thatSCAPrs12487736 and rs12490383 were nominally associated with obesity. We identified a 3-locus interaction on obesity in GMDR analyses(P=0.001), involving 3 genetic variants ofINSIG2,SCAP,andSREBP2. The individuals in high-risk group of the 3-locus combinations had a 79.9% increased risk of obesity compared with those in low-risk group (OR=1.799, 95% CI: 1.475–2.193,P=6.61×10-9).Conclusion.We identified interaction of three genes in INSIG-SCAP-SREBP pathway on risk of obesity, revealing that these genes affect obesity more likely through a complex interaction pattern than single gene effect.
13
Cheng, Xiang, Jianying Li e Deliang Guo. "SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy". Current Topics in Medicinal Chemistry 18, n. 6 (28 giugno 2018): 484–93. http://dx.doi.org/10.2174/1568026618666180523104541.
Testo completoAbstract (sommario):
Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.
14
Bitter, Andreas, Andreas K. Nüssler, Wolfgang E. Thasler, Kathrin Klein, Ulrich M. Zanger, Matthias Schwab e Oliver Burk. "Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression". Cellular Physiology and Biochemistry 35, n. 2 (2015): 803–15. http://dx.doi.org/10.1159/000369739.
Testo completoAbstract (sommario):
Background/Aims: Sterol regulatory element-binding protein (SREBP) 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.
15
Lewis, Caroline A., Beatrice Griffiths, Claudio R. Santos, Mario Pende e Almut Schulze. "Regulation of the SREBP transcription factors by mTORC1". Biochemical Society Transactions 39, n. 2 (22 marzo 2011): 495–99. http://dx.doi.org/10.1042/bst0390495.
Testo completoAbstract (sommario):
In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers. We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth. In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.
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Toth, Julia I., Shrimati Datta, Jyoti N. Athanikar, Leonard P. Freedman e Timothy F. Osborne. "Selective Coactivator Interactions in Gene Activation by SREBP-1a and -1c". Molecular and Cellular Biology 24, n. 18 (15 settembre 2004): 8288–300. http://dx.doi.org/10.1128/mcb.24.18.8288-8300.2004.
Testo completoAbstract (sommario):
ABSTRACT Requisite levels of intracellular cholesterol and fatty acids are maintained in part by the sterol regulatory element binding proteins (SREBPs). Three major SREBP isoforms exist; SREBP-1a and SREBP-1c are expressed from overlapping mRNAs, whereas SREBP-2 is encoded by a separate gene. The active forms of SREBP-1a and SREBP-1c differ only at their extreme N termini; SREBP-1c lacks 28 aa present in SREBP-1a and instead contains 4 unique aa of its own. While the SREBP-1a and -1c isoforms differentially activate transcription, the molecular basis of this difference is unknown. Here we define the differences between these proteins that confer the enhanced activity of SREBP-1a and demonstrate that this enhancement is a direct result of its avid binding to the coactivator CREB binding protein (CBP) and the mammalian mediator complex. While previous work determined that the C/H1 zinc finger and KIX domains of CBP bind to SREBP-1a, we provide evidence that the interaction with C/H1 is important for gene activation. We further show that the association between the activation domain of SREBP-1 and mediator is through aa 500 to 824 of DRIP150. Finally, we demonstrate the recruitment of mediator to an SREBP-responsive promoter in a sterol-dependent manner.
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McPherson, Ruth, e Andre Gauthier. "Molecular regulation of SREBP function: the Insig-SCAP connection and isoform-specific modulation of lipid synthesis". Biochemistry and Cell Biology 82, n. 1 (1 febbraio 2004): 201–11. http://dx.doi.org/10.1139/o03-090.
Testo completoAbstract (sommario):
Sterol regulatory element binding proteins (SREBPs) are a family of membrane-bound transcription factors that play a unique and fundamental role in both cholesterol and fatty acid metabolism, relevant to human disease. There are three SREBPs that regulate the expression of over 30 genes. SREBPs are subject to regulation at three levels: proteolytic cleavage, rapid degradation by the ubiquitin-proteasome pathway, and sumoylation. Recently, there have been exciting advances in our understanding of the molecular mechanism of SREBP trafficking and processing with new information on the role of insulin-induced genes and the differential role and regulation of SREBP-1c and -2, which may ultimately lead to novel strategies for the treatment of dyslipidemia and insulin resistance.Key words: SREBP, Insig, SCAP, cholesterol synthesis, lipid metabolism.
18
Ringseis, Robert, Christine Rauer, Susanne Rothe, Denise K. Gessner, Lisa-Marie Schütz, Sebastian Luci, Gaiping Wen e Klaus Eder. "Sterol Regulatory Element-Binding Proteins Are Regulators of the NIS Gene in Thyroid Cells". Molecular Endocrinology 27, n. 5 (1 maggio 2013): 781–800. http://dx.doi.org/10.1210/me.2012-1269.
Testo completoAbstract (sommario):
Abstract The uptake of iodide into the thyroid, an essential step in thyroid hormone synthesis, is an active process mediated by the sodium-iodide symporter (NIS). Despite its strong dependence on TSH, the master regulator of the thyroid, the NIS gene was also reported to be regulated by non-TSH signaling pathways. In the present study we provide evidence that the rat NIS gene is subject to regulation by sterol regulatory element-binding proteins (SREBPs), which were initially identified as master transcriptional regulators of lipid biosynthesis and uptake. Studies in FRTL-5 thyrocytes revealed that TSH stimulates expression and maturation of SREBPs and expression of classical SREBP target genes involved in lipid biosynthesis and uptake. Almost identical effects were observed when the cAMP agonist forskolin was used instead of TSH. In TSH receptor-deficient mice, in which TSH/cAMP-dependent gene regulation is blocked, the expression of SREBP isoforms in the thyroid was markedly reduced when compared with wild-type mice. Sterol-mediated inhibition of SREBP maturation and/or RNA interference-mediated knockdown of SREBPs reduced expression of NIS and NIS-specific iodide uptake in FRTL-5 cells. Conversely, overexpression of active SREBPs caused a strong activation of the 5′-flanking region of the rat NIS gene mediated by binding to a functional SREBP binding site located in the 5′-untranslated region of the rat NIS gene. These findings show that TSH acts as a regulator of SREBP expression and maturation in thyroid epithelial cells and that SREBPs are novel transcriptional regulators of NIS.
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Huber, Michael D., Paul W. Vesely, Kaustuv Datta e Larry Gerace. "Erlins restrict SREBP activation in the ER and regulate cellular cholesterol homeostasis". Journal of Cell Biology 203, n. 3 (11 novembre 2013): 427–36. http://dx.doi.org/10.1083/jcb.201305076.
Testo completoAbstract (sommario):
Cellular cholesterol levels are controlled by endoplasmic reticulum (ER) sterol sensing proteins, which include Scap and Insig-1. With cholesterol sufficiency, Insig inhibits the activation of sterol regulatory element binding proteins (SREBPs), key transcription factors for cholesterol and fatty acid biosynthetic genes, by associating with Scap–SREBP complexes to promote their ER retention. Here we show that the multimeric ER proteins erlins-1 and -2 are additional SREBP regulators. Depletion of erlins from cells grown with sterol sufficiency led to canonical activation of SREBPs and their target genes. Moreover, SREBPs, Scap, and Insig-1 were physically associated with erlins. Erlins bound cholesterol with specificity and strong cooperativity and responded to ER cholesterol changes with altered diffusional mobility, suggesting that erlins themselves may be regulated by cholesterol. Together, our results define erlins as novel cholesterol-binding proteins that are directly involved in regulating the SREBP machinery. We speculate that erlins promote stability of the SREBP–Scap–Insig complex and may contribute to the highly cooperative control of this system.
20
Dif, Nicolas, Vanessa Euthine, Estelle Gonnet, Martine Laville, Hubert Vidal e Etienne Lefai. "Insulin activates human sterol-regulatory-element-binding protein-1c (SREBP-1c) promoter through SRE motifs". Biochemical Journal 400, n. 1 (27 ottobre 2006): 179–88. http://dx.doi.org/10.1042/bj20060499.
Testo completoAbstract (sommario):
In the present study, we aimed to decipher the mechanisms involved in the transcriptional effect of insulin on the SREBP-1c specific promoter of the human srebf-1 gene. Using luciferase reporter gene constructs in HEK-293 cells (human embryonic kidney cells), we demonstrated that the full effect of insulin requires the presence of SREs (sterol response elements) in the proximal region of the promoter. Furthermore, insulin increases the binding of SREBP-1 (sterol-regulatory-element-binding protein-1) to this promoter region in chromatin immunoprecipitation assay. We also found that the nuclear receptors LXRs (liver X receptors) strongly activate SREBP-1c gene expression and identified the LXRE (LXR-response element) involved in this effect. However, our results suggested that these LXREs do not play a major role in the response to insulin. Finally, using expression vectors and adenoviruses allowing ectopic overexpressions of the human mature forms of SREBP-1a or SREBP-1c, we demonstrated the direct role of SREBP-1 in the control of SREBP-1c gene expression in human skeletal-muscle cells. Altogether, these results strongly suggest that the SREBP-1 transcription factors are the main mediators of insulin action on SREBP-1c expression in human tissues.
21
Di Pardo, Alba, John Monyror, Luis Carlos Morales, Vaibhavi Kadam, Susanne Lingrell, Vittorio Maglione, Richard W. Wozniak e Simonetta Sipione. "Mutant huntingtin interacts with the sterol regulatory element-binding proteins and impairs their nuclear import". Human Molecular Genetics 29, n. 3 (24 dicembre 2019): 418–31. http://dx.doi.org/10.1093/hmg/ddz298.
Testo completoAbstract (sommario):
Abstract Brain cholesterol homeostasis is altered in Huntington’s disease (HD), a neurodegenerative disorder caused by the expansion of a CAG nucleotide repeat in the HTT gene. Genes involved in the synthesis of cholesterol and fatty acids were shown to be downregulated shortly after the expression of mutant huntingtin (mHTT) in inducible HD cells. Nuclear levels of the transcription factors that regulate lipid biogenesis, the sterol regulatory element-binding proteins (SREBP1 and SREBP2), were found to be decreased in HD models compared to wild-type, but the underlying causes were not known. SREBPs are synthesized as inactive endoplasmic reticulum-localized precursors. Their mature forms (mSREBPs) are generated upon transport of the SREBP precursors to the Golgi and proteolytic cleavage, and are rapidly imported into the nucleus by binding to importin β. We show that, although SREBP2 processing into mSREBP2 is not affected in YAC128 HD mice, mSREBP2 is mislocalized to the cytoplasm. Chimeric mSREBP2-and mSREBP1-EGFP proteins are also mislocalized to the cytoplasm in immortalized striatal cells expressing mHTT, in YAC128 neurons and in fibroblasts from HD patients. We further show that mHTT binds to the SREBP2/importin β complex required for nuclear import and sequesters it in the cytoplasm. As a result, HD cells fail to upregulate cholesterogenic genes under sterol-depleted conditions. These findings provide mechanistic insight into the downregulation of genes involved in the synthesis of cholesterol and fatty acids in HD models, and have potential implications for other pathways modulated by SREBPs, including autophagy and excitotoxicity.
22
Todd, Bridget L., Emerson V. Stewart, John S. Burg, Adam L. Hughes e Peter J. Espenshade. "Sterol Regulatory Element Binding Protein Is a Principal Regulator of Anaerobic Gene Expression in Fission Yeast". Molecular and Cellular Biology 26, n. 7 (1 aprile 2006): 2817–31. http://dx.doi.org/10.1128/mcb.26.7.2817-2831.2006.
Testo completoAbstract (sommario):
ABSTRACT Fission yeast sterol regulatory element binding protein (SREBP), called Sre1p, functions in an oxygen-sensing pathway to allow adaptation to fluctuating oxygen concentrations. The Sre1p-Scp1p complex responds to oxygen-dependent sterol synthesis as an indirect measure of oxygen availability. To examine the role of Sre1p in anaerobic gene expression in Schizosaccharomyces pombe, we performed transcriptional profiling experiments after a shift to anaerobic conditions for 1.5 h. Of the 4,940 genes analyzed, expression levels of 521 (10.5%) and 686 (13.9%) genes were significantly increased and decreased, respectively, under anaerobic conditions. Sre1p controlled 68% of genes induced ≥2-fold. Oxygen-requiring biosynthetic pathways for ergosterol, heme, sphingolipid, and ubiquinone were primary targets of Sre1p. Induction of glycolytic genes and repression of mitochondrial oxidative phosphorylation genes largely did not require Sre1p. Using chromatin immunoprecipitation, we demonstrated that Sre1p acts directly at target gene promoters and stimulates its own transcription under anaerobic conditions. sre1 + promoter analysis identified two DNA elements that are both necessary and sufficient for oxygen-dependent, Sre1p-dependent transcription. Interestingly, these elements are homologous to sterol regulatory elements bound by mammalian SREBP, highlighting the evolutionary conservation between Sre1p and SREBP. We conclude that Sre1p is a principal activator of anaerobic gene expression, upregulating genes required for nonrespiratory oxygen consumption.
23
Giandomenico, Valeria, Maria Simonsson, Eva Grönroos e Johan Ericsson. "Coactivator-Dependent Acetylation Stabilizes Members of the SREBP Family of Transcription Factors". Molecular and Cellular Biology 23, n. 7 (1 aprile 2003): 2587–99. http://dx.doi.org/10.1128/mcb.23.7.2587-2599.2003.
Testo completoAbstract (sommario):
ABSTRACT Members of the SREBP family of transcription factors control cholesterol and lipid homeostasis and play important roles during adipocyte differentiation. The transcriptional activity of SREBPs is dependent on the coactivators p300 and CBP. We now present evidence that SREBPs are acetylated by the intrinsic acetyltransferase activity of p300 and CBP. In SREBP1a, the acetylated lysine residue resides in the DNA-binding domain of the protein. Coexpression with p300 dramatically increases the expression of both SREBP1a and SREBP2, and this effect is dependent on the acetyltransferase activity of p300, indicating that acetylation of SREBPs regulates their stability. Indeed, acetylation or mutation of the acetylated lysine residue in SREBP1a stabilizes the protein. We demonstrate that the acetylated residue in SREBP1a is also targeted by ubiquitination and that acetylation inhibits this process. Thus, our studies define acetylation-dependent stabilization of transcription factors as a novel mechanism for coactivators to regulate gene expression.
24
Hu, Xiaoying, Bo Shi, Min Jin, Xuexi Wang, Ye Yuan, Jiaxiang Luo e Qicun Zhou. "Molecular cloning, tissue distribution and gene expression in response to nutritional regulation of sterol regulatory element binding protein-1 from the swimming crab Portunus trituberculatus (Miers, 1876) (Decapoda, Portunidae)". Crustaceana 94, n. 2 (15 febbraio 2021): 235–50. http://dx.doi.org/10.1163/15685403-bja10095.
Testo completoAbstract (sommario):
Abstract The sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors known to activate the transcription of genes encoding key lipogenic enzymes. The present study reports on the molecular cloning, tissue expression and nutritional regulation of SREBP-1 from the swimming crab Portunus trituberculatus (Miers, 1876). The SREBP-1 full-length cDNA was 3785 bp, encoding a polypeptide of 1039 amino acids. Quantitative PCR analysis revealed that SREBP-1 expression was detected in various tissues, and the significantly higher expression levels were found in eyestalk and hepatopancreas compared with other tested tissues. Additionally, the effects of dietary iron on expression of SREBP-1 were investigated, and the results indicated that SREBP-1 expressions were down-regulated by crabs fed diets containing 218.9 and 373.9 mg/kg iron compared with that fed the basal diet (55.2 mg/kg). Suggesting that the relative expression level of SREBP-1 can be suppressed by dietary iron supplementation. These findings provide further insight into the regulatory capacity of SREBP-1 in the lipid anabolism of P. trituberculatus.
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Fajas, Lluis, Kristina Schoonjans, Laurent Gelman, Jae B. Kim, Jamila Najib, Genevieve Martin, Jean-Charles Fruchart, Michael Briggs, Bruce M. Spiegelman e Johan Auwerx. "Regulation of Peroxisome Proliferator-Activated Receptor γ Expression by Adipocyte Differentiation and Determination Factor 1/Sterol Regulatory Element Binding Protein 1: Implications for Adipocyte Differentiation and Metabolism". Molecular and Cellular Biology 19, n. 8 (1 agosto 1999): 5495–503. http://dx.doi.org/10.1128/mcb.19.8.5495.
Testo completoAbstract (sommario):
ABSTRACT Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor implicated in adipocyte differentiation and insulin sensitivity. We investigated whether PPARγ expression is dependent on the activity of adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1 (ADD-1/SREBP-1), another transcription factor associated with both adipocyte differentiation and cholesterol homeostasis. Ectopic expression of ADD-1/SREBP-1 in 3T3-L1 and HepG2 cells induced endogenous PPARγ mRNA levels. The related transcription factor SREBP-2 likewise induced PPARγ expression. In addition, cholesterol depletion, a condition known to result in proteolytic activation of transcription factors of the SREBP family, induced PPARγ expression and improved PPRE-driven transcription. The effect of the SREBPs on PPARγ expression was mediated through the PPARγ1 and -3 promoters. Both promoters contain a consensus E-box motif that mediates the regulation of the PPARγ gene by ADD-1/SREBP-1 and SREBP-2. These results suggest that PPARγ expression can be controlled by the SREBP family of transcription factors and demonstrate new interactions between transcription factors that can regulate different pathways of lipid metabolism.
26
Lecomte, Virginie, Emmanuelle Meugnier, Vanessa Euthine, Christine Durand, Damien Freyssenet, Georges Nemoz, Sophie Rome, Hubert Vidal e Etienne Lefai. "A New Role for Sterol Regulatory Element Binding Protein 1 Transcription Factors in the Regulation of Muscle Mass and Muscle Cell Differentiation". Molecular and Cellular Biology 30, n. 5 (22 dicembre 2009): 1182–98. http://dx.doi.org/10.1128/mcb.00690-09.
Testo completoAbstract (sommario):
ABSTRACT The role of the transcription factors sterol regulatory element binding protein 1a (SREBP-1a) and SREBP-1c in the regulation of cholesterol and fatty acid metabolism has been well studied; however, little is known about their specific function in muscle. In the present study, analysis of recent microarray data from muscle cells overexpressing SREBP1 suggested that they may play a role in the regulation of myogenesis. We then demonstrated that SREBP-1a and -1c inhibit myoblast-to-myotube differentiation and also induce in vivo and in vitro muscle atrophy. Furthermore, we have identified the transcriptional repressors BHLHB2 and BHLHB3 as mediators of these effects of SREBP-1a and -1c in muscle. Both repressors are SREBP-1 target genes, and they affect the expression of numerous genes involved in the myogenic program. Our findings identify a new role for SREBP-1 transcription factors in muscle, thus linking the control of muscle mass to metabolic pathways.
27
Bensinger, Steven, Yoko Kidani, M. Benjamin Hock, Joseph Argus, Evangelia Komisopoulou e Thomas Graeber. "An essential role for SREBP signaling in T cell blastogenesis (47.17)". Journal of Immunology 188, n. 1_Supplement (1 maggio 2012): 47.17. http://dx.doi.org/10.4049/jimmunol.188.supp.47.17.
Testo completoAbstract (sommario):
Abstract Accumulating evidence indicates that cellular metabolism is an important regulator of T cell immunity. We and others have shown that activation of T cell rapidly initiates a robust genetic and biochemical program that drives the biosynthesis of lipids. Surprisingly, inhibiting lipid synthesis markedly decreases DNA synthesis and lymphocyte proliferation, suggesting a fundamental link between lipid anabolism and cell cycle progression. To date, the molecular mechanisms underlying these intriguing observations are largely undefined. The Sterol Regulatory Element Binding Proteins (SREBP) are b-HLH transcription factors with a well-placed role in lipid homeostasis. The impact of SREBPs on T cell development and function has not been evaluated. Herein we demonstrate an essential role for SREBPs in CD8 T cell blastogenesis. Gene expression and ChIP studies coupled with metabolic flux analysis revealed an essential role for SREBP signaling in the acquisition of a lipid anabolic program by blasting T cells. In the absence of SREBP activity, mitogen-stimulated T cells do not efficiently enlarge and arrest in G0/G1 of cell cycle before undergoing apoptosis-independent cell death. Homeostatic proliferation and antigen-specific viral immunity is also compromised in the absence of SREBP activity. Taken together, these data delineate a critical role for SREBPs in T cell growth and provide a mechanistic understanding of how SREBPs regulate the acquisition of anabolic metabolism in T cells.
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ZHANG, Chengkang, Dong-Ju SHIN e Timothy F. OSBORNE. "A simple promoter containing two Sp1 sites controls the expression of sterol-regulatory-element-binding protein 1a (SREBP-1a)". Biochemical Journal 386, n. 1 (8 febbraio 2005): 161–68. http://dx.doi.org/10.1042/bj20041514.
Testo completoAbstract (sommario):
The mammalian gene for SREBP-1 (sterol-regulatory-element-binding protein 1) contains two promoters that control the production of two proteins, SREBP-1a and -1c, and each contains a unique N-terminal transcriptional activation domain, but they are otherwise identical. The relative level of each mRNA varies from tissue to tissue and they respond differently to regulatory stimuli. SREBP-1c is more abundantly expressed in liver, where its level is also regulated by insulin and liver X receptor activators, and it is also autoregulated by SREBPs. In contrast, SREBP-1a mRNA levels are relatively low and constant in different tissues and few studies have specifically analysed its pattern of expression and regulation. In the present study, we show that the promoter for SREBP-1a is contained in a very small promoter-proximal region containing two Sp1 sites. The small and relatively simple structure for its promoter provides an explanation for the low level of SREBP-1a expression. Additionally, since Sp1 has been implicated in the modest regulation of several genes by insulin, its involvement in the expression of the SREBP-1a promoter provides an explanation for the modest insulin regulation observed in animal experiments.
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Wilentz, Robb E., Lee A. Witters e Ellen S. Pizer. "Lipogenic Enzymes Fatty Acid Synthase and Acetyl-Coenzyme A Carboxylase are Coexpressed with Sterol Regulatory Element Binding Protein and Ki-67 in Fetal Tissues". Pediatric and Developmental Pathology 3, n. 6 (novembre 2000): 525–31. http://dx.doi.org/10.1007/s100240010116.
Testo completoAbstract (sommario):
Endogenous fatty acid synthesis has been observed in some rapidly proliferating cells and tissues, both normal and neoplastic, and probably supports membrane synthesis. Sterol regulatory element binding proteins (SREBPs) are transcription factors that regulate the expression of genes for both cholesterol and fatty acid synthesis. The inactive precursor form resides in cytoplasmic membranes. Intracellular lipid depletion triggers proteolytic cleavage of SREBP, allowing the amino terminus to enter the nucleus and activate the expression of enzymes, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), major biosynthetic enzymes for fatty acid synthesis. The expression patterns of ACC, FAS, SREBP, and Ki-67 in fetal tissues were compared to determine whether SREBP is likely to participate in the regulation of proliferation-associated fatty acid synthesis during fetal growth. Tissues from 22 fetuses, 12 first-trimester and 10 second-trimester (range 7.0 to 21.6 weeks), were studied. Serial 5-μm sections were stained with antibodies to ACC, FAS, SREBP, and Ki-67 and were compared. ACC, FAS, SREBP, and Ki-67 were coexpressed in the proliferative compartments of the intestines, skin, and kidney. ACC, FAS, and Ki-67 were coexpressed with little SREBP in lung and cytotrophoblast. SREBP, ACC, and FAS were coexpressed without Ki-67 in hepatocytes, ganglion cells, and intermediate trophoblast. The close linkage of SREBP, ACC, FAS, and Ki-67 in some proliferating fetal tissues suggests that in these tissues SREBP participates in the transcriptional regulation of lipogenic genes during proliferation. SREBP, ACC, and FAS coexpression without Ki-67 occurs in differentiated tissues that may synthesize fatty acids for other functions.
30
Eid, Walaa, Kristin Dauner, Kevin C. Courtney, AnneMarie Gagnon, Robin J. Parks, Alexander Sorisky e Xiaohui Zha. "mTORC1 activates SREBP-2 by suppressing cholesterol trafficking to lysosomes in mammalian cells". Proceedings of the National Academy of Sciences 114, n. 30 (10 luglio 2017): 7999–8004. http://dx.doi.org/10.1073/pnas.1705304114.
Testo completoAbstract (sommario):
mTORC1 is known to activate sterol regulatory element-binding proteins (SREBPs) including SREBP-2, a master regulator of cholesterol synthesis. Through incompletely understood mechanisms, activated mTORC1 triggers translocation of SREBP-2, an endoplasmic reticulum (ER) resident protein, to the Golgi where SREBP-2 is cleaved to translocate to the nucleus and activate gene expression for cholesterol synthesis. Low ER cholesterol is a well-established trigger for SREBP-2 activation. We thus investigated whether mTORC1 activates SREBP-2 by reducing cholesterol delivery to the ER. We report here that mTORC1 activation is accompanied by low ER cholesterol and an increase of SREBP-2 activation. Conversely, a decrease in mTORC1 activity coincides with a rise in ER cholesterol and a decrease in SERBP-2 activity. This rise in ER cholesterol is of lysosomal origin: blocking the exit of cholesterol from lysosomes by U18666A or NPC1 siRNA prevents ER cholesterol from increasing and, consequently, SREBP-2 is activated without mTORC1 activation. Furthermore, when mTORC1 activity is low, cholesterol is delivered to lysosomes through two membrane trafficking pathways: autophagy and rerouting of endosomes to lysosomes. Indeed, with dual blockade of both pathways by Atg5−/−and dominant-negative rab5, ER cholesterol fails to increase when mTORC1 activity is low, and SREBP-2 is activated. Conversely, overexpressing constitutively active Atg7, which forces autophagy and raises ER cholesterol even when mTORC1 activity is high, suppresses SREBP-2 activation. We conclude that mTORC1 actively suppresses autophagy and maintains endosomal recycling, thereby preventing endosomes and autophagosomes from reaching lysosomes. This results in a reduction of cholesterol in the ER and activation of SREBP-2.
31
Camargo, Nutabi, August B. Smit e Mark H. G. Verheijen. "SREBPs: SREBP function in glia-neuron interactions". FEBS Journal 276, n. 3 (24 dicembre 2008): 628–36. http://dx.doi.org/10.1111/j.1742-4658.2008.06808.x.
Testo completo
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Nadeau, Kristen J., Lindsay B. Ehlers, Lina E. Aguirre, Russell L. Moore, Korinne N. Jew, Heidi K. Ortmeyer, Barbara C. Hansen, Jane E. B. Reusch e Boris Draznin. "Exercise training and calorie restriction increase SREBP-1 expression and intramuscular triglyceride in skeletal muscle". American Journal of Physiology-Endocrinology and Metabolism 291, n. 1 (luglio 2006): E90—E98. http://dx.doi.org/10.1152/ajpendo.00543.2005.
Testo completoAbstract (sommario):
Intramuscular triglyceride (IMTG) deposition in skeletal muscle is associated with obesity and type 2 diabetes (T2DM) and is thought to be related to insulin resistance (IR). Curiously, despite enhanced skeletal muscle insulin sensitivity, highly trained athletes and calorie-restricted (CR) monkeys also have increased IMTG. Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate the biosynthesis of cholesterol and fatty acids. SREBP-1 is increased by insulin in skeletal muscle in vitro and in skeletal muscle of IR subjects, but SREBP-1 expression has not been examined in exercise training or calorie restriction. We examined the relationship between IMTG and SREBP-1 expression in animal models of exercise and calorie restriction. Gastrocnemius and soleus muscle biopsies were obtained from 38 Sprague-Dawley rats (18 control and 20 exercise trained). Triglyceride content was higher in the gastrocnemius and soleus muscles of the trained rats. SREBP-1c mRNA, SREBP-1 precursor and mature proteins, and fatty acid synthase (FAS) protein were increased with exercise training. Monkeys ( Macaca mulatta) were CR for a mean of 10.4 years, preventing weight gain and IR. Vastus lateralis muscle was obtained from 12 monkeys (6 CR and 6 controls). SREBP-1 precursor and mature proteins and FAS protein were higher in the CR monkeys. In addition, phosphorylation of ERK1/ERK2 was increased in skeletal muscle of CR animals. In summary, SREBP-1 protein and SREBP-1c mRNA are increased in interventions that increase IMTG despite enhanced insulin sensitivity. CR and exercise-induced augmentation of SREBP-1 expression may be responsible for the increased IMTG seen in skeletal muscle of highly conditioned athletes.
33
Damiano, Fabrizio, Simone Alemanno, Gabriele V. Gnoni e Luisa Siculella. "Translational control of the sterol-regulatory transcription factor SREBP-1 mRNA in response to serum starvation or ER stress is mediated by an internal ribosome entry site". Biochemical Journal 429, n. 3 (14 luglio 2010): 603–12. http://dx.doi.org/10.1042/bj20091827.
Testo completoAbstract (sommario):
SREBPs (sterol-regulatory-element-binding proteins) are a family of transcription factors that modulate the expression of several enzymes implicated in endogenous cholesterol, fatty acid, triacylglycerol and phospholipid synthesis. In the present study, evidence for SREBP-1 regulation at the translational level is reported. Using several experimental approaches, we have demonstrated that the 5′-UTR (untranslated region) of the SREBP-1a mRNA contains an IRES (internal ribosome entry site). Transfection experiments with the SREBP-1a 5′-UTR inserted in a dicistronic reporter vector showed a remarkable increase in the downstream cistron translation, through a cap-independent mechanism. Insertion of the SREBP-1c 5′-UTR in the same vector also stimulated the translation of the downstream cistron, but the observed effect can be ascribed, at least in part, to a cryptic promoter activity. Cellular stress conditions, such as serum starvation, caused an increase in the level of SREBP-1 precursor and mature form in both Hep G2 and HeLa cells, despite the overall reduction in protein synthesis, whereas mRNA levels for SREBP-1 were unaffected by serum starvation. Transfection experiments carried out with a dicistronic construct demonstrated that the cap-dependent translation was affected more than IRES-mediated translation by serum starvation. The thapsigargin- and tunicamycin-induced UPR (unfolded protein response) also increased SREBP-1 expression in Hep G2 cells, through the cap-independent translation mediated by IRES. Overall, these findings indicate that the presence of IRES in the SREBP-1a 5′-UTR allows translation to be maintained under conditions that are inhibitory to cap-dependent translation.
34
Gholkar, Ankur A., Keith Cheung, Kevin J. Williams, Yu-Chen Lo, Shadia A. Hamideh, Chelsea Nnebe, Cindy Khuu, Steven J. Bensinger e Jorge Z. Torres. "Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division". Journal of Biological Chemistry 291, n. 33 (4 luglio 2016): 17001–8. http://dx.doi.org/10.1074/jbc.c116.737346.
Testo completoAbstract (sommario):
The sterol regulatory element-binding protein (SREBP) transcription factors have become attractive targets for pharmacological inhibition in the treatment of metabolic diseases and cancer. SREBPs are critical for the production and metabolism of lipids and cholesterol, which are essential for cellular homeostasis and cell proliferation. Fatostatin was recently discovered as a specific inhibitor of SREBP cleavage-activating protein (SCAP), which is required for SREBP activation. Fatostatin possesses antitumor properties including the inhibition of cancer cell proliferation, invasion, and migration, and it arrests cancer cells in G2/M phase. Although Fatostatin has been viewed as an antitumor agent due to its inhibition of SREBP and its effect on lipid metabolism, we show that Fatostatin's anticancer properties can also be attributed to its inhibition of cell division. We analyzed the effect of SREBP activity inhibitors including Fatostatin, PF-429242, and Betulin on the cell cycle and determined that only Fatostatin possessed antimitotic properties. Fatostatin inhibited tubulin polymerization, arrested cells in mitosis, activated the spindle assembly checkpoint, and triggered mitotic catastrophe and reduced cell viability. Thus Fatostatin's ability to inhibit SREBP activity and cell division could prove beneficial in treating aggressive types of cancers such as glioblastomas that have elevated lipid metabolism and fast proliferation rates and often develop resistance to current anticancer therapies.
35
Tiong, Tung-Yu, Pei-Wei Weng, Chun-Hua Wang, Syahru Agung Setiawan, Vijesh Kumar Yadav, Narpati Wesa Pikatan, Iat-Hang Fong, Chi-Tai Yeh, Chia-Hung Hsu e Kuang-Tai Kuo. "Targeting the SREBP-1/Hsa-Mir-497/SCAP/FASN Oncometabolic Axis Inhibits the Cancer Stem-like and Chemoresistant Phenotype of Non-Small Cell Lung Carcinoma Cells". International Journal of Molecular Sciences 23, n. 13 (30 giugno 2022): 7283. http://dx.doi.org/10.3390/ijms23137283.
Testo completoAbstract (sommario):
Background: Lung cancer remains a leading cause of cancer-related death, with an annual global mortality rate of 18.4%. Despite advances in diagnostic and therapeutic technologies, non–small cell lung carcinoma (NSCLC) continues to be characterized by a poor prognosis. This may be associated with the enrichment of cancer stem cells (CSCs) and the development of chemoresistance—a double-edged challenge that continues to impede the improvement of long-term outcomes. Metabolic reprogramming is a new hallmark of cancer. Sterol regulatory element-binding proteins (SREBPs) play crucial regulatory roles in the synthesis and uptake of cholesterol, fatty acids, and phospholipids. Recent evidence has demonstrated that SREBP-1 is upregulated in several cancer types. However, its role in lung cancer remains unclear. Objective: This study investigated the role of SREBP-1 in NSCLC biology, progression, and therapeutic response and explored the therapeutic exploitability of SREBP-1 and SREBP-1-dependent oncometabolic signaling and miRNA epigenetic regulation. Methods: We analyzed SREBP-1 levels and biological functions in clinical samples and the human NSCLC cell lines H441 and A549 through shRNA-based knock down of SREBP function, cisplatin-resistant clone generation, immunohistochemical staining of clinical samples, and cell viability, sphere-formation, Western blot, and quantitative PCR assays. We conducted in-silico analysis of miRNA expression in NSCLC samples by using the Gene Expression Omnibus (GSE102286) database. Results: We demonstrated that SREBP-1 and SCAP are highly expressed in NSCLC and are positively correlated with the aggressive phenotypes of NSCLC cells. In addition, downregulation of the expression of tumor-suppressing hsa-miR-497-5p, which predictively targets SREBP-1, was observed. We also demonstrated that SREBP-1/SCAP/FASN lipogenic signaling plays a key role in CSCs-like and chemoresistant NSCLC phenotypes, especially because the fatostatin or shRNA targeting of SREBP-1 significantly suppressed the viability, cisplatin resistance, and cancer stemness of NSCLC cells and because treatment induced the expression of hsa-miR-497. Conclusion: Targeting the SREBP-1/hsa-miR-497 signaling axis is a potentially effective anticancer therapeutic strategy for NSCLC.
36
Horton, J. D. "Sterol regulatory element-binding proteins: transcriptional activators of lipid synthesis". Biochemical Society Transactions 30, n. 6 (1 novembre 2002): 1091–95. http://dx.doi.org/10.1042/bst0301091.
Testo completoAbstract (sommario):
Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors that regulate lipid homoeostasis. Three SREBP iso-forms control the expression of more than 30 genes required for the biosynthesis of cholesterol, fatty acids, triacylglycerols and phospholipids. The unique regulation and activation properties of each SREBP isoform facilitates the co-ordinate regulation of all essential lipid building blocks required for cell membranes as well as for very-low-density lipoprotein formation in hepatocytes.
37
Mustafa, Maria, Tony N. Wang, Xing Chen, Bo Gao e Joan C. Krepinsky. "SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction". American Journal of Physiology-Renal Physiology 311, n. 3 (1 settembre 2016): F614—F625. http://dx.doi.org/10.1152/ajprenal.00140.2016.
Testo completoAbstract (sommario):
Tubulointerstitial fibrosis is a major feature associated with declining kidney function in chronic kidney disease of diverse etiology. No effective means as yet exists to prevent the progression of fibrosis. We have shown that the transcription factor sterol-regulatory element-binding protein 1 (SREBP-1) is an important mediator of the profibrotic response to transforming growth factor-β (TGF-β) and angiotensin II, both key cytokines in the fibrotic process. Here, we examined the role of SREBP in renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model. The two isoforms of SREBP (-1 and -2) were activated by 3 days after UUO, with SREBP-1 showing a more sustained activation to 21 days. We then examined whether SREBP1/2 inhibition with the small-molecule inhibitor fatostatin could attenuate fibrosis after 14 days of UUO. SREBP activation was confirmed to be inhibited by fatostatin. Treatment decreased interstitial fibrosis, TGF-β signaling, and upregulation of α-smooth muscle actin (SMA), a marker of fibroblast activation. Fatostatin also attenuated inflammatory cell infiltrate and apoptosis. Associated with this, fatostatin preserved proximal tubular mass. The significant increase in atubular glomeruli observed after UUO, known to correlate with irreversible renal functional decline, was also decreased by treatment. In cultured primary fibroblasts, TGF-β1 induced the activation of SREBP-1 and -2. Fatostatin blocked TGF-β1-induced α-SMA and matrix protein upregulation. The inhibition of SREBP is thus a potential novel therapeutic target in the treatment of fibrosis in chronic kidney disease.
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Ivashchenko, Christine Y., Benjamin T. Bradley, Zhaohui Ao, James Leiper, Patrick Vallance e Douglas G. Johns. "Regulation of the ADMA-DDAH system in endothelial cells: a novel mechanism for the sterol response element binding proteins, SREBP1c and -2". American Journal of Physiology-Heart and Circulatory Physiology 298, n. 1 (gennaio 2010): H251—H258. http://dx.doi.org/10.1152/ajpheart.00195.2009.
Testo completoAbstract (sommario):
Asymmetric dimethylarginine (ADMA) has been implicated in the progression of cardiovascular disease as an endogenous inhibitor of nitric oxide synthase. The regulation of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme responsible for metabolizing ADMA, is poorly understood. The transcription factor sterol response element binding protein (SREBP) is activated by statins via a reduction of membrane cholesterol content. Because the promoters of both DDAH1 and DDAH2 isoforms contain sterol response elements, we tested the hypothesis that simvastatin regulates DDAH1 and DDAH2 transcription via SREBP. In cultured endothelial cells, simvastatin increased DDAH1 mRNA expression compared with vehicle. In an ADMA loading experiment, simvastatin treatment resulted in a decrease in ADMA content, an indication of increased DDAH activity. The knockdown of SREBP1c protein led to an increase in DDAH1 mRNA expression and activity, whereas the knockdown of SREBP2 led to a decrease in DDAH1 mRNA expression. The role of SREBP2 in the activation of the DDAH1 was supported by chromatin immunoprecipitation studies demonstrating increased binding of SREBP2 to the DDAH1 promoter upon simvastatin stimulation. These data indicate that SREBP1c might act as a repressor and SREBP2 as an activator of DDAH transcription and activity. This study describes a novel mechanism of reciprocal regulation by the SREBP family members of the DDAH-ADMA system, which represents a potential link between cellular cholesterol content and endothelial dysfunction observed in cardiovascular disease.
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Li, Yin-Xia, Xingzi Guo, Thippeswamy Gulappa, Bindu Menon e K. M. J. Menon. "SREBP Plays a Regulatory Role in LH/hCG Receptor mRNA Expression in Human Granulosa-Lutein Cells". Journal of Clinical Endocrinology & Metabolism 104, n. 10 (31 maggio 2019): 4783–92. http://dx.doi.org/10.1210/jc.2019-00913.
Testo completoAbstract (sommario):
AbstractContextLH receptor (LHR) expression has been shown to be regulated posttranscriptionally by LHR mRNA binding protein (LRBP) in rodent and human ovaries. LRBP was characterized as mevalonate kinase. The gene that encodes mevalonate kinase is a member of a family of genes that encode enzymes involved in lipid synthesis and are regulated by the transcription factor sterol regulatory element binding proteins (SREBPs).ObjectiveThe current study examined the regulation of LHR mRNA expression in human granulosa-lutein cells in response to alterations in cholesterol metabolism.DesignUsing atorvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase to inhibit cholesterol biosynthesis, we examined its effect on LHR mRNA expression. The effect of atorvastatin on SREBP and mRNA expression as well as LHR mRNA binding protein expression was examined. Finally, the effect of atorvastatin on human chorionic gonadotropin (hCG)–stimulated progesterone production and the expression of key steroidogenic enzymes was also examined.ResultsStatin treatment reduced LHR mRNA expression by increasing the levels of SREBP1a and SREBP2, leading to an increase in LRBP. RNA gel shift assay showed that increased binding of LHR mRNA to LRBP occurred in response to atorvastatin, leading to LHR mRNA degradation. The granulosa-lutein cells pretreated with atorvastatin also showed decreased responsiveness to hCG by decreasing the mRNA and protein expression of steroidogenic enzymes. Atorvastatin also attenuated LH/hCG-induced progesterone production.ConclusionThese results imply that LHR mRNA expression by the human granulosa-lutein cells is regulated by cholesterol, through a mechanism involving SREBP and SREBP cleavage activating protein serving as the cholesterol sensor.
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Kidani, Yoko, Heidi Elsaesser, M. Hock, Laurent Vergnes, Kevin Williams, Joseph Argus, Beth Marbois et al. "Towards understanding the influence of lipid metabolism on CD8 T cell biology (P1136)". Journal of Immunology 190, n. 1_Supplement (1 maggio 2013): 64.15. http://dx.doi.org/10.4049/jimmunol.190.supp.64.15.
Testo completoAbstract (sommario):
Abstract A hallmark of the adaptive immune system is the ability of CD8 T cells to undergo rapid clonal expansion in response to antigenic stimulation. To meet the biosynthetic requirements of rapid growth and proliferation, effector T cells must reprogram their metabolism to provide essential macromolecules. We have previously shown that mitogen signaling induces a gene expression program that drives de novo cholesterol and fatty acid biosynthesis, however the molecular events linking antigen receptor signaling with lipid anabolism remain poorly understood. Herein, we demonstrate an essential role for sterol regulatory element binding proteins (SREBPs) in the acquisition of effector cell metabolism. Without SREBP signaling, CD8 T cells are unable to grow and acquire the effector cell metabolism program, resulting in attenuated clonal expansion during viral infection. In contrast, SREBPs are dispensable for homeostatic proliferation, demonstrating a context-specific requirement for SREBP signaling during effector T cell blastogenesis. Mechanistic studies indicate that SREBP activity is required to maintain a level of cellular cholesterol sufficient to permit rapid ER and cellular growth. Taken together, these studies provide novel insights into the molecular signals underlying the metabolic reprogramming of CD8 T cell during the transition from quiescence to activation, and demonstrate the importance of SREBPs in regulating a cholesterol metabolic checkpoint during blastogenesis.
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Yang, Shui-Bo, Tao Zhao, Li-Xiang Wu, Yi-Chuang Xu e Xiao-Ying Tan. "Effects of dietary carbohydrate sources on lipid metabolism and SUMOylation modification in the liver tissues of yellow catfish". British Journal of Nutrition 124, n. 12 (30 giugno 2020): 1241–50. http://dx.doi.org/10.1017/s0007114520002408.
Testo completoAbstract (sommario):
AbstractDysregulation in hepatic lipid synthesis by excess dietary carbohydrate intake is often relevant with the occurrence of fatty liver; therefore, the thorough understanding of the regulation of lipid deposition and metabolism seems crucial to search for potential regulatory targets. In the present study, we examined TAG accumulation, lipid metabolism-related gene expression, the enzyme activities of lipogenesis-related enzymes, the protein levels of transcription factors or genes involving lipogenesis in the livers of yellow catfish fed five dietary carbohydrate sources, such as glucose, maize starch, sucrose, potato starch and dextrin, respectively. Generally speaking, compared with other carbohydrate sources, dietary glucose promoted TAG accumulation, up-regulated lipogenic enzyme activities and gene expressions, and down-regulated mRNA expression of genes involved in lipolysis and small ubiquitin-related modifier (SUMO) modification pathways. Further studies found that sterol regulatory element binding protein 1 (SREBP1), a key transcriptional factor relevant to lipogenic regulation, was modified by SUMO1. Mutational analyses found two important sites for SUMOylation modification (K254R and K264R) in SREBP1. Mutant SREBP lacking lysine 264 up-regulated the transactivation capacity on an SREBP-responsive promoter. Glucose reduced the SUMOylation level of SREBP1 and promoted the protein expression of SREBP1 and its target gene stearoyl-CoA desaturase 1 (SCD1), indicating that SUMOylation of SREBP1 mediated glucose-induced hepatic lipid metabolism. Our study elucidated the molecular mechanism of dietary glucose increasing hepatic lipid deposition and found that the SREBP-dependent transactivation was regulated by SUMO1 modification, which served as a new target for the transcriptional programmes governing lipid metabolism.
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Lee, Jae-Ho, Peter Phelan, Minsang Shin, Byung-Chul Oh, Xianlin Han, Seung-Soon Im e Timothy F. Osborne. "SREBP-1a–stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1". Proceedings of the National Academy of Sciences 115, n. 52 (10 dicembre 2018): E12228—E12234. http://dx.doi.org/10.1073/pnas.1813458115.
Testo completoAbstract (sommario):
There is a growing appreciation for a fundamental connection between lipid metabolism and the immune response. Macrophage phagocytosis is a signature innate immune response to pathogen exposure, and cytoplasmic membrane expansion is required to engulf the phagocytic target. The sterol regulatory element binding proteins (SREBPs) are key transcriptional regulatory proteins that sense the intracellular lipid environment and modulate expression of key genes of fatty acid and cholesterol metabolism to maintain lipid homeostasis. In this study, we show that TLR4-dependent stimulation of macrophage phagocytosis requires mTORC1-directed SREBP-1a−dependent lipid synthesis. We also show that the phagocytic defect in macrophages from SREBP-1a−deficient mice results from decreased interaction between membrane lipid rafts and the actin cytoskeleton, presumably due to reduced accumulation of newly synthesized fatty acyl chains within major membrane phospholipids. We show that mTORC1-deficient macrophages also have a phagocytic block downstream from TLR4 signaling, and, interestingly, the reduced level of phagocytosis in both SREBP-1a− and mTORC1-deficient macrophages can be restored by ectopic SREBP-1a expression. Taken together, these observations indicate SREBP-1a is a major downstream effector of TLR4−mTORC1 directed interactions between membrane lipid rafts and the actin cytoskeleton that are required for pathogen-stimulated phagocytosis in macrophages.
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Shimano, Hitoshi. "SREBPs: physiology and pathophysiology of the SREBP family". FEBS Journal 276, n. 3 (24 dicembre 2008): 616–21. http://dx.doi.org/10.1111/j.1742-4658.2008.06806.x.
Testo completo
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Jianhua, Li, Miao Xueqin e Hu Jifen. "Expression and clinical significance of LXRα and SREBP-1c in placentas of preeclampsia". Open Medicine 11, n. 1 (1 gennaio 2016): 292–96. http://dx.doi.org/10.1515/med-2016-0057.
Testo completoAbstract (sommario):
AbstractObjectiveTo evaluate the expression and correlations of liver X receptor alpha (LXRa) and its target gene sterol regulatory element-binding protein-1c (SREBP-1c) in placentas of preeclampsia (PE) and their significance in PE.MethodsPregnancies were divided into two groups, 60 cases (29 cases of mild and 31 cases of severe) of PE group and 56 cases of normal group. The level of mRNA and protein of LXRa and SREBP-1c were analyzed by reverse transcription-polymerase chain reaction (RTPCR) and immunohistochemistry (IHC) in the placentas.ResultsRT-PCR and IHC results showed that the mRNA and protein expression of both LXRa and SREBP-1c increased gradually with the extent of PE among normal pregnancy, mild PE and severe PE groups, and the differences were of statistically significance (P<0.01 or P<0.05). There were positive correlations between the expression of LXRa mRNA and SREBP-1c mRNA, also between LXRa mRNA and LXRa protein (r=0.521, P<0.01; r=0.422, P<0.01). The expression of SREBP-1c mRNA positively correlated with its protein level (r=0.598, P<0.01). There were positive correlations between the expression of LXRa protein and SREBP-1c protein (r=0.612, P<0.01).ConclusionThe expression of LXRa is elevated significantly in placentas of PE patients, and might contribute for promoting the transcription and translation of its target gene SREBP1-c, which is related to the occurrence and development of PE.
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Rawson, Robert B. "Control of lipid metabolism by regulated intramembrane proteolysis of sterol regulatory element binding proteins (SREBPs)". Biochemical Society Symposia 70 (1 settembre 2003): 221–31. http://dx.doi.org/10.1042/bss0700221.
Testo completoAbstract (sommario):
In mammalian cells, the supply of lipids is co-ordinated with demand through the transcriptional control of genes encoding proteins required for synthesis or uptake. The sterol regulatory element binding proteins (SREBPs) are responsible for increased transcription of these genes when lipid level fall. Mammals have three SREBPs (-1a, -1c and -2), which are the products of two distinct genes. Synthesized as approximately 120 kDa precursors, they are inserted into membranes of the endoplasmic reticulum (ER) in a hairpin fashion. Both the N-terminal transcription factor domain and the C-terminal regulatory domain face the cytoplasm. These are connected by two transmembrane helices separated by a short loop projecting into the ER lumen. The C-terminal domain of SREBP interacts with the C-terminal domain of SREBP-cleavage-activating protein (SCAP). The N-terminal half of SCAP contains eight transmembrane helices, five of which (helices 2-6) form the sterol-sensing domain. In response to cellular demand for lipid, this complex exits the ER and transits to the Golgi apparatus, where two distinct proteases cleave the SREBP precursor to release the transcriptionally active N-terminus. This process was the first example of regulated intramembrane proteolysis for which the proteases were identified. Recent work has additionally uncovered integral membrane proteins, insig-1 and insig-2, that are required to retain the SREBP-SCAP complex in the ER in the presence of sterols, thus providing a more complete understanding of the control of proteolysis in this complex regulatory pathway.
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Athanikar, J. N., H. B. Sanchez e T. F. Osborne. "Promoter selective transcriptional synergy mediated by sterol regulatory element binding protein and Sp1: a critical role for the Btd domain of Sp1." Molecular and Cellular Biology 17, n. 9 (settembre 1997): 5193–200. http://dx.doi.org/10.1128/mcb.17.9.5193.
Testo completoAbstract (sommario):
Cellular cholesterol and fatty acid levels are coordinately regulated by a family of transcriptional regulatory proteins designated sterol regulatory element binding proteins (SREBPs). SREBP-dependent transcriptional activation from all promoters examined thus far is dependent on the presence of an additional binding site for a ubiquitous coactivator. In the low-density lipoprotein (LDL) receptor, acetyl coenzyme A carboxylase (ACC), and fatty acid synthase (FAS) promoters, which are all regulated by SREBP, the coactivator is the transcription factor Sp1. In this report, we demonstrate that Sp3, another member of the Sp1 family, is capable of substituting for Sp1 in coactivating transcription from all three of these promoters. Results of an earlier study showed that efficient activation of transcription from the LDL receptor promoter required domain C of Sp1; however, this domain is not crucial for activation of the simian virus 40 promoter, where synergistic activation occurs through multiple Sp1 binding sites and does not require SREBP. Also in the present report, we further localize the critical determinant of the C domain required for activation of the LDL receptor to a small region that is highly conserved between Sp1 and Sp3. This crucial domain encompasses the buttonhead box, which is a 10-amino-acid stretch that is present in several Sp1 family members, including the Drosophila buttonhead gene product. Interestingly, neither the buttonhead box nor the entire C domain is required for the activation of the FAS and ACC promoters even though both SREBP and Sp1 are critical players. ACC and FAS each contain two critical SREBP sites, whereas there is only one in the LDL receptor promoter. This finding suggested that buttonhead-dependent activation by SREBP and Sp1 may be limited to promoters that naturally contain a single SREBP recognition site. Consistent with this model, a synthetic construct containing three tandem copies of the native LDL receptor SREBP site linked to a single Sp1 site was also significantly activated in a buttonhead-independent fashion. Taken together, these studies indicate that transcriptional activation through the concerted action of SREBP and Sp1 can occur by at least two different mechanisms, and promoters that are activated by each one can potentially be identified by the number of critical SREBP binding sites that they contain.
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Logette, E., C. Le Jossic-Corcos, D. Masson, S. Solier, A. Sequeira-Legrand, I. Dugail, S. Lemaire-Ewing, L. Desoche, E. Solary e L. Corcos. "Caspase-2, a Novel Lipid Sensor under the Control of Sterol Regulatory Element Binding Protein 2". Molecular and Cellular Biology 25, n. 21 (1 novembre 2005): 9621–31. http://dx.doi.org/10.1128/mcb.25.21.9621-9631.2005.
Testo completoAbstract (sommario):
ABSTRACT Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5′-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.
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Ai, Wandong, Ying Liu e Timothy C. Wang. "Yin yang 1 (YY1) represseshistidine decarboxylasegene expression with SREBP-1a in part through an upstream Sp1 site". American Journal of Physiology-Gastrointestinal and Liver Physiology 290, n. 6 (giugno 2006): G1096—G1104. http://dx.doi.org/10.1152/ajpgi.00199.2005.
Testo completoAbstract (sommario):
Histidine decarboxylase (HDC) is the enzyme that converts histidine to histamine, a bioamine that plays an important role in many physiological aspects including allergic responses, inflammation, neurotransmission, and gastric acid secretion. In previous studies, we demonstrated that Kruppel-like factor 4 represses HDC promoter activity in a gastric cell line through both an upstream Sp1-binding GC box (GGGCGG sequence) and downstream gastrin-responsive elements. In the current study, Yin Yang 1 (YY1), a pleiotropic transcriptional factor, was also shown in cotransfection assays to repress HDC promoter activity through the upstream GC box. DNA affinity purification assay demonstrated that YY1 was pulled down specifically by the upstream GC box. In addition, sterol-responsive element-binding protein 1a (SREBP-1a), a transcriptional factor that binds YY1, represses the HDC promoter. Interestingly, deletion analysis and cotransfection assays indicated that mutation of the upstream GC box or truncation of downstream gastrin-responsive elements in the HDC promoter disrupted the inhibitory effect of YY1 and SREBP-1a in an identical fashion. Furthermore, quantitative real-time PCR analysis indicated that gastrin treatment downregulated SREBP-1a gene expression and reduced the DNA binding activity of SREBP in EMSAs. Taken together, these results suggest that YY1 and SREBP-1a form a complex to inhibit HDC gene expression through both the upstream GC box and downstream gastrin-responsive elements and gastrin-induced activation of HDC gene expression is mediated at least partly through downregulation of transcriptional repressors such as SREBPs.
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SAKAI, Juro. "The SREBP pathway". Journal of Japan Atherosclerosis Society 28, n. 4-5 (2001): 97–102. http://dx.doi.org/10.5551/jat1973.28.4-5_97.
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Yang, Jing, e M. Sharon Stack. "Lipid Regulatory Proteins as Potential Therapeutic Targets for Ovarian Cancer in Obese Women". Cancers 12, n. 11 (21 novembre 2020): 3469. http://dx.doi.org/10.3390/cancers12113469.
Testo completoAbstract (sommario):
Obesity has become a recognized global epidemic that is associated with numerous comorbidities including type II diabetes, cardiovascular disease, hypertension, and cancer incidence and progression. Ovarian cancer (OvCa) has a unique mechanism of intra-peritoneal metastasis, already present in 80% of women at the time of diagnosis, making it the fifth leading cause of death from gynecological malignancy. Meta-analyses showed that obesity increases the risk of OvCa progression, leads to enhanced overall and organ-specific tumor burden, and adversely effects survival of women with OvCa. Recent data discovered that tumors grown in mice fed on a western diet (40% fat) have elevated lipid levels and a highly increased expression level of sterol regulatory element binding protein 1 (SREBP1). SREBP1 is a master transcription factor that regulates de novo lipogenesis and lipid homeostasis, and induces lipogenic reprogramming of tumor cells. Elevated SREBP1 levels are linked to cancer cell proliferation and metastasis. This review will summarize recent findings to provide a current understanding of lipid regulatory proteins in the ovarian tumor microenvironment with emphasis on SREBP1 expression in the obese host, the role of SREBP1 in cancer progression and metastasis, and potential therapeutic targeting of SREBPs and SREBP-pathway genes in treating cancers, particularly in the context of host obesity.