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SREBP transcription factors: master regulators of lipid homeostasis 总被引:41,自引:0,他引:41
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Regulation of gene expression by SREBP and SCAP 总被引:22,自引:0,他引:22
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Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor
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Inoue N Shimano H Nakakuki M Matsuzaka T Nakagawa Y Yamamoto T Sato R Takahashi A Sone H Yahagi N Suzuki H Toyoshima H Yamada N 《Molecular and cellular biology》2005,25(20):8938-8947
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Rishi V Gal J Krylov D Fridriksson J Boysen MS Mandrup S Vinson C 《The Journal of biological chemistry》2004,279(12):11863-11874
The mammalian SREBP family contains two genes that code for B-HLH-ZIP proteins that bind sequence-specific DNA to regulate the expression of genes involved in lipid metabolism. We have designed a dominant negative (DN), termed A-SREBP-1, that inhibits the DNA binding of either SREBP protein. A-SREBP-1 consists of the dimerization domain of B-SREBP-1 and a polyglutamic acid sequence that replaces the basic region. A-SREBP-1 heterodimerizes with either B-SREBP-1 or B-SREBP-2, and both heterodimers are more stable than B-SREBP-1 bound to DNA. Circular dichroism thermal denaturation studies show that the B-SREBP-1.A-SREBP-1 heterodimer is -9.8 kcal mol(-1) dimer(-1) more stable than the B-SREBP-1 homodimer. EMSA assays demonstrate that A-SREBP-1 can inhibit the DNA binding of either B-SREBP-1 or B-SREBP-2 in an equimolar competition but does not inhibit the DNA binding of the three B-HLH-ZIP proteins MAX, USF, or MITF, even at 100 molar eq. Chimeric proteins containing the HLH domain of SREBP-1 and the leucine zipper from either MAX, USF, or MITF indicate that both the HLH and leucine zipper regions of SREBP-1 contribute to its dimerization specificity. Transient co-transfection studies demonstrate that A-SREBP-1 can inhibit the transactivation of SREBP-1 and SREBP-2 but not USF. A-SREBP-1 may be useful in metabolic diseases where SREBP family members are overexpressed. 相似文献
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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
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Zoumi A Datta S Liaw LH Wu CJ Manthripragada G Osborne TF Lamorte VJ 《Molecular and cellular biology》2005,25(8):2946-2956
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Genotype of bovine sterol regulatory element binding protein-1 (SREBP-1) is associated with fatty acid composition in Japanese Black cattle 总被引:1,自引:0,他引:1
Shogo Hoashi Nobuhisa Ashida Hideki Ohsaki Takeshi Utsugi Shinji Sasazaki Masaaki Taniguchi Kenji Oyama Fumio Mukai Hideyuki Mannen 《Mammalian genome》2007,18(12):880-886
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Bennett MK Seo YK Datta S Shin DJ Osborne TF 《The Journal of biological chemistry》2008,283(23):15628-15637
Mice were subjected to different dietary manipulations to selectively alter expression of hepatic sterol regulatory element-binding protein 1 (SREBP-1) or SREBP-2. mRNA levels for key target genes were measured and compared with the direct binding of SREBP-1 and -2 to the associated promoters using isoform specific antibodies in chromatin immunoprecipitation studies. A diet supplemented with Zetia (ezetimibe) and lovastatin increased and decreased nuclear SREBP-2 and SREBP-1, respectively, whereas a fasting/refeeding protocol dramatically altered SREBP-1 but had modest effects on SREBP-2 levels. Binding of both SREBP-1 and -2 increased on promoters for 3-hydroxy-3-methylglutaryl-CoA reductase, fatty-acid synthase, and squalene synthase in livers of Zetia/lovastatin-treated mice despite the decline in total SREBP-1 protein. In contrast, only SREBP-2 binding was increased for the low density lipoprotein receptor promoter. Decreased SREBP-1 binding during fasting and a dramatic increase upon refeeding indicates that the lipogenic "overshoot" for fatty-acid synthase gene expression known to occur during high carbohydrate refeeding can be attributed to a similar overshoot in SREBP-1 binding. SREBP co-regulatory protein recruitment was also increased/decreased in parallel with associated changes in SREBP binding, and there were clear distinctions for different promoters in response to the dietary manipulations. Taken together, these studies reveal that there are alternative molecular mechanisms for activating SREBP target genes in response to the different dietary challenges of Zetia/lovastatin versus fasting/refeeding. This underscores the mechanistic flexibility that has evolved at the individual gene/promoter level to maintain metabolic homeostasis in response to shifting nutritional states and environmental fluctuations. 相似文献
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Nan Li Min Li Wenxuan Hong Jing Shao Huihui Xu Hitoshi Shimano Jun Lu Yong Xu 《生物化学与生物物理学报:疾病的分子基础》2018,1864(9):2881-2889
Alteration of hepatic lipid metabolism contributes to a range of human diseases including steatosis. Sterol response element binding protein (SREBP) is the master regulator of lipid metabolism. The epigenetic mechanism whereby SREBP activity is regulated remains incompletely understood. We have previously shown that systemic knockdown of brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuates steatosis in mice by down-regulating the synthesis of pro-inflammatory mediators. Here we show that hepatocyte conditional Brg1 knockout (HepcKO) mice were largely protected from high-fat diet (HFD) induced steatosis as evidenced by decelerated weight gains, improved insulin sensitivity, ameliorated steatotic injuries, and diminished hepatic inflammation. Brg1 contributed to lipid metabolism by trans-activating the genes involved in fatty acid esterification. Mechanistically, Brg1 interacted with and was recruited by sterol response element binding protein (SREBP1c) to the promoters of SREBP target genes and optimized the chromatin structure to facilitate SREBP1c binding. Therefore, our data have identified a previously unrecognized role for Brg1 in hepatic lipid metabolism by portraying Brg1 as an essential epigenetic co-factor for SREBP1c. 相似文献
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Le Lay S Lefrère I Trautwein C Dugail I Krief S 《The Journal of biological chemistry》2002,277(38):35625-35634