The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane pr...The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.展开更多
文章旨在研究延边黄牛不同生长阶段固醇调节元件结合蛋白1（Sterol regulatory ele-ment binding factor 1,SREBP1）和硬脂酰辅酶A去饱和酶1（Stearoyl Co A desaturease 1,SCD1）基因表达的发育性变化与IMF含量的相关性以及这两个基因...文章旨在研究延边黄牛不同生长阶段固醇调节元件结合蛋白1（Sterol regulatory ele-ment binding factor 1,SREBP1）和硬脂酰辅酶A去饱和酶1（Stearoyl Co A desaturease 1,SCD1）基因表达的发育性变化与IMF含量的相关性以及这两个基因表达水平的关联性。试验选取12月龄的延边黄牛公牛（去势）8头,利用微量微创活体采样枪（韩国忠北大学提供）,分别在12月龄,16月龄,20月龄,采集肌肉组织（臀肌）;利用实时荧光定量PCR方法分析SREBP1和SCD1基因在延边黄牛不同生长阶段肌肉组织中的m RNA发育性变化。结果表明：1延边黄牛SREBP1基因相对表达水平在12、16、20月龄具有极其显著差异（P〈0.01）,其中20月龄时SREBP1基因表达量相对最高;SCD1基因相对表达水平在12、16、20月龄具有显著差异（P〈0.05）,其中20月龄时SCD1基因表达量相对最高。2肌肉组织中SREBP1基因的表达量在12~20月龄期间与IMF含量具有正向相关性,相关系数为0.910（P〈0.05）;SCD1基因的表达量在12~20月龄期间与IMF含量具有正向相关性,相关系数为0.934（P〈0.05）。结果表明,SREBP1和SCD1基因在延边黄牛不同生长阶段存在显著或极显著差异,SREBP1和SCD1基因的协同表达对延边黄牛不同生长阶段肌内脂肪的沉积有一定的正向调控作用。展开更多
AIM:To study the effect of Daxx on cholesterol accumulation in hepatic cells. METHODS: Sprague Dawley (SD) rats were fed a normal or high fat diet for 6 wk, and serum lipids and Daxx expression of hepatic tissues were...AIM:To study the effect of Daxx on cholesterol accumulation in hepatic cells. METHODS: Sprague Dawley (SD) rats were fed a normal or high fat diet for 6 wk, and serum lipids and Daxx expression of hepatic tissues were measured by immunoblot assays. HepG2 cells were transfected with the pEGFP-C1/Daxx or pEGFP-C1 plasmid. Cells stably transfected with Daxx were identified by RT- PCR analysis. Total cholesterol levels were determined by high performance liquid chromatography. Activated- SREBP and caveolin-1 were assayed by western blotting. RESULTS: Hepatic Daxx protein was higher in normal rats than in high fat diet-fed rats. Noticeable negative correlations were seen between Daxx and LDL-C (γ = -7.56, P = 0.018), and between Daxx and TC (γ = -9.07, P = 0.01), respectively. The total cholesterol of HepG2/GFP-Daxx cells was lower than that of control cells or HepG2/GFP cells (9.28 ± 0.19 vs 14.36 ± 4.45 or 13.94 ± 2.62, both P < 0.05). Furthermore, in HepG2/GFP cells, the expression of activated SREBP was lower than that of control cells, whereas caveolin-1 expression was higher. CONCLUSION: Overexpression of Daxx in HepG2 cells decreased intracellular cholesterol accumulation, which might be associated with inhibition of SREBP activity and an increase in caveolin-1 expression.展开更多
固醇调节元件结合蛋白1(Sterol regulatory element-binding protein 1,SREBP-1)是重要的核转录因子之一,能调控内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需酶的表达,以维持血脂动态平衡。研究表明,SREBP-1及其靶基因网络的异常可引...固醇调节元件结合蛋白1(Sterol regulatory element-binding protein 1,SREBP-1)是重要的核转录因子之一,能调控内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需酶的表达,以维持血脂动态平衡。研究表明,SREBP-1及其靶基因网络的异常可引起胰岛素抵抗、Ⅱ型糖尿病、心功能紊乱、血管并发症和肝脂肪变等一系列代谢性疾病。近年高通量组学技术的发展极大扩展了对SREBP-1靶基因及其转录调控模式的了解。文章对SREBP-1蛋白结构、活化过程、DNA结合位点及其调控的靶基因等方面的研究进展进行了综述,并着重介绍了基于组学数据的转录调控网络的构建,这将有助于更好的认识SREBP-1在脂类代谢中的作用,为深入探讨脂质代谢性疾病的治疗提供新线索。展开更多
文摘The molecular mechanism of how hepatocytes maintain cholesterol homeostasis has become much more transparent with the discovery of sterol regulatory element binding proteins (SREBPs) in recent years. These membrane proteins aremembers of the basic helix-loop-helix-leucine zipper (bHLHZip) family of transcription factors. They activate the expression of at least 30 genes involved in the synthesis of cholesterol and lipids. SREBPs are synthesized as precursor proteins in the endoplasmic reticulum (ER), where they form a complex with another protein, SREBP cleavage activating protein (SCAP). The SCAP molecule contains a sterol sensory domain. In the presence of high cellular sterol concentrations SCAP confines SREBP to the ER. With low cellular concentrations, SCAP escorts SREBP to activation in the Golgi. There, SREBP undergoes two proteolytic cleavage steps to release the mature, biologically active transcription factor, nuclear SREBP (nSREBP). nSREBP translocates to the nucleus and binds to sterol response elements (SRE) in the promoter/enhancer regions of target genes. Additional transcription factors are required to activate transcription of these genes. Three different SREBPs are known, SREBPs-1a, -1c and -2. SREBP-1a and -1c are isoforms produced from a single gene by alternate splicing. SREBP-2 is encoded by a different gene and does not display any isoforms. It appears that SREBPs alone, in the sequence described above, can exert complete control over cholesterol synthesis, whereas many additional factors (hormones, cytokines, etc.) are required for complete control of lipid metabolism. Medicinal manipulation of the SREBP/SCAP system is expected to prove highly beneficial in the management of cholesterol-related disease.
基金This work was supported by grants from the National Natural Science Foundation of China （ No. 81173047 and No. 31371161 ） and the Natural Science Foundation of Hunan （No. 12JJ5068）.
基金The National Natural Science Foundation of China, No. 30470719 and 30600249The National Major Basic Research Program of China (973), No. 2006CB503808The Sanitarian Research Foundation of Hunan province, No. B2004-078
文摘AIM:To study the effect of Daxx on cholesterol accumulation in hepatic cells. METHODS: Sprague Dawley (SD) rats were fed a normal or high fat diet for 6 wk, and serum lipids and Daxx expression of hepatic tissues were measured by immunoblot assays. HepG2 cells were transfected with the pEGFP-C1/Daxx or pEGFP-C1 plasmid. Cells stably transfected with Daxx were identified by RT- PCR analysis. Total cholesterol levels were determined by high performance liquid chromatography. Activated- SREBP and caveolin-1 were assayed by western blotting. RESULTS: Hepatic Daxx protein was higher in normal rats than in high fat diet-fed rats. Noticeable negative correlations were seen between Daxx and LDL-C (γ = -7.56, P = 0.018), and between Daxx and TC (γ = -9.07, P = 0.01), respectively. The total cholesterol of HepG2/GFP-Daxx cells was lower than that of control cells or HepG2/GFP cells (9.28 ± 0.19 vs 14.36 ± 4.45 or 13.94 ± 2.62, both P < 0.05). Furthermore, in HepG2/GFP cells, the expression of activated SREBP was lower than that of control cells, whereas caveolin-1 expression was higher. CONCLUSION: Overexpression of Daxx in HepG2 cells decreased intracellular cholesterol accumulation, which might be associated with inhibition of SREBP activity and an increase in caveolin-1 expression.
文摘固醇调节元件结合蛋白1(Sterol regulatory element-binding protein 1,SREBP-1)是重要的核转录因子之一,能调控内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需酶的表达,以维持血脂动态平衡。研究表明,SREBP-1及其靶基因网络的异常可引起胰岛素抵抗、Ⅱ型糖尿病、心功能紊乱、血管并发症和肝脂肪变等一系列代谢性疾病。近年高通量组学技术的发展极大扩展了对SREBP-1靶基因及其转录调控模式的了解。文章对SREBP-1蛋白结构、活化过程、DNA结合位点及其调控的靶基因等方面的研究进展进行了综述,并着重介绍了基于组学数据的转录调控网络的构建,这将有助于更好的认识SREBP-1在脂类代谢中的作用,为深入探讨脂质代谢性疾病的治疗提供新线索。
