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
Background Sterol regulatory element binding protein （SREBP）-2 plays a key role in lipid homeostasis by stimulating gene expression of cholesterol biosynthetic pathways. The insulin-like growth factor binding prote...Background Sterol regulatory element binding protein （SREBP）-2 plays a key role in lipid homeostasis by stimulating gene expression of cholesterol biosynthetic pathways. The insulin-like growth factor binding protein （IGFBP） family regulates growth and metabolism, especially bone cell metabolism, and correlates with osteonecrosis. However, association of their gene polymorphisms with risk of avascular necrosis of the femoral head （ANFH） has rarely been reported. We determined whether SREBP-2 and IGFBP-3 gene polymorphisms were associated with increased ANFH risk in the Chinese population. Methods Two single nucleotide polymorphisms of SREBP2 gene, rs2267439 and rs2267443, and one of IGFBP-3 gene, rs2453839, were selected and genotyped in 49 ANFH patients and 42 control individuals by direct sequencing assay. Results The frequencies of rs2267439 TT and rs2267443 GA of SREBP2 and rs2453839 TT and CT of IGFBP-3 in the ANFH group showed increased and decreased tendencies （against normal control group）, respectively. Interaction analysis of genes revealed that the frequency of carrying rs2267439 TT and rs2267443 GA genotypes of SREBF-2 in ANFH patients was significantly higher than in the control group （P 〈0.05）. Association analysis between polymorphisms and clinical phenotype demonstrated that the disease course in ANFH patients with the rs2453839 TT genotype of IGFBP-3 was significantly shorter than that of CT＋CC carriers （P 〈0.01）. CT＋CC genotype frequency in patients with stage Ill/IV bilateral hip lesions was significantly higher than in those with stage Ill/IV unilateral lesions and stage II/111 bilateral lesions （P 〈0.05-0.02）. Conclusions Our results suggested that interaction of SREBP-2 gene polymorphisms and the relationship between the polymorphisms and clinical phenotype of IGFBP-3 were closely related to increased ANFH risk in the Chinese population. The most significant finding was that the CT＋CC genotype carriers of IGFBP-3 rs2453839 were highly associated with the development of ANFH.展开更多
目的：研究胆固醇调节元件结合蛋白2基因（sterol regulatory element binding protein 2 gene，SREBP2） rs2228314多态性与儿童青少年肥胖和血脂水平的关系。方法：研究对象来自前期工作中收集的两批样本，共2030名7岁至18岁中小学生...目的：研究胆固醇调节元件结合蛋白2基因（sterol regulatory element binding protein 2 gene，SREBP2） rs2228314多态性与儿童青少年肥胖和血脂水平的关系。方法：研究对象来自前期工作中收集的两批样本，共2030名7岁至18岁中小学生，对这些学生进行身体测量和血清总胆固醇（total cholesterol，TC）、三酰甘油（triacylgly-ceride，TG）、高密度脂蛋白胆固醇（low density lipoprotein-cholesterol，HDL-C）、低密度脂蛋白胆固醇（low density lipo-protein-cholesterol ，LDL-C）的检测。采用基质支持的激光释放/电离飞行时间质谱分析检测rs2228314多态性基因型。在显性模型下进行统计学分析，采用t检验比较不同基因型组间血脂水平（计量资料）的差异，采用Logistic回归分析rs2228314多态性与血脂水平的异常（分类资料）和肥胖的关系。结果：rs2228314多态性GC/CC基因型组的HDL-C水平低于GG纯合子，差异有统计学意义（0．10＆#177;0．35 vs．0．14＆#177;0．36，P＝0．020），在显性模型下，调整研究样本、性别和年龄后，rs2228314多态性与 HDL-C 水平的异常相关（ OR ＝1．400，95％ CI：1．027～1．907， P ＝0．033）。调整研究样本、性别、年龄和HDL-C 水平后，rs2228314多态性与肥胖的相关性无统计学意义（OR ＝1．178，95％CI：0．971～1．430， P＝0．096）。结论：携带SREBP2基因rs2228314多态性GC/CC基因型的儿童青少年发生HDL-C水平异常的风险高于GG基因型携带者。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.
文摘Background Sterol regulatory element binding protein （SREBP）-2 plays a key role in lipid homeostasis by stimulating gene expression of cholesterol biosynthetic pathways. The insulin-like growth factor binding protein （IGFBP） family regulates growth and metabolism, especially bone cell metabolism, and correlates with osteonecrosis. However, association of their gene polymorphisms with risk of avascular necrosis of the femoral head （ANFH） has rarely been reported. We determined whether SREBP-2 and IGFBP-3 gene polymorphisms were associated with increased ANFH risk in the Chinese population. Methods Two single nucleotide polymorphisms of SREBP2 gene, rs2267439 and rs2267443, and one of IGFBP-3 gene, rs2453839, were selected and genotyped in 49 ANFH patients and 42 control individuals by direct sequencing assay. Results The frequencies of rs2267439 TT and rs2267443 GA of SREBP2 and rs2453839 TT and CT of IGFBP-3 in the ANFH group showed increased and decreased tendencies （against normal control group）, respectively. Interaction analysis of genes revealed that the frequency of carrying rs2267439 TT and rs2267443 GA genotypes of SREBF-2 in ANFH patients was significantly higher than in the control group （P 〈0.05）. Association analysis between polymorphisms and clinical phenotype demonstrated that the disease course in ANFH patients with the rs2453839 TT genotype of IGFBP-3 was significantly shorter than that of CT＋CC carriers （P 〈0.01）. CT＋CC genotype frequency in patients with stage Ill/IV bilateral hip lesions was significantly higher than in those with stage Ill/IV unilateral lesions and stage II/111 bilateral lesions （P 〈0.05-0.02）. Conclusions Our results suggested that interaction of SREBP-2 gene polymorphisms and the relationship between the polymorphisms and clinical phenotype of IGFBP-3 were closely related to increased ANFH risk in the Chinese population. The most significant finding was that the CT＋CC genotype carriers of IGFBP-3 rs2453839 were highly associated with the development of ANFH.
文摘目的：研究胆固醇调节元件结合蛋白2基因（sterol regulatory element binding protein 2 gene，SREBP2） rs2228314多态性与儿童青少年肥胖和血脂水平的关系。方法：研究对象来自前期工作中收集的两批样本，共2030名7岁至18岁中小学生，对这些学生进行身体测量和血清总胆固醇（total cholesterol，TC）、三酰甘油（triacylgly-ceride，TG）、高密度脂蛋白胆固醇（low density lipoprotein-cholesterol，HDL-C）、低密度脂蛋白胆固醇（low density lipo-protein-cholesterol ，LDL-C）的检测。采用基质支持的激光释放/电离飞行时间质谱分析检测rs2228314多态性基因型。在显性模型下进行统计学分析，采用t检验比较不同基因型组间血脂水平（计量资料）的差异，采用Logistic回归分析rs2228314多态性与血脂水平的异常（分类资料）和肥胖的关系。结果：rs2228314多态性GC/CC基因型组的HDL-C水平低于GG纯合子，差异有统计学意义（0．10＆#177;0．35 vs．0．14＆#177;0．36，P＝0．020），在显性模型下，调整研究样本、性别和年龄后，rs2228314多态性与 HDL-C 水平的异常相关（ OR ＝1．400，95％ CI：1．027～1．907， P ＝0．033）。调整研究样本、性别、年龄和HDL-C 水平后，rs2228314多态性与肥胖的相关性无统计学意义（OR ＝1．178，95％CI：0．971～1．430， P＝0．096）。结论：携带SREBP2基因rs2228314多态性GC/CC基因型的儿童青少年发生HDL-C水平异常的风险高于GG基因型携带者。
