Insulin-like growth factor-i regulation of hepatic scavenger receptor class BI
Insulin-like growth factor-i regulation of hepatic scavenger receptor class BI
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DOI：
10.1210/en.2004-0330
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发表时间：
2004-12-01
期刊：
影响因子：
4.8
通讯作者：
Ishida, T
中科院分区：
文献类型：
--
作者：
Cao, WM;Murao, K;Ishida, T
高密度脂蛋白调节一种称为胆固醇反向运输的正常生理过程。这一过程使得胆固醇能够从外周组织转移到肝脏，进行进一步的新陈代谢，最终以胆汁的形式分泌。B类清道夫受体(SR-BI)、人类SR-BI同源物以及CD36和LIMPII类似物-1(CLA-1)是同一受体的不同名称，该受体促进肝细胞从高密度脂蛋白中摄取胆固醇。该受体在胆固醇和胆盐的肠-肝循环中起着关键作用，这是我们研究肝脏SR-BI基因对IGF-I作用的调控的基础。我们的研究结果表明，GH或IGF-I可抑制培养的HepG2细胞内源性SR-BI/CLA-1的表达。这一观察扩展到了持续注入IGF-I的大鼠的整个动物模型。IGF-I降低SR-BI启动子的转录活性。然而，IGF-I对SR-BI/CLA-1启动子活性的抑制作用可被磷脂酰肌醇3-激酶(PI3-K)的特异性抑制剂Wortmannin所阻断。Hep G2细胞暴露于IGF-I可引起Akt的快速磷酸化。我们还证明了PI3-K亚单位p110和Akt的结构性活性形式都抑制了人SR-BI/CLA-1启动子的活性。此外，Akt的显性负性突变取消了IGF-I抑制SR-BI/CLA-1启动子活性的能力。综上所述，PI3-K/Akt通路参与IGF-I抑制SR-BI/CLA-1的表达，提示Akt的激活在肝脏胆固醇代谢中起重要作用。
High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. This process enables the transfer of cholesterol from peripheral tissues to the liver for further metabolism and eventual secretion in the form of bile. The scavenger receptor of the B class (SR-BI), human homolog of SR-BI, and CD36 and LIMPII analogous-1 (CLA-1) are different names for the same receptor that facilitates hepatocellular uptake of cholesterol from high-density lipoprotein. The pivotal role of this receptor in enterohepatic circulation of cholesterol and bile salts underlies our interest to study the regulation of hepatic SR-BI gene in response to the actions of IGF-I. The results of our studies showed that endogenous expression of SR-BI/CLA-1 was suppressed by exposure to GH or IGF-I in cultured HepG2 cells. This observation extended to a whole animal model of rats continuously infused with IGF-I. IGF-I decreased transcriptional activity of the SR-BI promoter. However, the inhibitory effect of IGF-I on SR-BI/CLA-1 promoter activity was abrogated by wortmannin, a specific inhibitor of phosphoinositide 3-kinase (PI3-K). Exposure of HepG2 cells to IGF-I elicited a rapid phosphorylation of Akt. We also demonstrated that the constitutively active form of both p110, a subunit of PI3-K, and Akt inhibited activity of the human SR-BI/CLA-1 promoter. Furthermore, the dominant-negative mutant of Akt abolished the ability of IGF-I to suppress activity of the SR-BI/CLA-1 promoter. In conclusion, PI3-K/Akt pathways participate in IGF-I-suppression of SR-BI/CLA-1 expression, which suggests that the activation of Akt plays an important role in cholesterol metabolism in liver.