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Abstract：
The scavenger receptor class B type 1 (SR-B1), a high-density lipoprotein (HDL) receptor, is a membrane glycoprotein that mediates selective uptake of HDL-cholesterol and cholesterol ester (CE) into cells. SR-B1 is subject to posttranslational regulation; however, the underlying mechanisms still remain obscure. Here, we identified a novel SR-B1-interacting protein, GIPC1 (GAIP-interacting protein, C terminus 1) that interacts with SR-B1 and stabilizes SR-B1 by negative regulation of its proteasomal and lysosomal degradation pathways. The physiological interaction between SR-B1 and GIPC1 was supported by co-immunoprecipitation of wild-type and mutant GIPC1 constructs in SR-B1 ± GIPC1 overexpressing cells, in native liver cells, and in mouse liver tissues. Overexpression of GIPC1 increased endogenous SR-B1 protein levels, subsequently increasing selective HDL-cholesterol/CE uptake and cellular triglyceride (TG) and total cholesterol (TC) levels, whereas silencing of GIPC1 in the mouse liver was associated with blunted hepatic SR-B1 levels, elevated plasma TG and TC, and attenuated hepatic TG and TC content. A positive correlation was identified between GIPC1 and SR-B1 expression, and both expressions of GIPC1 and SR-B1 from human liver samples were inversely correlated with body mass index (BMI) from human subjects. We therefore conclude that GIPC1 plays a key role in the stability and function of SR-B1 and can also effectively regulate hepatic lipid and cholesterol metabolism. These findings expand our knowledge of the regulatory roles of GIPC1 and suggest that GIPC1 exerts a major effect on cell surface receptors such as SR-B1 and its associated hepatic lipid and cholesterol metabolic processes.
摘要：
B类清道夫受体1型（SR-B1），高密度脂蛋白（HDL）受体，是介导HDL-胆固醇和胆固醇酯(CE)选择性摄取到细胞中的膜糖蛋白。SR-B1受翻译后调节；然而，潜在的机制仍然模糊。这里,我们鉴定了一种新的SR-B1相互作用蛋白，GIPC1(GAIP相互作用蛋白，C末端1）与SR-B1相互作用并通过负调节其蛋白酶体和溶酶体降解途径来稳定SR-B1。SR-B1和GIPC1之间的生理相互作用通过在SR-B1±GIPC1过表达细胞中野生型和突变型GIPC1构建体的免疫共沉淀来支持，在天然肝细胞中，和小鼠肝脏组织。GIPC1的过表达增加了内源性SR-B1蛋白水平，随后增加选择性HDL-胆固醇/CE摄取和细胞甘油三酯（TG）和总胆固醇（TC）水平，而小鼠肝脏中GIPC1的沉默与肝脏SR-B1水平钝化有关，血浆TG和TC升高，并降低肝脏TG和TC含量。GIPC1和SR-B1表达呈正相关,人类肝脏样本中GIPC1和SR-B1的表达与人类受试者的体重指数（BMI）呈负相关。因此，我们得出结论，GIPC1在SR-B1的稳定性和功能中起关键作用，并且还可以有效调节肝脏脂质和胆固醇代谢。这些发现扩大了我们对GIPC1的调节作用的认识，并表明GIPC1对SR-B1及其相关的肝脏脂质和胆固醇代谢过程等细胞表面受体发挥主要作用。
