孤儿核受体小异二聚体伴侣在胆汁酸及糖脂代谢中的作用研究进展

Roles of Orphan Nuclear Receptor Small Heterodimer Partner in Bile Acid, Glucose and Lipid Metabolism

小异二聚体伴侣(small heterodimer partner,SHP)是一种转录抑制因子,可与多种核受体及转录因子相互作用形成复杂的调节网络,参与包括胆汁酸、胆固醇、甘油三酯及葡萄糖等在内的多条代谢通路。SHP在肝脏、脂肪和胰腺等组织中均有表达。在肝脏中,SHP可通过影响一系列与胆固醇降解、胆汁酸生成、葡萄糖异生以及脂肪生成等相关的基因表达调控肝脏代谢途径,持续表达SHP可造成胆汁酸池耗竭和肝脏甘油三酯水平的积聚,而敲除SHP则会抑制脂肪肝的发展。在脂肪组织中,过表达SHP会加重葡萄糖耐受不良和高脂饮食诱导的肥胖。在胰腺内,调节SHP的表达则可能影响葡萄糖刺激的胰岛素分泌以及内质网应激引起的β细胞功能障碍。此外,SHP遗传突变与肥胖相关,并可能增加部分人群对2型糖尿病的易感性。本文将重点讨论SHP调控胆汁酸及糖脂代谢的机制,并总结SHP的主要生理功能及其在2型糖尿病发生发展中的作用。

Small heterodimer partner(SHP)is a transcriptional inhibitor of gene expression that interacts with a wide variety of nuclear receptors and transcription factors and involves in multiple metabolic pathways,including bile acid,glucose and lipid metabolism.SHP is predominately expressed in the gallbladder and liver,and at lower levels in the adipose tissue and pancreas.In the liver,SHP is known to perform several metabolic functions.It regulates hepatic metabolism by modulating the expression of a series of genes related to cholesterol degradation,bile acid synthesis,gluconeogenesis and adipogenesis.Overexpression of SHP in the liver leads to depletion of hepatic bile acid pool and concomitant accumulation of triglycerides.SHP deletion in the liver of mice prevents the development of fatty liver.In adipose tissue,SHP overexpression predominantly increases glucose intolerance and exacerbates high-fat diet-induced obesity.In the pancreas,regulating the expression of SHP may affect glucose-stimulated insulin secretion andβ-cell dysfunction caused by endoplasmic reticulum stress.In addition,the mutation of SHP is associated with obesity and most likely to increase the susceptibility to type 2 diabetes in a particular population.Herein,the mechanism of SHP regulating bile acid,glucose and lipid metabolism is focused,and recent findings are summarized to demonstrate the main physiological functions of SHP and its role in the development of type 2 diabetes.