Li Tiangang, Chen Wenling, Chiang John Y L
Department of Microbiology, Immunology, and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
J Lipid Res. 2007 Feb;48(2):373-84. doi: 10.1194/jlr.M600282-JLR200. Epub 2006 Nov 6.
Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27-hydroxylation of cholesterol in most tissues. Recent studies suggest that 27-hydroxycholesterol (27-HOC) activates liver orphan receptor alpha (LXRalpha) and induces the cholesterol efflux transporters ABCA1 and ABCG1 in macrophages. The steroid- and bile acid-activated pregnane X receptor (PXR) plays critical roles in the detoxification of bile acids, cholesterol metabolites, and xenobiotics. The role of CYP27A1 in the intestine is not known. This study investigated PXR and CYP27A1 regulation of cholesterol metabolism in the human intestinal cell lines Caco2 and Ls174T. A human PXR ligand, rifampicin, induced CYP27A1 mRNA expression in intestine cells but not in liver cells. Rifampicin induced CYP27A1 gene transcription, increased intracellular 27-HOC levels, and induced ABCA1 and ABCG1 mRNA expression only in intestine cells. A functional PXR binding site was identified in the human CYP27A1 gene. Chromatin immunoprecipitation assays revealed that rifampicin induced the PXR recruitment of steroid receptor coactivator 1 to CYP27A1 chromatin. Cholesterol loading markedly increased intracellular 27-HOC levels in intestine cells. Rifampicin, 27-HOC, and a potent LXRalpha agonist, T0901317, induced ABCA1 and ABCG1 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL. This study suggests an intestine-specific PXR/CYP27A1/LXRalpha pathway that regulates intestine cholesterol efflux and HDL assembly.
线粒体固醇27-羟化酶（CYP27A1）催化肝脏胆汁酸生物合成途径中固醇侧链的氧化裂解以及大多数组织中胆固醇的27-羟化。最近的研究表明，27-羟胆固醇（27-HOC）可激活肝脏孤儿受体α（LXRα）并诱导巨噬细胞中胆固醇流出转运蛋白ABCA1和ABCG1。类固醇和胆汁酸激活的孕烷X受体（PXR）在胆汁酸、胆固醇代谢产物和外源性物质的解毒中起关键作用。CYP27A1在肠道中的作用尚不清楚。本研究调查了人肠道细胞系Caco2和Ls174T中PXR和CYP27A1对胆固醇代谢的调节作用。人PXR配体利福平可诱导肠道细胞而非肝细胞中CYP27A1 mRNA表达。利福平诱导CYP27A1基因转录，增加细胞内27-HOC水平，并且仅在肠道细胞中诱导ABCA1和ABCG1 mRNA表达。在人CYP27A1基因中鉴定出一个功能性PXR结合位点。染色质免疫沉淀试验表明，利福平诱导类固醇受体辅激活因子1被招募至CYP27A1染色质上的PXR。胆固醇负载显著增加肠道细胞内27-HOC水平。利福平、27-HOC以及一种强效LXRα激动剂T0901317可诱导ABCA1和ABCG1蛋白表达，并刺激胆固醇从肠道细胞流出至载脂蛋白A-I和高密度脂蛋白。本研究提示了一条调节肠道胆固醇流出和高密度脂蛋白组装的肠道特异性PXR/CYP27A1/LXRα途径。
