Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes
Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes
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DOI：
10.3858/emm.2008.40.4.407
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发表时间：
2008-08-31
影响因子：
12.8
通讯作者：
Jeong, Tae-Sook
中科院分区：
文献类型：
--
作者：
An, Sojin;Jang, Young-Soon;Jeong, Tae-Sook
我们研究了酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制诱导的自发性胆固醇流出的机制，以及巨噬细胞中胆固醇代谢的改变如何影响HepG 2细胞中的胆固醇代谢。油酸酰苯胺（OAA），一种已知的ACAT抑制剂，通过促进胆固醇催化剂和抑制胆固醇酯积累，在乙酰化低密度脂蛋白负载的THP-1巨噬细胞中显著降低脂质储存，而不进一步增加细胞毒性。对表达的mRNA和蛋白质的分析表明，胆固醇7 α-羟化酶（CYP 7A 1）、氧固醇7 α-羟化酶（CYP 7 B1）和胆固醇27-羟化酶（CYP 27）受到ACAT抑制的高度诱导。通过定量细胞单层和细胞外培养基中的胆汁胆固醇质量证实了功能性细胞色素P450途径的存在。值得注意的是，在HepG 2细胞中，巨噬细胞大量分泌的胆汁胆固醇以法尼醇X受体（FXR）依赖的方式抑制CYP 7蛋白的表达。本研究结果为胆固醇自发外排机制提供了新的见解，并提示ACAT抑制剂可能通过胆汁胆固醇（BC）诱导的FXR，刺激病变-巨噬细胞中的胆固醇分解代谢（细胞色素P450）途径，而抑制肝细胞中的胆固醇分解代谢（细胞色素P450）途径。
We investigated the mechanism of spontaneous cholesterol efflux induced by acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition, and how an alteration of cholesterol metabolism in macrophages impacts on that in HepG2 cells. Oleic acid anilide (OAA), a known ACAT inhibitor reduced lipid storage substantially by promotion of cholesterol catabolism and repression of cholesteryl ester accumulation without further increase of cytotoxicity in acetylated low-density lipoprotein-loaded THP-1 macrophages. Analysis of expressed mRNA and protein revealed that cholesterol 7 alpha-hydroxylase (CYP7A1), oxysterol 7 alpha-hydroxylase (CYP7B1), and cholesterol 27-hydroxylase (CYP27) were highly induced by ACAT inhibition. The presence of a functional cytochrome P450 pathway was confirmed by quantification of the biliary cholesterol mass in cell monolayers and extracelluar medium. Notably, massively secreted biliary cholesterol from macrophages suppressed the expression of CYP7 proteins in a farnesoid X receptor (FXR)-dependent manner in HepG2 cells. The findings reported here provide new insight into mechanisms of spontaneous cholesterol efflux, and suggest that ACAT inhibition may stimulate cholesterol-catabolic (cytochrome P450) pathway in lesion-macrophages, in contrast, suppress it in hepatocyte via FXR induced by biliary cholesterol (BC).