Björkhem Ingemar, Araya Zufan, Rudling Mats, Angelin Bo, Einarsson Curt, Wikvall Kjell
Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Box 578, S-751 23 Uppsala, Sweden.
J Biol Chem. 2002 Jul 26;277(30):26804-7. doi: 10.1074/jbc.M202343200. Epub 2002 May 13.
It has been reported that there is a coordinate regulation of sterol 27-hydroxylase (CYP27A1) and cholesterol 7alpha-hydroxylase (CYP7A1) in rats. Thus, the levels of the mRNA corresponding to these two enzymes were found to change in the same direction in rat liver and in isolated rat hepatocytes. In contrast, other groups have not seen such regulation of CYP27A1 in rabbit liver or in rat liver when using an activity assay. In the present work, the effect of bile acid treatment on human CYP27A1/luciferase reporter activity was studied in a transient transfection assay in human liver-derived HepG2 cells. Neither the endogenous 27-hydroxylase activity nor the CYP27A1/luciferase reporter activity were down-regulated by treatment of HepG2 cells with chenodeoxycholic acid or taurochenodeoxycholic acid. We also measured CYP27A1 mRNA and CYP7A1 mRNA in liver of humans subjected to treatment with chenodeoxycholic acid, ursodeoxycholic acid, hydroxymethylglutaryl (HMG)-CoA reductase inhibitor and a combination of HMG-CoA reductase inhibitor and cholestyramine. There was a 60-fold variation in the levels of CYP7A1 mRNA but only a 5-fold variation in the levels of CYP27A1 mRNA. There was no correlation between the two mRNA species. It is concluded that, in humans, there is little or no coordinate regulation of CYP7A1 and CYP27A1 at the transcriptional level, and that CYP27A1 is not subject to a negative feedback control by bile acids. The results underline that marked species differences may exist in mechanisms for control of synthesis of bile acids and cholesterol homeostasis.
据报道，大鼠体内存在固醇27 - 羟化酶（CYP27A1）和胆固醇7α - 羟化酶（CYP7A1）的协同调节。因此，在大鼠肝脏和分离的大鼠肝细胞中，发现这两种酶对应的mRNA水平呈相同方向变化。相比之下，其他研究小组在使用活性测定法时，未在兔肝脏或大鼠肝脏中观察到CYP27A1的这种调节。在本研究中，在人源化HepG2细胞的瞬时转染试验中，研究了胆汁酸处理对人CYP27A1/荧光素酶报告基因活性的影响。用鹅去氧胆酸或牛磺鹅去氧胆酸处理HepG2细胞，内源性27 - 羟化酶活性和CYP27A1/荧光素酶报告基因活性均未被下调。我们还测量了接受鹅去氧胆酸、熊去氧胆酸、羟甲基戊二酰（HMG）-辅酶A还原酶抑制剂以及HMG - 辅酶A还原酶抑制剂与消胆胺联合治疗的人的肝脏中CYP27A1 mRNA和CYP7A1 mRNA的水平。CYP7A1 mRNA水平有60倍的变化，但CYP27A1 mRNA水平只有5倍的变化。这两种mRNA之间没有相关性。得出的结论是，在人类中，CYP7A1和CYP27A1在转录水平上几乎没有或不存在协同调节，并且CYP27A1不受胆汁酸的负反馈控制。结果强调，在胆汁酸合成控制和胆固醇稳态机制中可能存在明显的物种差异。
