Vlahcevic Z R, Jairath S K, Heuman D M, Stravitz R T, Hylemon P B, Avadhani N G, Pandak W M
Section of Gastroenterology, McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA.
Am J Physiol. 1996 Apr;270(4 Pt 1):G646-52. doi: 10.1152/ajpgi.1996.270.4.G646.
The study objective was to determine whether and to what extent sterol 27-hydroxylase, the initial step in the "acidic" pathway of bile acid biosynthesis, is regulated by bile acids. Rats were fed diets supplemented with cholestyramine (CT, 5%), cholate (CA, 1%), chenodeoxycholate (CDCA, 1%), or deoxycholate (DCA, 0.25%). When compared with paired controls, sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase specific activities increased after CT administration by 188 +/- 20% (P < 0.05) and 415 +/- 36% (P < 0.01), respectively. Similarly, mRNA levels increased by 159 +/- 14% (P < 0.05) and 311 +/- 106% (P < 0.05), respectively. Feeding CA, CDCA, or DCA decreased sterol 27-hydroxylase specific activity to 57 +/- 6, 61 +/- 8, and 74 +/- 8% of controls, respectively (P < 0.05). By comparison, the specific activity of cholesterol 7 alpha-hydroxylase decreased to 46 +/- 7 , 32 +/- 10, and 26 +/- 8% (P = 0.001). mRNA levels and transcriptional activities for sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase transcriptional activity were changed to the same extent as the specific activities after CT or bile acid feeding. We conclude that sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase are subject to negative feedback regulation by hydrophobic bile acids at the level of transcription. However, the responses of sterol 27-hydroxylase to manipulation of the bile acid pool are less prominent than those of cholesterol 7 alpha-hydroxylase. During the diurnal cycle the specific activities of sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase changed in tandem, suggesting that both may be under control of glucocorticoids.
本研究的目的是确定胆汁酸生物合成“酸性”途径的起始步骤——甾醇27-羟化酶是否受胆汁酸调节以及受调节的程度。给大鼠喂食补充了消胆胺（CT，5%）、胆酸盐（CA，1%）、鹅去氧胆酸盐（CDCA，1%）或脱氧胆酸盐（DCA，0.25%）的饲料。与配对对照组相比，给予CT后，甾醇27-羟化酶和胆固醇7α-羟化酶的比活性分别增加了188±20%（P<0.05）和415±36%（P<0.01）。同样，mRNA水平分别增加了159±14%（P<0.05）和311±106%（P<0.05）。喂食CA、CDCA或DCA分别使甾醇27-羟化酶的比活性降至对照组的57±6%、61±8%和74±8%（P<0.05）。相比之下，胆固醇7α-羟化酶的比活性降至46±7%、32±10%和26±8%（P = 0.001）。喂食CT或胆汁酸后，甾醇27-羟化酶和胆固醇7α-羟化酶的mRNA水平及转录活性的变化程度与比活性相同。我们得出结论，甾醇27-羟化酶和胆固醇7α-羟化酶在转录水平上受到疏水性胆汁酸的负反馈调节。然而，甾醇27-羟化酶对胆汁酸池变化的反应不如胆固醇7α-羟化酶明显。在昼夜循环中，甾醇27-羟化酶和胆固醇7α-羟化酶的比活性同步变化，表明两者可能都受糖皮质激素的控制。
