Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol 7α-hydroxylase activities in the rat, guinea pig, and rabbit:: Effects of cholesterol and bile acids
Comparative regulation of hepatic sterol 27-hydroxylase and cholesterol 7α-hydroxylase activities in the rat, guinea pig, and rabbit:: Effects of cholesterol and bile acids
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DOI：
10.1016/s0026-0495(99)90243-3
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发表时间：
1999-12-01
影响因子：
9.8
通讯作者：
Salen, G
中科院分区：
文献类型：
--
作者：
Nguyen, LB;Xu, GR;Salen, G
在大鼠、豚鼠和兔的胆汁酸消耗和替代以及胆固醇喂养实验中，检查了关键肝酶活性（分别为微粒体胆固醇7 α-羟化酶和线粒体甾醇27-羟化酶）对经典和替代胆汁酸合成途径的调节。通过建立胆汁瘘（BF）并收集胆汁2 - 5天来耗尽胆汁酸池，并以与胆汁酸的肝流量测量值相当的速率通过十二指肠内输注主要胆汁酸（分别在大鼠、豚鼠和家兔中为牛磺胆酸[TCA]、甘氨鹅去氧胆酸[GCDCA]和甘氨胆酸[GCA]）来替代。为了研究胆固醇的影响，动物被喂食7天的基础饮食有和没有2%的胆固醇。胆固醇7 α-羟化酶和甾醇27-羟化酶的活性，通过同位素掺入试验测定，与胆汁酸输出和组成和肝胆固醇浓度有关。十二指肠内输注胆汁酸增加了测试胆汁酸的输出，但没有显着改变肝胆固醇浓度，对甾醇27-羟化酶活性没有影响。当测试三种不同的底物（胆固醇、5 β-胆甾烷-3 α，7 α-二醇和5 β-胆甾烷-3 α，7 α，12 α-三醇）时，胆汁酸消耗或替代均不影响甾醇27-羟化酶活性。相比之下，喂食2%胆固醇分别使大鼠、豚鼠和兔的肝脏胆固醇浓度增加3倍、2倍和8倍，并在所有三种动物模型中增加肝脏线粒体固醇α; l-羟化酶活性（胆固醇转化为27-羟基胆固醇）。在所有三种动物模型中均观察到胆汁酸消耗和替代对胆固醇7 α-羟化酶活性的刺激和反馈抑制，而胆固醇喂养的影响具有种属依赖性（大鼠中胆固醇7 α-羟化酶活性增加，豚鼠中胆固醇7 α-羟化酶活性无变化，家兔中胆固醇7 α-羟化酶活性受到抑制）。因此，与胆固醇27-羟化酶相反，胆固醇27-羟化酶在所有三种动物模型中均受胆固醇上调，但不受胆汁酸消耗和替代的影响，胆固醇7 α-羟化酶活性始终受胆汁酸肝流量的反向控制，但对2%胆固醇喂养1周的反应具有种属依赖性。版权所有（C）1999 W.B.桑德斯公司
The regulation of the classic and alternative bile acid synthetic pathways by key hepatic enzyme activities (microsomal cholesterol 7 alpha-hydroxylase and mitochondrial sterol 27-hydroxylase, respectively) was examined in bile acid depletion and replacement and cholesterol-feeding experiments with rats, guinea pigs, and rabbits. The bile acid pool was depleted by creating a bile fistula (BF) and collecting bile for 2 to 5 days, and it was replaced by intraduodenal infusion of the major biliary bile acids (taurocholic acid [TCA], glycochenodeoxycholic acid [GCDCA], and glycocholic acid [GCA] in the rat, guinea pig, and rabbit, respectively) at rates equivalent to the measured hepatic flux of the bile acids. To study the effects of cholesterol, the animals were fed for 7 days on a basal diet with and without 2% cholesterol. Cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase activities, measured by isotope incorporation assays, were related to bile acid output and composition and hepatic cholesterol concentrations Intraduodenal infusion of bile acids increased the output of the tested bile acids, but did not significantly change hepatic cholesterol concentrations and had no effect on sterol 27-hydroxylase activity. Neither bile acid depletion nor replacement affected sterol 27-hydroxylase activity when three different substrates (cholesterol, 5 beta-cholestane-3 alpha,7 alpha-diol, and 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol) were tested. In contrast, feeding 2% cholesterol increased hepatic cholesterol concentrations in rats, guinea pigs, and rabbits threefold, twofold, and eightfold, respectively, and increased hepatic mitochondrial sterol a;l-hydroxylase activity (conversion of cholesterol to 27-hydroxycholesterol) in all three animal models. The stimulation and feedback inhibition of cholesterol 7 alpha-hydroxylase activity by bile acid depletion and replacement were observed in all three animal models, whereas the effect of cholesterol feeding was species-dependent (cholesterol 7 alpha-hydroxylase activity increased in the rat, did not change in the guinea pig, and was inhibited in the rabbit). Thus, in contrast to sterol 27-hydroxylase, which was upregulated by cholesterol but not affected by bile acid depletion and replacement in all three animal models, cholesterol 7 alpha-hydroxylase activity was controlled consistently and inversely by the hepatic flux of bile acids, but was species-dependent in its response to a 1-week feeding with 2% cholesterol. Copyright(C) 1999 by W.B. Saunders Company.