Regulation of bile acid synthesis. III. Correlation between biliary bile salt hydrophobicity index and the activities of enzymes regulating cholesterol and bile acid synthesis in the rat.
Regulation of bile acid synthesis. III. Correlation between biliary bile salt hydrophobicity index and the activities of enzymes regulating cholesterol and bile acid synthesis in the rat.
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发表时间：
1989-08
影响因子：
6.5
通讯作者：
D. Heuman;P. Hylemon;Z. Vlahcevic
中科院分区：
文献类型：
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作者：
D. Heuman;P. Hylemon;Z. Vlahcevic
肝脏胆汁酸的合成被认为受到肠-肝循环中胆盐的负反馈控制，作用于胆固醇7α-羟基酶(C7αH)的水平，这是胆汁酸生物合成途径中的初始和限速步骤。胆盐还抑制胆固醇合成限速酶3-羟基-3-甲基戊二酰辅酶A还原酶(HMG-CoA-R)的活性。人们对这些监管效应的机制知之甚少，其中一种或两种都可能是间接的。先前的数据表明，胆盐的亲水-疏水平衡是其胆固醇溶解性能的主要决定因素，也决定了它们作为胆汁酸和胆固醇合成调节剂的效力。为了进一步评估胆汁酸的理化性质和调节性质之间的关系，我们改变了大鼠胆盐池的组成，通过喂食七种不同胆汁酸中的一种或多种(1%w/w连续14天)。然后，我们测定了胆汁中胆盐的平均亲水-疏水平衡(疏水指数)，并将其与C7αH和HMG-CoA-R，以及调节胆固醇酯化的第三种肝微粒体酶--酰基-CoA：胆固醇酰基转移酶(ACAT)的比活性进行了关联。在胆汁酸喂养后的所有情况下，喂食的胆汁酸的结合物(S)成为胆汁中的主要胆盐。胆盐疏水性指数与C7αH活性和HMG-CoA-R活性呈极显著负相关(P<0.0001)。相比之下，ACAT活性与胆汁盐的疏水性指数之间没有明显的相关性。HMG-CoA-R活性与C7αH的相关性也非常显著(r=0.81；P<0.0001)。ACAT与HMG-CoA-R或C7αH均无显著相关性。因此，循环胆盐作为调节胆汁酸和胆固醇合成的酶的抑制物的效力随着疏水性的增加而增加。胆盐池的疏水-亲水平衡可能在胆固醇和胆汁酸合成的调节中起重要作用。
Hepatic bile acid synthesis is thought to be under negative feedback control by bile salts in the enterohepatic circulation, acting at the level of cholesterol 7 alpha-hydroxylase (C7 alpha H), the initial and rate-limiting step in the bile acid biosynthetic pathway. Bile salts also suppress the activity of the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R). The mechanisms of these regulatory effects are poorly understood, and one or both may be indirect. Previous data suggest that the hydrophilic-hydrophobic balance of bile salts, a major determinant of their cholesterol solubilizing properties, also determines their potency as regulators of bile acid and cholesterol synthesis. To further evaluate the relationship between the physicochemical and regulatory properties of bile acids, we altered the composition of the bile salt pool of rats by feeding one or more of seven different bile acids (1% w/w for 14 days). We then determined the mean hydrophilic-hydrophobic balance (hydrophobicity index) of the bile salts in bile, and correlated this with the specific activities of C7 alpha H and HMG-CoA-R, and of acyl-CoA:cholesterol acyltransferase (ACAT), a third hepatic microsomal enzyme which regulates cholesterol esterification. In all instances following bile acid feeding, conjugates of the fed bile acid(s) became the predominant bile salts in bile. Highly significant negative linear correlations (each P less than 0.0001) were found between the hydrophobicity indices of biliary bile salts and the activities of C7 alpha H (r = 0.79) or HMG-CoA-R (r = 0.63). By contrast, no significant correlation could be demonstrated between ACAT activity and the hydrophobicity index of biliary bile salts. The correlation between activities of HMG-CoA-R and C7 alpha H was also highly significant (r = 0.81; P less than 0.0001). No significant correlation existed between ACAT and either HMG-CoA-R or C7 alpha H. Microsomal free cholesterol was not consistently altered by bile acid feeding. Thus, the potency of circulating bile salts as suppressors of the enzymes regulating bile acid and cholesterol synthesis increases with increasing hydrophobicity. The hydrophobic-hydrophilic balance of the bile salt pool may play an important role in the regulation of cholesterol and bile acid synthesis.