Heuman D M, Hylemon P B, Vlahcevic Z R
McGuire VA Medical Center, Richmond, VA.
J Lipid Res. 1989 Aug;30(8):1161-71.
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.
肝胆汁酸合成被认为受肠肝循环中胆盐的负反馈控制，作用于胆固醇7α-羟化酶（C7αH）水平，这是胆汁酸生物合成途径中的起始和限速步骤。胆盐还抑制胆固醇合成的限速酶3-羟基-3-甲基戊二酰辅酶A还原酶（HMG-CoA-R）的活性。这些调节作用的机制尚不清楚，可能其中之一或两者都是间接的。先前的数据表明，胆盐的亲水-疏水平衡是其胆固醇溶解特性的主要决定因素，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物理化学性质与调节特性之间的关系，我们通过给大鼠喂食七种不同胆汁酸中的一种或多种（1% w/w，持续14天）来改变胆盐池的组成。然后我们测定了胆汁中胆盐的平均亲水-疏水平衡（疏水性指数），并将其与C7αH、HMG-CoA-R以及酰基辅酶A：胆固醇酰基转移酶（ACAT）的比活性相关联，ACAT是第三种调节胆固醇酯化的肝微粒体酶。在喂食胆汁酸后的所有情况下，喂食的胆汁酸的共轭物成为胆汁中主要的胆盐。在胆汁胆盐的疏水性指数与C7αH（r = 0.79）或HMG-CoA-R（r = 0.63）的活性之间发现了高度显著的负线性相关性（每个P均小于0.0001）。相比之下，ACAT活性与胆汁胆盐的疏水性指数之间未显示出显著相关性。HMG-CoA-R和C7αH的活性之间的相关性也非常显著（r = 0.81；P小于0.0001）。ACAT与HMG-CoA-R或C7αH之间均不存在显著相关性。胆汁酸喂食并未持续改变微粒体游离胆固醇。因此，循环胆盐作为胆汁酸和胆固醇合成调节酶抑制剂的效力随着疏水性的增加而增强。胆盐池的亲水-疏水平衡可能在胆固醇和胆汁酸合成的调节中起重要作用。
