Shoda J, He B F, Tanaka N, Matsuzaki Y, Osuga T, Yamamori S, Miyazaki H, Sjövall J
Department of Gastroenterology, University of Tsukuba, Ibaraki, Japan.
Hepatology. 1995 May;21(5):1291-302.
A total of 100 nonobese and normolipidemic subjects (29 control subjects, 49 patients with cholesterol stones [CSs], and 22 patients with brown pigment stones) were studied to elucidate the pathogenetic contributions of deoxycholate (DC) to supersaturated bile formation with special reference to de novo syntheses of cholesterol and bile acids in the liver. A higher proportion of DC was observed in gallbladder bile from patients with CSs (CSs; 21.7 +/- 1.4%, mean +/- SEM, vs. control subjects; 10.2 +/- 0.9%). Cholesterol saturation in bile was elevated parallel to the increase of DC (r = .48; P = .0002), irrespective of the existence of stones. In a comparison between the 52 subjects with increased DC in bile (> 10% of biliary bile acids) and the 20 subjects without the increase (< 10%), the molar percentage of cholesterol in bile was significantly higher in the former (9.4 +/- 0.5%) than in the latter (6.7 +/- 0.4%) (P < .001). Consistent with the decrease in steady-state level of low-density lipoprotein (LDL) receptor-messenger RNA (mRNA), the catalytic activity and mRNA level of microsomal hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for de novo cholesterol synthesis, were significantly lower in the former (2.9 +/- 0.3 pmol/min/mg protein) than in the latter (5.1 +/- 0.6) (P < .0001). Biliary molar percentage of bile acids was significantly lower in the former (69.8 +/- 1.1%) than in the latter (75.2 +/- 1.5%) (P < .01). However, contrary to expectations, the catalytic activity and mRNA level of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme for bile acid synthesis, were significantly higher in the former (5.8 +/- 0.4 pmol/min/mg protein) than in the latter (3.7 +/- 0.6) (P < .01). The magnitude of the impaired gallbladder emptying (control subjects; 78.4 +/- 4% vs. CSs; 58 +/- 3%; P < .0005) together with the prolonged small intestinal transit (control subjects; 126 +/- 9 minutes vs. CSs; 198 +/- 9 minutes; P < .01) correlated significantly with the increased percentage of DC in bile. It is concluded that in cholesterol gallstone disease an increase of DC in bile, linked to an impaired gallbladder emptying together with a prolonged small intestinal transit, may play a significant role in downregulating de novo cholesterol synthesis but not bile acid synthesis in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)
共对100名非肥胖且血脂正常的受试者（29名对照受试者、49名胆固醇结石（CS）患者和22名棕色色素结石患者）进行了研究，以阐明脱氧胆酸盐（DC）对胆汁过饱和形成的致病作用，特别参考肝脏中胆固醇和胆汁酸的从头合成。在CS患者的胆囊胆汁中观察到较高比例的DC（CS患者；21.7±1.4%，平均值±标准误，对照受试者为10.2±0.9%）。无论是否存在结石，胆汁中的胆固醇饱和度均随DC的增加而升高（r = 0.48；P = 0.0002）。在胆汁中DC增加的52名受试者（>胆汁酸的10%）与DC未增加的20名受试者（<10%）之间的比较中，前者胆汁中胆固醇的摩尔百分比（9.4±0.5%）显著高于后者（6.7±0.4%）（P < 0.001）。与低密度脂蛋白（LDL）受体信使核糖核酸（mRNA）稳态水平降低一致，肝脏微粒体3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶（胆固醇从头合成的限速酶）的催化活性和mRNA水平，前者（2.9±0.3 pmol/min/mg蛋白质）显著低于后者（5.1±0.6）（P < 0.0001）。前者胆汁酸的胆汁摩尔百分比（69.8±1.1%）显著低于后者（75.2±1.5%）（P < 0.01）。然而，与预期相反，胆汁酸合成的限速酶胆固醇7α-羟化酶的催化活性和mRNA水平，前者（5.8±0.4 pmol/min/mg蛋白质）显著高于后者（3.7±0.6）（P < 0.01）。胆囊排空受损的程度（对照受试者；78.4±4% vs. CS患者；58±3%；P < 0.0005）以及小肠转运时间延长（对照受试者；126±9分钟 vs. CS患者；198±9分钟；P < 0.01）与胆汁中DC百分比的增加显著相关。得出的结论是，在胆固醇结石病中，胆汁中DC的增加与胆囊排空受损以及小肠转运时间延长有关，可能在下调肝脏中胆固醇的从头合成而非胆汁酸合成方面发挥重要作用。（摘要截断于400字）
