Heuman D M, Vlahcevic Z R, Pandak W M, Hylemon P B, Kim Y S, Lillienau J, Hofmann A F
Department of Medicine, Medical College of Virginia, Richmond.
Gastroenterology. 1992 Nov;103(5):1641-8. doi: 10.1016/0016-5085(92)91190-f.
The regulatory and secretory properties of cholylsarcosine (C-sar), a synthetic conjugated bile acid analogue that resists deconjugation and dehydroxylation, were compared with those of the natural conjugates of cholic acid. After continuous intraduodenal infusion of cholylsarcosine (C-sar), cholyltaurine (C-tau), or cholylglycine (C-gly) at 36 mumol/100 g.h, the infused bile acid in each case became the predominant biliary bile acid. After 48 hours, infusion of C-sar, C-tau, and C-gly suppressed the activity of cholesterol 7 alpha-hydroxylase (C7 alpha H; rate-limiting for bile acid synthesis) by 65%, 78%, and 92%, respectively, compared with biliary fistula controls. After C-sar infusion, levels of C7 alpha H protein, messenger RNA, and transcriptional activity were depressed to the same extent as specific activity, indicating that C-sar, like C-tau, down-regulates C7 alpha H principally at the level of gene transcription. All three bile acids also suppressed activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (rate-limiting for cholesterol synthesis). Both short- and long-term, the three cholyl conjugates caused similar increases in bile flow and in biliary secretion of cholesterol and phospholipid. It is concluded that in the rat, cholyl conjugates per se can suppress cholesterol and bile acid biosynthesis without prior conversion to deoxycholate. The effects of C-sar on hepatic cholesterol and bile acid synthesis as well as on induced bile flow and biliary lipid secretion are essentially identical to those of the naturally occurring cholyl conjugates.
将一种抗去结合和去羟基化的合成共轭胆汁酸类似物胆酰肌氨酸（C-sar）的调节和分泌特性与胆酸的天然共轭物进行了比较。以36 μmol/100 g·h的速率持续十二指肠内输注胆酰肌氨酸（C-sar）、胆酰牛磺酸（C-tau）或胆酰甘氨酸（C-gly）后，每种情况下输注的胆汁酸都成为胆汁中主要的胆汁酸。48小时后，与胆瘘对照相比，输注C-sar、C-tau和C-gly分别使胆固醇7α-羟化酶（C7αH；胆汁酸合成的限速酶）的活性降低了65%、78%和92%。输注C-sar后，C7αH蛋白、信使核糖核酸和转录活性水平降低到与比活性相同的程度，表明C-sar与C-tau一样，主要在基因转录水平下调C7αH。所有三种胆汁酸还抑制了3-羟基-3-甲基戊二酰辅酶A还原酶（胆固醇合成的限速酶）的活性。短期和长期来看，三种胆酰共轭物均使胆汁流量以及胆固醇和磷脂的胆汁分泌产生相似的增加。得出的结论是，在大鼠中，胆酰共轭物本身可以抑制胆固醇和胆汁酸的生物合成，而无需预先转化为脱氧胆酸盐。C-sar对肝脏胆固醇和胆汁酸合成以及对诱导的胆汁流量和胆汁脂质分泌的影响与天然存在的胆酰共轭物的影响基本相同。
