Nguyen L B, Shefer S, Salen G, Ness G C, Batta A, Chowdhary I R, Paroulek E, Hauser S
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103.
Metabolism. 1994 Nov;43(11):1446-50. doi: 10.1016/0026-0495(94)90043-4.
We investigated the effects of intestinal bile acid flux, orientation of the 7-hydroxy group, and administration of lovastatin on the regulation of intestinal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity in the rat ileum. HMG-CoA reductase activities in villous and crypt cells from the ileal mucosa were similar, and the study was performed on whole mucosa that contained both cell types. Taurocholate feeding decreased ileal reductase activity 48%, whereas tauroursocholate, the 7 beta-hydroxy epimer of taurocholate, had no effect. Feeding lovastatin (inhibitor of HMG-CoA reductase) stimulated total ileal HMG-CoA reductase activity threefold in washed microsomes, which were dissociated from the inhibitor. However, the proportion of active enzyme in the ileum of lovastatin-fed rats was 50% lower than in controls, whereas there was no change in the percentage of expressed enzyme with bile acid treatments. Interruption of the enterohepatic circulation (bile fistula) increased HMG-CoA reductase activity in the ileum 73%. Duodenal infusion of taurocholate to bile-fistula rats significantly decreased microsomal HMG-CoA reductase activity in the ileal mucosa. In contrast, infusion of the 7 beta-hydroxy epimer tauroursocholate failed to inhibit the derepressed HMG-CoA reductase activity in the ileum of bile-fistula rats. The inhibition of intestinal HMG-CoA reductase activity by taurocholate occurred without accumulation of mucosal cholesterol. Furthermore, the stimulation of total ileal HMG-CoA reductase activity by lovastatin treatment was observed without a decrease in mucosal cholesterol. In summary, the regulation of ileal HMG-CoA reductase activity by the intestinal luminal flux of bile acids is dependent on the orientation of the hydroxyl groups.(ABSTRACT TRUNCATED AT 250 WORDS)
我们研究了肠道胆汁酸通量、7-羟基的取向以及洛伐他汀的给药对大鼠回肠中肠道3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶活性调节的影响。回肠黏膜绒毛和隐窝细胞中的HMG-CoA还原酶活性相似，该研究在包含这两种细胞类型的全黏膜上进行。喂食牛磺胆酸盐使回肠还原酶活性降低48%，而牛磺熊去氧胆酸盐（牛磺胆酸盐的7β-羟基差向异构体）则无影响。喂食洛伐他汀（HMG-CoA还原酶抑制剂）使洗涤后的微粒体中回肠总HMG-CoA还原酶活性增加了三倍，这些微粒体已与抑制剂解离。然而，喂食洛伐他汀的大鼠回肠中活性酶的比例比对照组低50%，而胆汁酸处理后表达酶的百分比没有变化。肠肝循环中断（胆瘘）使回肠中HMG-CoA还原酶活性增加73%。向胆瘘大鼠十二指肠输注牛磺胆酸盐可显著降低回肠黏膜微粒体HMG-CoA还原酶活性。相反，输注7β-羟基差向异构体牛磺熊去氧胆酸盐未能抑制胆瘘大鼠回肠中去抑制的HMG-CoA还原酶活性。牛磺胆酸盐对肠道HMG-CoA还原酶活性的抑制作用发生时，黏膜胆固醇并未积累。此外，观察到洛伐他汀治疗可刺激回肠总HMG-CoA还原酶活性，而黏膜胆固醇并未降低。总之，胆汁酸的肠道腔内通量对回肠HMG-CoA还原酶活性的调节取决于羟基的取向。（摘要截短至250字）
