Li A C, Tanaka R D, Callaway K, Fogelman A M, Edwards P A
Department of Medicine, School of Public Health, University of California Los Angeles 90024.
J Lipid Res. 1988 Jun;29(6):781-96.
In the normal fed rat, both 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) synthase and HMG-CoA reductase are found in high concentrations in hepatocytes that are localized periportally. The majority of the liver cells show little or no evidence of either enzyme. Addition of cholestyramine and mevinolin to the diet resulted in all liver cells showing strong positive staining for both HMG-CoA reductase and HMG-CoA synthase. These two drugs increased the hepatic HMG-CoA reductase and HMG-CoA synthase activities 92- and 6-fold, respectively, and also increased the HMG-CoA reductase activity in intestine, heart, and kidney 3- to 15-fold. We used immunofluorescence and avidin-biotin labeled antibody to localize HMG-CoA reductase in the rat intestine. In rats fed a normal diet, the most HMG-CoA reductase-positive cells were the villi of the ileum greater than jejunum greater than duodenum. Crypt cells showed no evidence of HMG-CoA reductase. Addition of cholestyramine and mevinolin to the diet led to a dramatic increase in the concentration of HMG-CoA reductase in the apical region of the villi of the ileum and jejunum and in the crypt cells of the duodenum. Hence these two drugs affected both the relative concentration and distribution of intestinal HMG-CoA reductase. Cholestyramine and mevinolin feeding induced in the liver, but not intestine, whorls of smooth endoplasmic reticulum that were proximal to the nucleus and contained high concentrations of HMG-CoA reductase. Administration of mevalonolactone led to the rapid dissolution of the hepatic whorls within 15 min, at a time when there is little or no change in the mass of HMG-CoA reductase. We conclude that the whorls are present in the livers of rats fed cholestyramine and mevinolin because the cells are deprived of a cellular product normally synthesized from mevalonate.
在正常进食的大鼠中，3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）合酶和HMG-CoA还原酶在位于门静脉周围的肝细胞中浓度很高。大多数肝细胞几乎没有或没有这两种酶的迹象。在饮食中添加消胆胺和洛伐他汀导致所有肝细胞对HMG-CoA还原酶和HMG-CoA合酶均呈现强阳性染色。这两种药物分别使肝脏HMG-CoA还原酶和HMG-CoA合酶活性提高了92倍和6倍，还使肠道、心脏和肾脏中的HMG-CoA还原酶活性提高了3至15倍。我们使用免疫荧光和抗生物素蛋白-生物素标记抗体在大鼠肠道中定位HMG-CoA还原酶。在喂食正常饮食的大鼠中，HMG-CoA还原酶阳性细胞最多的是回肠绒毛大于空肠大于十二指肠。隐窝细胞没有HMG-CoA还原酶的迹象。在饮食中添加消胆胺和洛伐他汀导致回肠和空肠绒毛顶端区域以及十二指肠隐窝细胞中HMG-CoA还原酶浓度急剧增加。因此，这两种药物影响了肠道HMG-CoA还原酶的相对浓度和分布。喂食消胆胺和洛伐他汀在肝脏而非肠道中诱导出靠近细胞核且含有高浓度HMG-CoA还原酶的光滑内质网涡。给予甲羟戊酸内酯在15分钟内导致肝脏涡迅速溶解，此时HMG-CoA还原酶的量几乎没有变化。我们得出结论，在喂食消胆胺和洛伐他汀的大鼠肝脏中出现涡是因为细胞被剥夺了通常由甲羟戊酸合成的细胞产物。
