Hydroxymethylglutaryl-coenzyme A reductase-containing hepatocytes are distributed periportally in normal and mevinolin-treated rat livers.

Abstract

Mevinolin is a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34), an enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. We have been studying the hepatic distribution of reductase with immunofluorescence microscopy and liver ultrastructure with electron microscopy in normal and drug-treated rats. In control animals, only about 20% of the hepatocytes were reductase positive. These cells were localized in the periportal lobular zones. The numbers of positive hepatocytes in animals given mevinolin or cholestyramine (or both) were directly proportional to the activities of the HMG-CoA reductase determined biochemically. This induction of HMG-CoA reductase immunofluorescence was centered periportally. Rats given 0.075% mevinolin alone had a homogeneous distribution of reductase staining in their hepatocyte cytoplasm, whereas a combination of 0.25% mevinolin and 3% cholestyramine caused a 150-fold increase in enzyme activity and induced prominent juxtanuclear immunofluorescent globules of HMG-CoA reductase in all hepatocytes. With electron microscopy, these bodies were composed of tightly packed stacks of smooth endoplasmic reticulum cysternae and aggregates of branched smooth endoplasmic reticulum tubules. Our data suggest that a subpopulation of periportal rat hepatocytes may be uniquely specialized for cholesterol synthesis.Mevinolin, a fungal metabolite isolated from Aspergillus terreus, is a potent competitive inhibitor of the rate-limiting enzyme of cholesterol biosynthesis, microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase; EC 1.1.1.34) (1). A similar but somewhat less active inhibitor, compactin (ML-236B), has been purified from Penicillium citrium (2). These compounds are effective cholesterol-lowering agents in several species, including dogs (1, 3, 4) and humans (5-10) but not rats (11,12). Furthermore, 50-70% reductions in the plasma cholesterol levels of dogs and humans have been obtained with combinations of bile acid sequestrants and mevinolin or compactin (4, 8-10).The synthesis of HMG-CoA reductase in rat liver is exquisitely sensitive to a number of factors, including diurnal variation (13,14). Treatment of rats with either an HMGCoA reductase inhibitor or a bile acid sequestrant (or both) results in a marked elevation of enzyme level (14-17). This induction is the result of a dramatic increase in reductase mRNA levels and an enhancement of enzyme stability (15-17). Similarly, in UT-1 cells, a compactin-resistant line, reductase levels are greatly elevated but may be repressed abruptly by low density lipoprotein administration (18). Microscopic studies of these cells reveal a dramatic development of the smooth endoplasmic reticulum (SER) associated with high concentrations of HMG-CoA reductase (19-21).The purpose of this study was to determine the hepatic distribution of HMG-CoA reductase and to correlate putative alterations in reductase patterns and ultrastructure with the extent of enzyme ...

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase induce reductase accumulation and altered lamellar bodies in rat forestomach keratinocytes.

“…Because the occurrence and severity of the accompanying histological alterations were also directly related to HMGCoA reductase inhibitor potency in this and previous studies, 2627 we suggest that both events are due to inhibition of cholesterol or of other products of mevalonate by HMG-CoA reductase inhibitors. Because a similar induction of HMG-CoA reductase IF occurs in the livers but not in the esophageal keratinocytes of rats given lovastatin and/or cholestyramine, 14 ' 15 we believe that HMG-CoA reductase inhibitors stimulate synthesis of additional HMGCoA reductase to compensate for the inhibition of cholesterol production in certain susceptible rodent cell types. Although it is not understood why lovastatin hydroxyacid induces reductase in forestomach keratinocytes while histologically analogous esophageal cells lack this effect, the difference may be due to the continuous presence of L-154,819 in the forestomach as opposed to the esophagus.…”

Cholesterol 7?-hydroxylase (CYP7A): Patterns of messenger RNA expression during rat liver development

“…Although, like C7␣H, 3-hydroxy-3-methylglutaryl Coenzyme A reductase mRNA is expressed in every hepatocyte in the newborn, 53 in the adult liver, reductase mRNA 53 and protein 54 were detectable only in periportal cells, in marked contrast to the localization of C7␣H. This raises questions about the mechanisms of coordinate regulation of these two important rate-limiting enzymes for cholesterol synthesis and catabolism, and how and why they are expressed preferentially in discrete populations of hepatocytes at many developmental time points and in the adult.…”

Decreased Expression of ARV1 Results in Cholesterol Retention in the Endoplasmic Reticulum and Abnormal Bile Acid Metabolism*

“…For SREBP-2 detection, a rabbit anti-SREBP-2 polyclonal antibody (Cayman 10007663) was used. The blots were also probed using a rabbit polyclonal antibody against HMG-CoA reductase (a gift of Dr. Ness) (18). A polyclonal anti-␤-actin antibody (clone I-19) (Santa Cruz Biotechnology) was used to normalize sample loading.…”