Liver-Specific Deletion of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Causes Hepatic Steatosis and Death

Abstract

Objective-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo. Methods and Results-To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c. Conclusion-Hepatocyte

Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: A model for statin-induced myopathy

“…HMGCR floxed mice [16] were kindly provided by Shun Ishibashi (Jichi Medical University, Tochigi, Japan). Transgenic mice overexpressing Cre recombinase under the control of the human alpha skeletal actin promoter (HSA-Cre mice) [17] were purchased from The Jackson Laboratory.…”

“…HMGCR enzyme activity in the gastrocnemius muscle microsomal fraction was measured as previously described [16].…”

“…The following primers were used for analysis: HMGCS forward primer, 5 0 -AACTGGTGCA-GAAATCTCTAGC-3 0 ; HMGCS reverse primer, 5 0 -GGTTGAA-TAGCTCAGAACTAGCC-3 0 ; GAPDH forward primer, 5 0 -GTCGTGGATCTGACGTGCC-3 0 ; and GAPDH reverse primer, 5 0 -ATGCCTGCTTCACCACCTTC-3 0 . Other primers used in this study were as previously described [16]. Gene expression was normalized to GAPDH expression.…”

“…We developed mKO mice by crossing HMGCR flox/flox mice [16] with HSA-Cre mice [17]. As shown in Fig.…”

Controlling Cholesterol Synthesis beyond 3-Hydroxy-3-methylglutaryl-CoA Reductase (HMGCR)

“…HMGCR occurs before a branch point directing flux to sterols or isoprenoids (Fig. 1), and ablation of its activity can have dire consequences, as illustrated by knock-out of hepatic HMGCR being lethal to mice (6). Furthermore, over the last couple of decades, discovery and characterization of inborn errors of cholesterol synthesis have not only emphasized the importance of cholesterol but have also drawn attention to the post-HMGCR pathway: how these genetic diseases manifest is likely due to accumulation of intermediates and not solely due to a lack of cholesterol synthesis (reviewed in Ref.…”