Abstract 5520: Lethal Hepatic Failure with Steatosis in Liver-Sepecific 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Knockout Mice
Three-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is the late-limiting enzyme for cholesterol biosynthesis in the mevalonate pathway. Furthermore, HMGCR is involved in the generation of isoprenoids that are essential for diverse cellular function. To define the role of HMGCR especially in the liver, we generated liver-specific HMGCR knockout (L-HMGCR KO) mice using cre/loxP technology. L-HMGCR KO mice developed fulminant liver failure with hepatocyte ballooning and died at 5 weeks of age. Although the mRNA levels of HMGCR were reduced by 96%, HMGCR activities were reduced only by 44% compared with control HMGCR lox/lox mice (L-HMGCR KO vs. HMGCR lox/lox = 45.8 ± 20.71 vs. 81.2 ±14.1 pmol/mg protein/min, p<0.05). Consistently, plasma total cholesterol levels were reduced only by 26% (47.2±8.8 vs. 64.1± 12.2 mg/dl, p<0.01). Surprisingly, Hepatic cholesterol biosynthesis from intraperitoneally injected [14C]-acetate did not differ between L-HMGCR KO and control mice. Hepatic lipid analyses showed that triglyceride ( TG ) contents in L-HMGCR KO mice was increased by 3.6-folds (20.9±10.5 vs. 5.9±2.0 mg/g liver, p=0.054), whereas cholesterol contents did not differ between two types of mice. Real-time PCR showed that L-HMGCR KO liver had increased gene expression levels of LDL receptor, sterol regulatory element binding transcription factor 2 and squalene synthase by 1.7-, 1.4- and 3.9-folds, respectively, when compared to control mice. Furthermore, stearoyl-CoA desaturase-2, an enzyme that catalyzes TG synthesis in embryonic mouse liver, was highly up-regulated by 21.9-folds. Conversely, Cyp7A1, an enzyme for bile acid synthesis, was decreased by 47% in L-HMGCR KO mice. Our data show that hepatic HMGCR is essential for survival. However, in vivo cholesterol biosynthesis was maintained in the liver at least before the onset of hepatic failure, suggesting the presence of other mechanisms which compensate for the absence of HMGCR.