Elucidation of novel functions of cholesterol and its metabolites using genetic manipulation in mice

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Cholesterol biosynthetic pathway is divided into two pathways: sterol pathway and non-sterol pathway. Then non-sterol pathway supplies various substances such as isoprenoids, dolichol, Haem A and ubiquinones. HMG-CoA reductase (HMGCR) produces mevalonate which is a precursor of both sterol and non-sterol pathways, whereas squalene synthase (SS) produces squalene which contributes only to sterol pathway. In the present study, we used Cre-LoxP system to disrupt genes of HMGCR or SS in a liver-specific manner to dissect out the functions of the respective enzymes in the liver. Liver-specific HMGCR knockout mice (L-HMGCRKO) were lethal at 1 month after the birth due to fulminant hepatic failure. Plasma cholesterol levels were reduced only by 10% and hepatic cholesterol biosynthesis was not reduced. mRNA expression of SREBP2 was induced, while expression of Cyp7A was reduced. The hepatocytes were filled with triglycerides. Liver-specific SS knockout mice (L-SSKO) showed transient hepatomegaly with liver dysfunction. Although hepatic VLDL production rate was reduced, hepatic cholesterol biosynthesis was not reduced at least in in vivo setting. In conclusion, HMGCR is essential for normal liver function and survival, while SS is dispensable. Normal cholesterol biosynthesis in both models suggests the presence of metabolic bypass pathway which produces cholesterol in the absence of these key enzymes in cholesterol biosynthesis.