Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver |
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Authors: | Shuichi Nagashima Hiroaki Yagyu Ryuichi Tozawa Fumiko Tazoe Manabu Takahashi Tetsuya Kitamine Daisuke Yamamuro Kent Sakai Motohiro Sekiya Hiroaki Okazaki Jun-ichi Osuga Akira Honda Shun Ishibashi |
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Institution: | *Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan;†Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;§Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki 300-0395, Japan |
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Abstract: | Squalene synthase (SS) catalyzes the biosynthesis of squalene, the first specific intermediate in the cholesterol biosynthetic pathway. To test the feasibility of lowering plasma cholesterol by inhibiting hepatic SS, we generated mice in which SS is specifically knocked out in the liver (L-SSKO) using Cre-loxP technology. Hepatic SS activity of L-SSKO mice was reduced by >90%. In addition, cholesterol biosynthesis in the liver slices was almost eliminated. Although the hepatic squalene contents were markedly reduced in L-SSKO mice, the hepatic contents of cholesterol and its precursors distal to squalene were indistinguishable from those of control mice, indicating the presence of sufficient centripetal flow of cholesterol and/or its precursors from the extrahepatic tissues. L-SSKO mice showed a transient liver dysfunction with moderate hepatomegaly presumably secondary to increased farnesol production. In a fed state, the plasma total cholesterol and triglyceride were significantly reduced in L-SSKO mice, primarily owing to reduced hepatic VLDL secretion. In a fasted state, the hypolipidemic effect was lost. mRNA expression of liver X receptor α target genes was reduced, while that of sterol-regulatory element binding protein 2 target genes was increased. In conclusion, liver-specific ablation of SS inhibits hepatic cholesterol biosynthesis and induces hypolipidemia without increasing significant mortality. |
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Keywords: | cholesterol/biosynthesis enzymology/enzyme regulation lipoproteins/metabolism very low density lipoprotein inborn errors of metabolism Cre recombinase gene targeting knockout |
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