Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver.

Journal of Lipid Research
Shuichi NagashimaShun Ishibashi

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 ...Continue Reading

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Citations

Dec 1, 2017·Molecular Biology Reports·Ghedeir M AlshammariThirunavukkarasu Chinnasamy
Dec 22, 2017·Artificial Cells, Nanomedicine, and Biotechnology·Nidhi GuptaSurendra Nimesh
Oct 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Kent SakaiShun Ishibashi
Apr 1, 2017·The Journal of Pharmacology and Experimental Therapeutics·Alastair G KerrRichard Wade-Martins
Oct 3, 2015·The Journal of Pharmacology and Experimental Therapeutics·Elizabeth A RondiniThomas A Kocarek
May 24, 2020·International Journal of Environmental Research and Public Health·William B SherwoodFaisal I Rezwan

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