title: Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver.
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.
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nagashima
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagyu
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tozawa
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tazoe
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitamine
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamuro
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Kent
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okazaki
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Osuga
authors.affiliation: Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki 300-0395, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.affiliation: Division of Endocrinology and Metabolism, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics* / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic
chemical_list: D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013186:Farnesyl-Diphosphate Farnesyltransferase
keywords: Cre recombinase; cholesterol/biosynthesis; enzymology/enzyme regulation; gene targeting; inborn errors of metabolism; knockout; lipoproteins/metabolism; very low density lipoprotein