title: Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver.
abstract: Squalene synthase (SS) is the first committed enzyme for cholesterol biosynthesis, located at a branch point in the mevalonate pathway. To examine the role of SS in the overall cholesterol metabolism, we transiently overexpressed mouse SS in the livers of mice using adenovirus-mediated gene transfer. Overexpression of SS increased de novo cholesterol biosynthesis with increased 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) reductase activity, in spite of the downregulation of its own mRNA expression. Furthermore, overexpression of SS increased plasma concentrations of LDL, irrespective of the presence of functional LDL receptor (LDLR). Thus, the hypercholesterolemia is primarily caused by increased hepatic production of cholesterol-rich VLDL, as demonstrated by the increases in plasma cholesterol levels after intravenous injection of Triton WR1339. mRNA expression of LDLR was decreased, suggesting that defective LDL clearance contributed to the development of hypercholesterolemia. Curiously, the liver was enlarged, with a larger number of Ki-67-positive cells. These results demonstrate that transient upregulation of SS stimulates cholesterol biosynthesis as well as lipoprotein production, providing the first in vivo evidence that SS plays a regulatory role in cholesterol metabolism through modulation of HMG-CoA reductase activity and cholesterol biosynthesis.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tazoe
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okazaki
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Isoo
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Ken
authors.initials: K
authors.lastname: Ohashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitamine
authors.forename: Ryu-Ichi
authors.initials: R
authors.lastname: Tozawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Inaba
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagyu
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Okazaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Ryo-Zo
authors.initials: RZ
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Osuga
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001835:Body Weight; D002784:Cholesterol / Q000096:biosynthesis* / Q000097:blood; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000235:genetics / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling / Q000379:methods; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000097:blood / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000214:Acyl Coenzyme A; D008055:Lipids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011973:Receptors, LDL; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase