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Journal of Lipid Research, Vol. 47, 1950-1958, September 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Increased cholesterol biosynthesis and hypercholesterolemia in mice overexpressing squalene synthase in the liver

Hiroaki Okazaki^*,1, Fumiko Tazoe^1,, Sachiko Okazaki^*, Naoyuki Isoo^*, Kazuhisa Tsukamoto^*, Motohiro Sekiya^*, Naoya Yahagi^*, Yoko Iizuka^*, Ken Ohashi^*, Tetsuya Kitamine^*, Ryu-ichi Tozawa^*, Toshihiro Inaba, Hiroaki Yagyu, Mitsuyo Okazaki, Hitoshi Shimano^**, Norihito Shibata, Hiroyuki Arai, Ryo-zo Nagai, Takashi Kadowaki^*, Jun-ichi Osuga^* and Shun Ishibashi^2,*,

^* Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Department of Cardiovascular Diseases, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Laboratory of Chemistry, College of Liberal Arts and Science, Tokyo Medical and Dental University, Chiba 272-0827, Japan
^** Metabolism, Endocrinology and Atherosclerosis, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 Japan
Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan

Published, JLR Papers in Press, June 1, 2006.

¹ H. Okazaki and F. Tazoe contributed equally to this work.

² To whom correspondence should be addressed. e-mail: ishibash{at}jichi.ac.jp

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.

Supplementary key words lipoprotein • adenovirus • hyperlipoproteinemia • 3-hydroxy-3-methyglutaryl-CoA reductase • farnesyl diphosphate • mevalonate • hepatomegaly • cell proliferation • feedback regulation

Abbreviations: Ad-SS, recombinant adenovirus carrying SS cDNA under the control of cytomegalovirus promoter; apoB, apolipoprotein B; E, embryonic day; ER, endoplasmic reticulum; LDLR, LDL receptor; m.o.i., multiplicity of infection; SREBP, sterol-regulatory element binding protein; SS, squalene synthase; TC total cholesterol; TG, triglyceride; TUNEL, terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling

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