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

Hiroaki Okazaki, Fumiko Tazoe, 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

Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498

Corresponding Author: 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 reductase (HMG-CoA reductase) activity, in spite of the down-regulation of its own mRNA expression. Furthermore, overexpression of SS increased plasma concentrations of low density lipoproteins (LDL), irrespective of the presence of functional LDL receptor. Thus the hypercholesterolemia is primarily caused by increased hepatic production of cholesterol-rich very low density lipoproteins, as demonstrated by the increases in plasma cholesterol levels after intravenous injection of Triton WR1339. mRNA expression of LDL receptor was decreased, suggesting that defective LDL clearance contributed to the development of hypercholesterolemia Curiously, the liver was enlarged with larger number of Ki-67-positive cells. These results demonstrate that transient up-regulation 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 modulating HMG-CoA reductase activity and cholesterol biosynthesis.

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