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Journal of Lipid Research, Vol. 44, 128-135, January 2003
Copyright © 2003 by Lipid Research, Inc.

Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes

Hironobu Hiyoshi¹, Mamoru Yanagimachi, Masashi Ito, Nobuyuki Yasuda, Toshimi Okada, Hironori Ikuta, Daisuke Shinmyo, Keigo Tanaka, Nobuyuki Kurusu, Ichiro Yoshida, Shinya Abe, Takao Saeki and Hiroshi Tanaka

Eisai Co. Ltd., Tsukuba Research Laboratories, Ibaraki, Japan

¹ To whom correspondence should be addressed. e-mail: h-hiyoshi{at}hhc.eisai.co.jp

We recently demonstrated that squalene synthase (SQS) inhibitors reduce plasma triglyceride through an LDL receptor-independent mechanism in Watanabe heritable hyperlipidemic rabbits (Hiyoshi et al. 2001. Eur. J. Pharmacol. 431: 345–352). The present study deals with the mechanism of the inhibition of triglyceride biosynthesis by the SQS inhibitors ER-27856 and RPR-107393 in rat primary cultured hepatocytes. Atorvastatin, an HMG-CoA reductase inhibitor, had no effect on triglyceride biosynthesis, but reversed the inhibitory effect of the SQS inhibitors. A squalene epoxidase inhibitor, NB-598, affected neither triglyceride biosynthesis nor its inhibition by ER-27856 and RPR-107393. The reduction of triglyceride biosynthesis by ER-27856 and RPR-107393 was potentiated by mevalonolactone supplementation. Treatment of hepatocytes with farnesol and its derivatives reduced triglyceride biosynthesis. In addition, we found that ER-27856 and RPR-107393 significantly reduced the incorporation of [1-¹⁴C]acetic acid into oleic acid, but not the incorporation of [1-¹⁴C]oleic acid into triglyceride. Though ER-27856 and RPR-107393 increased mitochondrial fatty acid ß-oxidation, the inhibition of ß-oxidation by RS-etomoxir had little effect on their inhibition of triglyceride biosynthesis.

These results suggest that SQS inhibitors reduce triglyceride biosynthesis by suppressing fatty acid biosynthesis via an increase in intracellular farnesol and its derivatives.

Abbreviations: CHD, coronary heart disease; CPT I, carnitine palmitoyltransferase I; SQS, squalene synthase; FPP, farnesyl pyrophosphate; MVL, mevalonolactone; SD rats, Sprague-Dawley rats; WHHL rabbit, Watanabe heritable hyperlipidemic rabbit

Supplementary key words ER-27856 • RPR-107393 • HMG-CoA reductase • squalene epoxidase • isoprenoid pathway

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