title: Squalene synthase inhibitors suppress triglyceride biosynthesis through the farnesol pathway in rat hepatocytes.
abstract: 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-(14)C]acetic acid into oleic acid, but not the incorporation of [1-(14)C]oleic acid into triglyceride. Though ER-27856 and RPR-107393 increased mitochondrial fatty acid beta-oxidation, the inhibition of beta-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.
authors.affiliation: Eisai Co. Ltd., Tsukuba Research Laboratories, Ibaraki, Japan. h-hiyoshi@hhc.eisai.co.jp
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hiyoshi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Yanagimachi
authors.forename: Masashi
authors.initials: M
authors.lastname: Ito
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yasuda
authors.forename: Toshimi
authors.initials: T
authors.lastname: Okada
authors.forename: Hironori
authors.initials: H
authors.lastname: Ikuta
authors.forename: Daisuke
authors.initials: D
authors.lastname: Shinmyo
authors.forename: Keigo
authors.initials: K
authors.lastname: Tanaka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kurusu
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshida
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.forename: Takao
authors.initials: T
authors.lastname: Saeki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005204:Farnesol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology; D050356:Lipid Metabolism; D008297:Male; D010084:Oxidation-Reduction; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013876:Thiophenes / Q000494:pharmacology; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D001596:Benzylamines; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D011758:Pyrroles; D013876:Thiophenes; D014280:Triglycerides; C066059:NB 598; D005204:Farnesol; D002784:Cholesterol; D000069059:Atorvastatin; D013186:Farnesyl-Diphosphate Farnesyltransferase