Atorvastatin Increases Fatty Acid Desaturases (FADSs) and Elongation of Very-Long-Chain Fatty Acids (ELOVLs) through Geranylgeranyl Pyrophosphate (GGPP)-Dependent Rho Kinase Pathway in HepG2 Cells

Abstract

Background: The plasma concentration of arachidonic acid, one of the omega-6 long-chain polyunsaturated fatty acids (LCPUFAs), was increased by the treatment of statin in several clinical studies indicating that statin affects the endogenous synthesis of LCPUFAs, which is regulated by the action of the fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids (ELOVLs). Aims: We investigated the roles of the intrinsic mevalonate cascade and rho-dependent pathway in the statin-induced regulation of these desaturases and elongases using human hepatocellular carcinoma cell line HepG2 cells. Methods: Cell viability was assessed by measuring mitochondrial activity of WST-8, and the activity of caspase-3 and -7 (caspase-3/7) was measured. Gene expression was analyzed by quantitative real-time PCR. Protein expressions were detected by Western blot analysis. Results: Although atorvastatin decreased the cell viability with increasing activity of caspase-3/7 in a dose-dependent manner, both mRNA and protein expression of FADS2 were stimulated by atorvastatin at lower dose of 12.5 and 25 uM, where mRNA expression of FADS1 and Elovl5 also increased. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), not cholesterol, fully restored the atorvastatin-induced inhibition of cell viability, and the atorvastatin-induced upregulation of mRNA and protein of FADS2. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibits the restoration of mevalonate and GGPP. Both EPA and DHA, but not AA, significantly suppressed the atorvastatin-induced upregulation of gene expression of FADS1, FADS2 and Elovl5. Conclusions: These data demonstrated that statin may affect the endogenous synthesis of LCPUFAs by the regulation of these desaturases and elongases through GGPP-dependent rho kinase pathway in HepG2 cells. Disclosure I. Tatsuno: None. S. Tanaka: None. N. Ishihara: None.