Fatty acid desaturase 2 is up-regulated by the treatment with statin through geranylgeranyl pyrophosphate-dependent Rho kinase pathway in HepG2 cells

Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway.