Regulation of fatty acid synthase expression by cholesterol in human cultured cells

The regulation of fatty acid synthase (FAS) expression by sterols in a cultured human hepatoblastoma cell line, Hep G2, was studied. When cells were treated with compactin in a medium containing lipoprotein deficient serum, FAS mRNA level increased 1.6-fold. A squalene synthase inhibitor, TAN1607A, decreased both free and esterified cholesterol contents in Hep G2 cells and increased mRNA levels for FAS, HMG-CoA reductase, squalene synthase and LDL receptor. However, for the increment of FAS mRNA, a 10-fold higher concentration of this inhibitor was needed. These results demonstrate that the concentration of cellular cholesterol which regulates FAS expression is necessarily lower than the levels which regulate other sterol sensitive genes. FAS mRNA was also increased by an inhibitor of SREBP degradation as well as chenodeoxycholic acid. These results indicate that FAS mRNA expression is regulated by cholesterol and is mediated through SREBPs. The implications of the different modes of sterol regulation of FAS and LDL receptor expression are discussed.