Conserved effects of squalene synthase inhibitors on gene expression changes in primary cultured rat and mouse hepatocytes (1148.2)

Squalene synthase inhibitors, such as squalestatin 1 (SQ1), are cholesterol-lowering drugs that block the first committed step in sterol biosynthesis. Unlike statins (e.g., pravastatin), inhibition of squalene synthase causes accumulation of non-sterol isoprenoids that can function as signaling molecules that modulate the activities of various nuclear receptors including the constitutive androstane receptor (CAR), farnesoid X receptor (FXR), and peroxisome proliferator-activated receptor (PPAR). To characterize the effect of isoprenoids on hepatocyte physiology further, we used microarray analysis to compare the gene expression responses in rat and mouse primary cultured hepatocytes that were treated with either SQ1 or pravastatin. In both species, genes involved in cholesterol biosynthesis were significantly up-regulated by either drug consistent with the depletion of cellular cholesterol. Compared to pravastatin, treatment with SQ1 differentially affected 1796 genes in rat hepatocytes and 3689 in mouse ...