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

Abstract

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 hepatocytes (蠅 ±1.5‐fold change). Among these, we identified 112 conserved genes that were differentially higher and 54 lower in SQ1‐treated hepatocytes. Functional annotation identified that conserved responses were associated with induction of fatty acid metabolism and inhibition of cell cycle processes. The magnitude of gene expression changes was species‐dependent, likely due to differences in isoprenoid metabolism. Our findings indicate in addition to sterol depletion, squalene synthase inhibitors may uniquely influence cellular energy metabolism and cell cycle regulation.Grant Funding Source: This work was supported by NIH grant HL050710.