Differential Regulation of Gene Expression by Cholesterol Biosynthesis Inhibitors That Reduce (Pravastatin) or Enhance (Squalestatin 1) Nonsterol Isoprenoid Levels in Primary Cultured Mouse and Rat Hepatocytes

Abstract

Squalene synthase inhibitors (SSIs), such as squalestatin 1 (SQ1), reduce cholesterol biosynthesis but cause the accumulation of isoprenoids derived from farnesyl pyrophosphate (FPP), which can modulate the activity of nuclear receptors, including the constitutive androstane receptor (CAR), farnesoid X receptor, and peroxisome proliferator-activated receptors (PPARs). In comparison, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (e.g., pravastatin) inhibit production of both cholesterol and nonsterol isoprenoids. To characterize the effects of isoprenoids on hepatocellular physiology, microarrays were used to compare orthologous gene expression from primary cultured mouse and rat hepatocytes that were treated with either SQ1 or pravastatin. Compared with controls, 47 orthologs were affected by both inhibitors, 90 were affected only by SQ1, and 51 were unique to pravastatin treatment (P , 0.05, $1.5-fold change). When the effects of SQ1 and pravastatin were compared directly, 162 orthologs were found to be differentially coregulated between the two treatments. Genes involved in cholesterol and unsaturated fatty acid biosynthesis were up-regulated by both inhibitors, consistent with cholesterol depletion; however, the extent of induction was greater in rat than in mouse hepatocytes. SQ1 induced several orthologs associated with microsomal, peroxisomal, and mitochondrial fatty acid oxidation and repressed orthologs involved in cell cycle regulation. By comparison, pravastatin repressed the expression of orthologs involved in retinol and xenobiotic metabolism. Several of the metabolic genes altered by isoprenoids were inducible by a PPARa agonist, whereas cytochrome P450 isoform 2B was inducible by activators of CAR. Our findings indicate that SSIs uniquely influence cellular lipid metabolism and cell cycle regulation, probably due to FPP catabolism through the farnesol pathway.

A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor

“…This enhanced efficacy has been shown in the clinic previously ( Stein et al, 2011 ); however, the liver side effects seen with the squalene synthase inhibitor may mean that a statin will have to be used alongside any squalene synthase inhibitor to inhibit a build up of FPP ( Wasko et al, 2011 ). Squalene synthase inhibitors have also been shown to lower triglycerides ( Ugawa et al, 2000 ), which may be explained by recent studies investigating the orthologs differentially affected by squalene synthase inhibitors and statins ( Rondini et al, 2016 ). Only squalene synthase inhibitors were shown to alter cellular lipid metabolism and thus may provide another added benefit to using them alongside a statin.…”

Implicating genes, pleiotropy and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

“…The remaining 63 high-confidence genes have 1-99 lipid related publications. Six high-confidence non-Mendelian genes ( ALS2CR12, BRI3, EML3, HIST1H2BF, BC1D13 , and TMEM150A ) had no lipid-related publications retrieved by the text-mining algorithm, but we did find a subtle implication of ALS2CR12 to lipid metabolism 42 , suggesting potential candidate genes, implicated by most of the approaches we used, for future experimental work ( Table S5 ).…”

FAK and p130Cas modulate stiffness-mediated early transcription and cellular metabolism

“…These include the genes for Stard4, which is known to regulate intracellular cholesterol homeostasis [80], Hsd17b7, which is an enzyme that produces zymosterol [81], a precursor for cholesterol biosynthesis, and estradiol [82]. Sc5d catalyzes the synthesis of 7-dehydrocholesterol [83] to form cholesterol, and Idi1 and Cyp51 are part of the superpathway of the canonical cholesterol biosynthesis pathway [84].…”