MicroRNAs as biomarkers of hepatotoxicity in a randomized placebo-controlled study of simvastatin and ubiquinol supplementation

Abstract

Statins are potent cholesterol-lowering drugs and are generally well tolerated. Hepatotoxicity is a rare but serious adverse effect of statins; however, its mechanisms are not clear. Coenzyme Q10 deficiency has been suggested, and supplementation of reduced coenzyme Q10 (ubiquinol) has been shown to have hepatoprotective effects. MicroRNAs (miRNAs) are small nucleotides that have been shown to be up-regulated in drug-induced liver injury. We hypothesized that circulating miRNAs may be differentially regulated after simvastatin treatment and by comparing with that of simvastatin and ubiquinol supplementation could potentially uncover signatory miRNA profile for simvastatin-induced liver injury. In this double-blind, prospective, randomized-controlled trial, miRNA profiles and liver enzymes were compared between simvastatin-treated patients, with and without ubiquinol supplementation, over 12 weeks compared to baseline. miRNA expression was further validated in HepG2 liver cell lines by real-time PCR. Changes in miR-192, miR-146a, miR-148a, miR-15a, and miR-21 were positively correlated (p<0.05) with alanine aminotransferase in simvastatin-only treated patients. In ubiquinol supplementation group, alanine aminotransferase and alkaline phosphatase were significantly down-regulated after 12 weeks and changes in miR-15a, miR-21 and miR-33a were negatively correlated with alkaline phosphatase (p < 0.05). Bioinformatics analyses predicted that miRNA regulation in simvastatin group was related to reduce proliferation and adenosine triphosphate-binding cassette transporters. Ubiquinol supplementation additionally regulated miRNAs that inhibit apoptotic and inflammatory pathways, suggesting potential hepatoprotective effects. Our results suggest that 20 mg/day of simvastatin does not have significant risk of hepatotoxicity and ubiquinol supplementation may, at the miRNA level, provide potential beneficial changes to reduce the effects of coenzyme Q10 deficiency in the liver.