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.