title: 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.
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore.
authors.forename: Sharon Lt
authors.initials: SL
authors.lastname: Pek
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore Diabetes Centre, Khoo Teck Puat Hospital, Singapore768828, Singapore Division of Endocrinology, Khoo Teck Puat Hospital, Singapore 768828, Singapore subramaniam.tavintharan@alexandrahealth.com.sg.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Tavintharan
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore.
authors.forename: Kaing
authors.initials: K
authors.lastname: Woon
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore.
authors.forename: Lifang
authors.initials: L
authors.lastname: Lin
authors.affiliation: Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117549, Singapore.
authors.forename: Choon Nam
authors.initials: CN
authors.lastname: Ong
authors.affiliation: Clinical Research Unit, Khoo Teck Puat Hospital, Singapore 768828, Singapore Diabetes Centre, Khoo Teck Puat Hospital, Singapore768828, Singapore Division of Endocrinology, Khoo Teck Puat Hospital, Singapore 768828, Singapore.
authors.forename: Su Chi
authors.initials: SC
authors.lastname: Lim
authors.affiliation: Diabetes Centre, Khoo Teck Puat Hospital, Singapore768828, Singapore Division of Endocrinology, Khoo Teck Puat Hospital, Singapore 768828, Singapore.
authors.forename: Chee Fang
authors.initials: CF
authors.lastname: Sum
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood*; D002460:Cell Line; D004311:Double-Blind Method; D005260:Female; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D010919:Placebos / Q000008:administration & dosage; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects*; D014451:Ubiquinone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
chemical_list: D000924:Anticholesteremic Agents; D015415:Biomarkers; D035683:MicroRNAs; D010919:Placebos; D014451:Ubiquinone; D019821:Simvastatin; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; C003741:ubiquinol
keywords: HMG-CoA reductase; Simvastatin; cholesterol; hepatotoxicity; miR-192; miR-21