Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter.

SOOKOIAN S; ROSSELLI MS; GEMMA C; BURGUEñO A,; FERNADEZ GIANNOTTI T; CASTANO GO,; PIROLA CJ

HEPATOLOGY (BALTIMORE, MD.)

JOHN WILEY & SONS INC

Lugar: United States; Año: 2010 vol. 52 p. 1992 - 2000

0270-9139

Insulin resistance (IR) and mitochondrial dysfunction play a central role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). We hypothesized thatgenetic factors and epigenetic modifications occurring in the liver contribute tothe IR phenotype. We specifically examined whether fatty liver and IR aremodified by hepatic DNA methylation of the peroxisome proliferator-activatedreceptor ã coactivator 1á (PPARGC1A) and mitochondrial transcription factor A(TFAM) promoters, and also evaluated whether liver mitochondrial DNA (mtDNA)content is associated with NAFLD and IR. We studied liver biopsies obtained from NAFLD patients in a case-control design. After bisulfite treatment of DNA, weused methylation-specific polymerase chain reaction (PCR) to assess the putative methylation of three CpG in the PPARGC1A and TFAM promoters. Liver mtDNAquantification using nuclear DNA (nDNA) as a reference was evaluated by way ofreal-time PCR. Liver PPARGC1A methylated DNA/unmethylated DNA ratio correlatedwith plasma fasting insulin levels and homeostasis model assessment of insulinresistance (HOMA-IR); TFAM methylated DNA/unmethylated DNA ratio was inverselycorrelated with insulin levels. PPARGC1A promoter methylation was inverselycorrelated with the abundance of liver PPARGC1A messenger RNA. The livermtDNA/nDNA ratio was significantly higher in control livers compared with NAFLDlivers. mtDNA/nDNA ratio was inversely correlated with HOMA-IR, fasting glucose, and insulin and was inversely correlated with PPARGC1A promoter methylation.Conclusion: Our data suggest that the IR phenotype and the liver transcriptional activity of PPARGC1A show a tight interaction, probably through epigeneticmodifications. Decreased liver mtDNA content concomitantly contributes toperipheral IR.