Epigenetic Regulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease

Insulin resistance (IR) and mitochondrial dysfunction play a central role in the patho-physiology of nonalcoholic fatty liver disease (NAFLD). We hypothesized that genetic fac-tors and epigenetic modifications occurring in the liver contribute to the IR phenotype. We specifically examined whether fatty liver and IR are modified by hepatic DNA methyla-tion of the peroxisome proliferator–activated receptor c coactivator 1a (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, we used methylation-specific polymerase chain reaction (PCR) to assess the puta-tive methylation of three CpG in the PPARGC1A and TFAM promoters. Liver mtDNA quantification using nuclear DNA (nDNA) as a reference was evaluated by way of real-time PCR. Liver PPARGC1A methylated DNA/unmethylated DNA ratio correlated with plasma fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR); TFAM methylated DNA/unmethylated DNA ratio was inversely correlated with insulin levels. PPARGC1A promoter methylation was inversely correlated with the abundance of liver PPARGC1A messenger RNA. The liver mtDNA/nDNA ratio was signif-icantly higher in control livers compared with NAFLD livers. mtDNA/nDNA ratio was inversely correlated with HOMA-IR, fasting glucose, and insulin and was inversely corre-lated 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 epigenetic modifications. Decreased liver mtDNA content concomi-tantly contributes to peripheral IR. (HEPATOLOGY 2010;52:1992-2000)