Journal
HEPATOLOGY
Volume 52, Issue 6, Pages 1992-2000Publisher
WILEY
DOI: 10.1002/hep.23927
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Funding
- University of Buenos Aires [UBACYT M055]
- National Agency for Scientific and Technological Promotion [PICT 2006 124]
- Research Council in Health Government of the City of Buenos Aires
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Insulin resistance (IR) and mitochondrial dysfunction play a central role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) We hypothesized that genetic factors 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 methylation of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) and mitochondrial transcription factor A (TEAM) 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 putative 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 significantly higher in control livers compared with NAFLD livers 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 epigenetic modifications Decreased liver mtDNA content concomitantly contributes to peripheral IR (HEPATOLOGY 2010,52 1992-2000)
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