CONICET | Buscador de Institutos y Recursos Humanos

ABSTRACT Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in nonalcoholic fatty liver disease (NAFLD) is not well understood. We evaluated the molecular mechanisms that may be involved in the regulation of liver mtDNA content in a high-fat-induced rat model of NAFLD. In particular, we tested the hypothesis that liver mtDNA copy number is associated with liver expression of HIF-1alpha. Rats were given either standard chow diet (SCD, n=10) or HFD (n=15) for 20 weeks. Subsequently, mtDNA quantification using nuclear DNA (nDNA) as a reference was carried out using real time quantitative PCR. HFD induced a significant increase in liver mtDNA/nDNA ratio, which significantly correlated with the liver triglyceride content (R: 0.29, p<0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1alpha mRNA (R: 0.37, p<0.001); liver HIF-1alpha mRNA was significantly higher in the HFD group. In addition, liver cytochrome c oxidase subunit IV isoform 1 (COX4I1) mRNA expression was also positively correlated with liver mtDNA content. The hepatic expression of mRNA of transcriptional factors that regulate mitochondrial biogenesis, including PGC-1alpha and PGC-1beta, NRF-1, PPARdelta, and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress were involved in the HIF-1alpha-mediated increase in mtDNA copy number. In conclusion, we found that HFD promotes an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1alpha, probably to enhance the mitochondrial function as well as to accommodate the metabolic load