title: High fat diet-induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia.
abstract: Mitochondrial DNA (mtDNA) copy number plays a key role in the pathophysiology of metabolic syndrome-related phenotypes, but its role in non-alcoholic 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-1α. Rats were given either standard chow diet (SCD, n = 10) or high-fat diet (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-1α mRNA (R: 0.37, P < 0.001); liver HIF-1α 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 peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PGC-1β, nuclear respiratory factor-1 (NRF-1), peroxisome proliferator-activated receptor δ and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1α-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-1α, probably to enhance the mitochondrial function as well as to accommodate the metabolic load.
authors.affiliation: Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Julieta
authors.initials: J
authors.lastname: Carabelli
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Burgueño
authors.forename: Maria Soledad
authors.initials: MS
authors.lastname: Rosselli
authors.forename: Tomas Fernández
authors.initials: TF
authors.lastname: Gianotti
authors.forename: Nestor R
authors.initials: NR
authors.lastname: Lago
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Pirola
authors.forename: Silvia
authors.initials: S
authors.lastname: Sookoian
mesh_terms: D000818:Animals; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000096:biosynthesis* / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000032:analysis
chemical_list: D004272:DNA, Mitochondrial; D004041:Dietary Fats; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014280:Triglycerides; D003576:Electron Transport Complex IV