High-fat Diet -induced liver steatosis promotes an increase in liver mitochondrial biogenesis in response to hypoxia.

J. CARABELLI.; AL BURGUEÑO.; MS ROSSELLI.; FERNANDEZ GIANOTTI, T; LAGO, NR; PIROLA CJ; SOOKOIAN S

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (PRINT)

WILEY-BLACKWELL PUBLISHING, INC

Año: 2011 vol. 15 p. 1329 - 1338

1582-1838

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-1. Rats were given either standard chow diet (SCD, n 10) or highfat 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-1 mRNA ( R: 0.37, P 0.001); liver HIF-1mRNA 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- 1 ( PGC-1) and PGC-1, nuclear respiratory factor-1 ( NRF-1), peroxisome proliferator-activated receptor  and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1-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-1, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. 10) or highfat 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-1 mRNA ( R: 0.37, P 0.001); liver HIF-1mRNA 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- 1 ( PGC-1) and PGC-1, nuclear respiratory factor-1 ( NRF-1), peroxisome proliferator-activated receptor  and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1-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-1, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. 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-1 mRNA ( R: 0.37, P 0.001); liver HIF-1mRNA 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- 1 ( PGC-1) and PGC-1, nuclear respiratory factor-1 ( NRF-1), peroxisome proliferator-activated receptor  and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1-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-1, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. 0.05). The liver mtDNA/nDNA ratio significantly correlated with the hepatic expression of HIF-1 mRNA ( R: 0.37, P 0.001); liver HIF-1mRNA 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- 1 ( PGC-1) and PGC-1, nuclear respiratory factor-1 ( NRF-1), peroxisome proliferator-activated receptor  and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1-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-1, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. 0.001); liver HIF-1mRNA 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- 1 ( PGC-1) and PGC-1, nuclear respiratory factor-1 ( NRF-1), peroxisome proliferator-activated receptor  and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1-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-1, probably to enhance the mitochondrial function as well as to accommodate the metabolic load. ( PGC-1) and PGC-1, nuclear respiratory factor-1 ( NRF-1), peroxisome proliferator-activated receptor  and Tfam, was not associated with the liver mtDNA content. Neither hepatocyte apoptosis nor oxidative stress was involved in the HIF-1-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-1, probably to enhance the mitochondrial function as well as to accommodate the metabolic load.