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.

Epigenetic regulation of insulin resistance in nonalcoholic fatty liver disease: Impact of liver methylation of the peroxisome proliferator-activated receptor γ coactivator 1α promoter

“…This observation is in line with our previous report in an animal model of diet-induced fatty liver about a compensatory increase in the liver mtDNA content in the absence of IR to accommodate the metabolic load. 28 Similar results have been shown to occur in skeletal muscle until the development of IR. 29 However, when IR is established, the decrease in mtDNA content is a common finding, even in leukocytes.…”

Genetic Basis of Alcoholic and Nonalcoholic Fatty Liver Disease

“…In agreement with these observations, Han et al reported that liver mitochondria undergo dynamic alterations following chronic alcohol feeding in mice that include increased mitochondrial NAD + and NADH levels with enhanced mitochondrial biogenesis in the liver to adapt to metabolic stress [ 74 ]. Our group observed a similar fi nding in rats, demonstrating that in rodents, metabolic insults, like high-fat diet, promote an increase in liver mitochondrial biogenesis in response to hypoxia via HIF-1alpha, probably to enhance the mitochondrial function and to accommodate the metabolic stress [ 75 ]. Nevertheless, once the NAFLD is established in humans and the disease progresses to NASH, mitochondrial DNA content is signifi cantly reduced in the liver, suggesting that the advanced disease is associated with a loss of the adaptive mechanism for the metabolic demands [ 66 ].…”

Characterization of an alcoholic hepatic steatosis model induced by ethanol and high-fat diet in rats

“…Fat accumulation in hepatocytes is the result of imbalanced fat metabolism, such as decreased mitochondrial lipid oxidation and enhanced synthesis of triglycerides. Therefore, the development of hepatic steatosis is associated with increased values of oxidative stress and structural defects in mitochondria (Sanyal et al 2001;Carabelli et al 2011), and it impacts mitochondrial respiration (Carabelli et al 2011). In this work, the activity of segments of the mitochondrial respiratory chain was analyzed in isolated hepatic mitochondria, thus accessing the sites in the respiratory chain on which inhibitions in response to diet occur.…”