Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial‐derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle‐aged mice. Susceptibility to diet‐induced obesity increased with age. Young adult and middle‐aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age‐related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat‐fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid‐derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet‐induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized.

The characterisation of hepatic mitochondrial function in patients with non-alcoholic fatty liver disease (NAFLD) using the 13 C-ketoisocaproate breath test

“…Our findings show an association between age and HMF and these data suggest that ageing may have a role in indirectly influencing HMF, perhaps due to decreased mitochondrial mass with age, as previously suggested in animal studies (16). AST is known to be present in both the cytosol and mitochondria of hepatocytes.…”

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

“…Aging itself induces cellular senescence leading to development and disease progression of NAFLD through several pathways . Age‐related mitochondrial dysfunction and elevated oxidative stress trigger fatty liver disease in aged mice on an HFD . Up‐regulation of the cyclin‐dependent kinase 4 (CDK4) with aging induces phosphorylation of C/EBPα and formation of C/EBPα‐p300 complexes, leading to steatosis, whereas pharmacological inhibition of CDK4 reduces hepatic lipid accumulation …”

“…(1,4,43) Age-related mitochondrial dysfunction and elevated oxidative stress trigger fatty liver disease in aged mice on an HFD. (44) Up-regulation of the cyclin-dependent kinase 4 (CDK4) with aging induces phosphorylation of C/EBPα and formation of C/EBPα-p300 complexes, leading to steatosis, whereas pharmacological inhibition of CDK4 reduces hepatic lipid accumulation. (45,46) Although the abovementioned studies imply that senescence is variously involved in NAFLD pathogenesis and progression, it is of interest whether data from animal studies can be translated into the human system, in order to design therapeutic strategies in the future.…”

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…High fat (lard; soybean oil) [201] Therefore, a decrease in respiratory capacity using glutamate/malate and pyruvate/malate as Complex I substrates or succinate plus rotenone as Complex II substrates has mostly been reported [117,159,200]. Nevertheless, the same trend was observed with the use of palmitoyl-carnitine as a lipid substrate in combination with malate [197,199]. However, a few contradictory studies have described an increase in mitochondrial respiration in the presence of the same mitochondrial substrates mentioned previously, namely, palmitoyl-carnitine [159,191,201,205].…”

“…High fat (palm oil) [197] Choline deficient diet [198] High fat (lard) [199] High fat (lard or fish oil)…”