부산대학교 도서관

Non-alcoholic fatty liver disease (NAFLD) is an epidemic affecting 30% of the US population. NAFLD is characterized by insulin resistance and by defective lipid metabolism and mitochondrial dysfunction in the liver. SLC25A34 is a major repressive target of miR-122, a microRNA that has a central role in NAFLD and liver cancer. However, little is known about the function of SLC25A34. To investigate SLC25A34 in vitro, mitochondrial respiration and bioenergetics were examined using hepatocytes depleted of Slc25a34or overexpressing Slc25a34. To test the function of SLC25A34 in vivo, a hepatocyte-specific knockout mouse was generated, and loss of SLC25A34 was assessed in mice maintained on chow diet and fast-food diet (FFD), a model for NAFLD. Hepatocytes depleted of Slc25a34displayed increased mitochondrial biogenesis, lipid synthesis, and ADP/ATP ratio while Slc25a34overexpression had the opposite effect. In the knockout model on chow diet, SLC25A34 loss modestly affected liver function with altered glucose metabolism as the most pronounced defect. RNA-seq revealed changes in metabolic processes, especially fatty acid metabolism. After 2 months of FFD, knockouts had a more severe phenotype, with increased lipid content and impaired glucose tolerance, which was attenuated after longer FFD feeding (6 months). In summary, this work presents a novel model for studying SLC25A34 in vivowhere SLC25A34 plays a role in mitochondrial respiration and bioenergetics during NAFLD.