Abstract
Background & Aims:
The prevalence of non-alcoholic fatty liver disease (NAFLD) imposes a huge burden on global health management. The ketogenic diet (KD) is considered to be an effective lifestyle to manage NAFLD. Here, we aimed to investigate the effect of KD on metabolic endpoints in NAFLD mice and explore the underlying mechanisms.
Methods
High fat diet (HFD)-induced NAFLD mice were fed with/without KD for 2 weeks in contrast with standard diet-fed (SD) mice. The metabolic endpoints of SD and NAFLD mice were determined by measuring liver fat and plasma ALT and AST. Then mitochondrial morphology of the liver was evaluated by transmission electron microscopy (TEM). Western blot was performed to identify the changes of mitochondrial dynamics related proteins. Mitochondrial function was assessed by qPCR and ATP content measurement. In vitro, HepG2 cells were treated with palmitic acid (PA), β-hydroxybutyric acid (β-OHB) and/or MFI8. Tom20 fluorescence staining was used to assess mitochondrial morphology. Mitochondrial function was assessed by qPCR, ATP content measurement and JC-1 staining. Furthermore, lipid deposition was examined by Nile Red and BODIPY staining.
Results
KD feeding for 2 weeks showed the improvement on NAFLD phenotype, which was associated withdecreased levels of Fis1 and Drp1 in the liver of NAFLD mice. Furthermore, KD also improved HFD-induced mitochondrial dysfunction as evidence by increased ATP content and the key genes involved in fatty acid oxidation. In vitro, β-OHB also improved PA-induced mitochondrial fragmentation and dysfunction in HepG2 cells. Moreover, β-OHB alleviated PA-induced lipid accumulation, and this effect was blunted by mitochondrial fusion inhibitor MFI8.
Conclusions
Collectively, these findings indicated that KD feeding improved lipid accumulation, balanced mitochondrial dynamics and improved mitochondrial dysfunction in the liver of NAFLD mice.