Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies, including steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD. Mitophagy is a mitochondrial quality control mechanism that allows for selective removal of damaged mitochondria from the cell. Whether changes in mitophagy occur during and contribute to NAFLD is unknown. PARKIN is a ubiquitin E3 ligase that regulates mitophagy by generating a ubiquitin signaling motif on the outer membrane of damaged mitochondria, marking them for degradation. We undertook the studies described to determine effects of genetic inhibition of mitophagy via conditional deletion of PARKIN in liver on progression of NAFLD. Twelve-week old male liver-specific PARKIN knockout (LKO) and wild type (WT) mice were fed a diet previously demonstrated to induce NAFLD that consisted of high-fat (45%), cholesterol (0.15%) and high-fructose corn syrup drinking water (42g/L) for 8 weeks. There was no difference in body weight or composition between groups. Plasma ALT and AST levels were increased 2-fold (p=0.18) and 1.7-fold (p<0.05), respectively, in LKO compared with WT mice, while plasma cholesterol and insulin levels were not different and plasma fatty acid levels were reduced by 27% (p<0.05). NAFLD activity score was increased 2-fold (p<0.05) in LKO mice reflecting an increase in steatosis, ballooning and inflammation. Gene expression markers of NAFLD progression including markers of inflammation (Ccl2, Cd68, Il-1b, ll-6) and fibrosis (Col1a1, Col3a1) were significantly increased in LKO mice. Consistent with these mouse data, we found PARKIN protein expression to be reduced in liver biopsies from patients with NASH compared with healthy controls. These data suggest that loss of PARKIN-mediated mitophagy may contribute to the progression of NAFLD.
R. Undamatla: None. L.R. Edmunds: None. B. Xie: None. A. Mills: None. I.J. Sipula: None. S.P. Monga: None. M.J. Jurczak: None.
National Institutes of Health (DK114012)