PARKIN, an ubiquitin E3 ligase, regulates mitochondrial homeostasis through a process called mitophagy, where damaged mitochondria are selectively targeted and removed via autophagy. Diminished hepatic mitophagy may play a role in mitochondrial dysfunction that occurs alongside insulin resistance and hepatic steatosis in association with obesity. Reduced hepatic mitophagy was observed in obese mice with fatty liver, raising the question as to whether loss of mitophagy contributes to the pathogenesis of fatty liver or is merely associated with the disease. To understand how loss of hepatic mitophagy affects obesity-associated liver disease, we developed a liver-specific PARKIN knockout mouse (LKO). There was no difference in body weight in LKO compared with WT mice fed regular chow (RC) or high-fat diet (HFD; 60% kcal, 12 weeks). There was also no difference in liver steatosis between RC groups, however, liver steatosis was 45% greater in HFD-LKO compared with WT mice (p<0.05). Liver histology demonstrated presence of microvesicular steatosis in zones 2-3 in both HFD groups, but only LKO mice presented with micro and macrosteatosis in zones 1-3. HFD-LKO samples showed presence of an inflammatory cell infiltrate that was less apparent in WT samples. Unbiased transcriptomic analysis by RNA-Seq demonstrated 113 significant differentially expressed genes (82 up, 31 down) in HFD-LKO mice. Unsupervised gene ontology and pathway analysis revealed significant changes in extracellular matrix accumulation, lipid metabolism, metabolic and ROS processes in HFD-LKO mice.

In summary, the increased steatosis and presence of macrovesicular steatosis and inflammation in HFD-LKO mice, alongside changes in gene expression suggesting collagen deposition and extracellular matrix remodeling, suggest that loss of PARKIN-mediated mitophagy increases susceptibility to HFD and may predispose mice to NAFLD.


L.R. Edmunds: None. A. Mills: None. M.J. Jurczak: None.


American Diabetes Association (1-19-PDF-102 to L.R.E.)

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