(253) Mitochondrial Quality Control and Fatty Liver Disease

Objective : Non-alcoholic steatohepatitis (NASH) is frequently associated with diet-induced obesity, which progressively leads to fibrosis, and cirrhosis. Therefore, developing a strategy to counter NASH is important. Published data and preliminary research from our laboratory suggest that dysregulation in mitochondrial quality control is central to the pathogenesis of NASH. Mitochondrial biogenesis and mitophagy critically regulate mitochondrial quality control. Our data suggest that high-fat diet (HFD)-feeding suppresses mitochondrial biogenesis and disrupts the removal of dysfunctional mitochondria and activation of transient receptor potential vanilloid subfamily 1 (TRPV1) countered this.

Methods: We fed wild-type (WT) and TRPV1-/- mice with either normal-chow diet or HFD (+/- Capsaicin; a TRPV1 agonist; 13.33 mg/kg) for 32 weeks and isolated the liver tissue to perform in vitro biochemical and quantitative RT-PCR experiments. We also measured mitochondrial fatty acid oxidation (FAO) in these tissues.

Results: Our data show that capsaicin promoted peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression and its activation-dependent mitochondrial biogenesis and unc-51 like kinase (ULK-1)-dependent mitophagy in the liver tissues of HFD-fed WT but not TRPV1-/- mice. The expression of PGC-1alpha and ULK-1 were reduced in the HFD-fed WT and TRPV1-/- mice and capsaicin countered this for the WT mice. Capsaicin feeding increased the mitochondrial numbers, enhanced the phosphorylation and sirtuin-1-dependent deacetylation of ULK-1. Moreover, the expression of mitochondrial uncoupling protein-2 (UCP-2) was enhanced in the liver of capsaicin-fed mice. Further, the mitochondrial FOA and oxygen consumption rate were reduced in the liver tissue isolated from HFD-fed WT mice while capsaicin reversed this.

Conclusions: Collectively, our data demonstrate that TRPV1 activation restores mitochondrial quality control in the liver via PGC-1alpha and ULK-1-dependent mechanisms and contributes for the advancement of capsaicin to counter NASH.