Adiponectin in alcoholic liver disease and liver regeneration

Alcoholic Liver Disease (ALD) is a significant cause of morbidity and mortality worldwide. The earliest clinical sign of ALD is hepatosteatosis, the accumulation of lipid droplets in the liver. Liver inflammation accompanied by hepatosteatosis is called steatohepatitis, and is generally considered progressive ALD. Steatohepatitis causes hepatocyte damage and apoptosis, requiring proliferation to restore lost tissue; however alcohol also suppresses the regenerative capacity of the liver. Despite the burden of disease and advances in understanding molecular mechanism, therapeutic options to treat ALD remain limited. Hepatosteatosis development is thought to be caused by decreases in fatty acid oxidation and insulin resistance. Chronic alcohol intake can inhibit activation of AMP-activated protein kinase (AMPK), which drives both fatty acid oxidation and hepatocyte proliferation during liver regeneration. Chronic alcohol intake elevates liver ceramide levels which promotes insulin resistance and modulates TNFα and IL-6, which are important drivers of liver regeneration. The serum adipokine adiponectin stimulates fatty acid oxidation through activation of AMPK and increases insulin sensitivity through reductions in liver ceramide levels. Adiponectin also normalizes responses to inflammatory cytokines. Serum adiponectin is reportedly reduced after alcohol feeding, and this has been proposed as a common mechanism accounting for multiple effects of alcohol on the liver. Therefore, therapeutic strategies aimed at elevating adiponectin levels have been suggested, however important questions regarding adiponectin\u27s mechanism of action remain. Work in this thesis tested the hypothesis that adiponectin protects the liver through regulation of liver ceramides and promotes hepatocyte proliferation through regulation of AMPK activation in addition to TNFα and IL-6. We compared liver regeneration after PHx and the effects of alcohol feeding in WT and adiponectin KO mice. We showed adiponectin suppressed hepatosteatosis development through regulation of liver ceramide levels after alcohol feeding. Additionally, while adiponectin was required for the onset of hepatocyte proliferation after PHx, elevated adiponectin in WT mice was also associated with delays in liver regeneration. This suggests that precise adiponectin regulation is required for liver regeneration and that therapeutics designed to elevate adiponectin may inhibit recovery of lost tissue. Importantly, our study demonstrating adiponectin regulates alcohol-mediated increases in liver ceramides provides novel therapeutic targets