Inhibition of Adipocyte Lipolysis Reduces Liver Injury in a Mouse Model of Ischemia Reperfusion Injury

Hepatic ischemia reperfusion injury (IRI) is unavoidable in most liver operations and is associated with poor patient and graft outcomes in the setting of liver transplantation. However, there are no pharmacological interventions available for treatment of IRI. Prior work has demonstrated that liver IRI leads to hepatic lipid accumulation, suggesting that increased adipocyte lipolytic rates may contribute to hepatic steatosis. Inhibition of adipose triglyceride lipase (ATGL), the rate-limiting enzyme involved in triglyceride hydrolysis, may be beneficial in cardiac injury and alcoholic liver disease, but its role in liver IRI has not been investigated. Our objective was to assess the effects of inhibition of adipose tissue lipolysis in the setting of liver IRI.

Wild-type mice were treated with Atglistatin, a small molecule inhibitor of ATGL, prior to IRI. Mice with hepatocyte- or adipocyte-specific deletion of Pnpla2, the gene encoding ATGL, were generated and subjected to a mouse model of IRI. Mouse hepatocytes were cultured with fatty acids in an in vitro model of IRI.

We demonstrated that experimental IRI was associated with increased adipocyte lipolysis. Pharmacological and genetic inhibition of adipocyte lipolysis reduced plasma and hepatic free fatty acids and decreased circulating transaminases and liver inflammation following hepatic IRI. Furthermore, exogenous fatty acids were sufficient to increase cell death and the expression of inflammatory cytokines in in vitro IRI.

These data suggest that targeting adipocyte lipolysis may represent a novel therapeutic approach in the prevention of hepatic IRI, which could improve patient and graft outcomes following liver transplantation.