Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of cirrhosis and major risk factors for hepatocellular carcinoma and liver-related death. Despite substantial clinical and basic research, the pathogenesis of obesity-related NAFLD remains poorly understood. In this study, we show that perforin can act as an immune regulator to prevent the progression of NAFLD. Aged perforin-deficient (Prf-/-) mice have increased lipid accumulation in the liver compared to WT mice. With high-fat diet (HFD) challenge, Prf-/- mice have increased liver weight, more severe liver damage, and increased liver inflammation when compared with WT controls. Mechanistic studies revealed that perforin specifically regulates intrinsic IFN-γ production in CD4 T cells, not CD8 T cells. We found that CD4 T cell depletion reduces liver injury and ameliorates the inflammation and metabolic morbidities in Prf-/- mice. Furthermore, improved liver characteristics in HFD Prf-/- and IFN-γR-/- double knockout mice confirmed that IFN-γ is a key factor for mediating perforin regulation of NAFLD progression. Overall, our findings reveal the important regulatory role perforin plays in the progression of obesity-related NAFLD and highlight novel strategies for treating NAFLD.