AUTHOR=Wang Qian , Li Dehai , Zhu Jing , Zhang Mingyue , Zhang Hua , Cao Guangchao , Zhu Leqing , Shi Qiping , Hao Jianlei , Wen Qiong , Liu Zonghua , Yang Hengwen , Yin Zhinan TITLE=Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00846 DOI=10.3389/fimmu.2020.00846 ISSN=1664-3224 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.