NCOA5 haploinsufficiency in myeloid cells sufficiently causes non-alcoholic steatohepatitis and hepatocellular carcinoma

Molecular and cellular mechanisms causing the onset and progression of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and HCC remain poorly understood. Here we show that myeloid-cell-specific heterozygous deletion of Ncoa5 (Ncoa5?M/+) sufficiently causes the development of NAFLD/NASH and HCC in male mice. The platelet factor 4 (PF4) overexpressed by Ncoa5?M/+ intrahepatic macrophages is identified as a potent mediator to trigger lipid accumulation in hepatocytes by inducing expression of genes promoting lipogenesis. Enrichment score of the gene expression signature derived from Ncoa5?M/+ hepatic macrophages correlated with unfavorable clinical parameters of NAFLD patients. Moreover, in HCC patients, the high PF4 expression correlated with poor overall survival and increased infiltrations of M2 macrophages, exhausted CD8 T cells, and MDSCs in HCCs. Our results reveal a novel macrophage-underlying mechanism for the onset of NAFLD and NASH-related HCC and suggest that NCOA5-PF4 axis is a potential target for therapeutic inhibition of NAFLD/NASH progression. Overall design: mRNA profiles of liver F4/80+ non-parenchymal cells from 6.5-month-old male mice with myeloid-lineage-cell-specific Ncoa5 heterozygous deletion and loxp control male mice. 4 mice in each group.