NCOA5 Haploinsufficiency in Myeloid-Lineage Cells Sufficiently Causes Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

作者：Yueqi Zhang, Yue Luo, Xinhui Liu, Matti Kiupel, Aimin Li, Hongbing Wang, Qing‐Sheng Mi, Hua Xiao · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2023 · DOI：10.1016/j.jcmgh.2023.09.007 · 被引用次数：8 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Liver Disease Diagnosis and Treatment、Peroxisome Proliferator-Activated Receptors

Background & Aims The nuclear receptor coactivator 5 (NCOA5) is a putative type 2 diabetes susceptibility gene. NCOA5 haploinsufficiency results in the spontaneous development of nonalcoholic fatty liver disease (NAFLD), insulin resistance, and hepatocellular carcinoma (HCC) in male mice; however, the cell-specific effect of NCOA5 haploinsufficiency in various types of cells, including macrophages, on the development of NAFLD and HCC remains unknown. Methods Control and myeloid-lineage–specific Ncoa5 deletion ( Ncoa5 ΔM/+ ) mice fed a normal diet were examined for the development of NAFLD, nonalcoholic steatohepatitis (NASH), and HCC. Altered genes and signaling pathways in the intrahepatic macrophages of Ncoa5 ΔM/+ male mice were analyzed and compared with those of obese human individuals. The role of platelet factor 4 (PF4) in macrophages and the underlying mechanism by which PF4 affects NAFLD/NASH were explored in vitro and in vivo. PF4 expression in HCC patient specimens and prognosis was examined. Results Myeloid-lineage–specific Ncoa5 deletion sufficiently causes spontaneous NASH and HCC development in male mice fed a normal diet. PF4 overexpression in Ncoa5 ΔM/+ intrahepatic macrophages is identified as a potent mediator to trigger lipid accumulation in hepatocytes by inducing lipogenesis-promoting gene expression. The transcriptome of intrahepatic macrophages from Ncoa5 ΔM/+ male mice resembles that of obese human individuals. High PF4 expression correlated with poor ...