核受体共激活物5（NCOA5）是一种潜在的2型糖尿病易感基因。NCOA5半缺失会导致雄性小鼠自发发展成非酒精性脂肪肝（NAFLD）、胰岛素抵抗和肝细胞癌（HCC）。然而，NCOA5半缺失在各种类型的细胞中（包括巨噬细胞）对NAFLD和HCC的发展的细胞特异性影响仍不清楚。我们研究了接受正常饮食的对照小鼠和特异性Ncoa5删除（Ncoa5ΔM/ +）小鼠的NAFLD、非酒精性脂肪性肝炎（NASH）和HCC的发展情况。我们分析了Ncoa5ΔM/+雄性小鼠肝内巨噬细胞中的基因和信号通路的变化，并与肥胖人群进行了比较。我们探索了巨噬细胞中血小板因子4（PF4）的作用，以及PF4对NAFLD/NASH的影响的潜在机制。我们还检测了HCC患者标本中PF4的表达和预后。我们发现特异性Ncoa5删除足以使雄性小鼠在正常饮食下自发发展成NASH和HCC。我们发现在Ncoa5ΔM/+肝内巨噬细胞中PF4的过表达是诱导肝细胞脂质积聚的一个强大介质，它通过诱导脂肪生成促进基因的表达来实现。Ncoa5ΔM/+雄性小鼠肝内巨噬细胞的转录组与肥胖人群相似。高PF4表达与HCC患者预后不良以及HCC中M2型巨噬细胞、调节性T细胞（Treg）和髓系抑制细胞（MDSC）的浸润增加相关。我们的研究揭示了由NCOA5缺乏的巨噬细胞引发NAFLD/NASH和HCC发生的一种新机制，这表明巨噬细胞中的NCOA5-PF4轴可能是预防和治疗NAFLD/NASH和HCC的潜在靶点。 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

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.Control and myeloid-lineage-specific Ncoa5 deletion (Ncoa5ΔM/+) mice fed a normal diet were examined for the development of NAFLD, non-alcoholic steatohepatitis (NASH), and HCC. Altered genes and signaling pathways in the intrahepatic macrophages of Ncoa5ΔM/+ male mice were analyzed and compared with that 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.Myeloid-lineage-specific Ncoa5 deletion sufficiently causes spontaneous NASH and HCC development in male mice fed a normal diet. PF4 overexpression in Ncoa5ΔM/+ 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 Ncoa5ΔM/+ male mice resembles that of obese human individuals. High PF4 expression correlated with poor prognosis of HCC patients and increased infiltrations of M2 macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs) in HCCs.Our findings reveal a novel mechanism for the onset of NAFLD/NASH and HCC initiated by NCOA5-deficient macrophages, suggesting the NCOA5-PF4 axis in macrophages as a potential target for developing preventive and therapeutic interventions against NAFLD/NASH and HCC.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.