Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan; Department of Physiology, Michigan State University, East Lansing, Michigan.
Department of Physiology, Michigan State University, East Lansing, Michigan; Cancer Center, Southern Medical University, Guangzhou, Guangdong, China; Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, China.
Cell Mol Gastroenterol Hepatol. 2024;17(1):1-27. doi: 10.1016/j.jcmgh.2023.09.007. Epub 2023 Sep 19.
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.
Control and myeloid-lineage-specific Ncoa5 deletion (Ncoa5) 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 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.
Myeloid-lineage-specific Ncoa5 deletion sufficiently causes spontaneous NASH and HCC development in male mice fed a normal diet. PF4 overexpression in Ncoa5 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 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, and myeloid-derived suppressor cells 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.
核受体共激活因子 5（NCOA5）是一种潜在的 2 型糖尿病易感基因。NCOA5 杂合不足导致雄性小鼠自发发生非酒精性脂肪性肝病（NAFLD）、胰岛素抵抗和肝细胞癌（HCC）；然而，NCOA5 杂合不足在各种类型的细胞（包括巨噬细胞）中对 NAFLD 和 HCC 的发展的细胞特异性影响尚不清楚。
用正常饮食喂养对照和髓系特异性 Ncoa5 缺失（Ncoa5）小鼠，观察其 NAFLD、非酒精性脂肪性肝炎（NASH）和 HCC 的发生情况。分析和比较 Ncoa5 雄性小鼠肝内巨噬细胞中改变的基因和信号通路与肥胖人类个体的基因和信号通路。在体外和体内研究血小板因子 4（PF4）在巨噬细胞中的作用及其影响 NAFLD/NASH 的潜在机制。检查 HCC 患者标本中 PF4 的表达和预后。
髓系特异性 Ncoa5 缺失足以导致雄性小鼠在正常饮食喂养下自发发生 NASH 和 HCC。PF4 在 Ncoa5 肝内巨噬细胞中的过表达被鉴定为一种有效的介质，通过诱导促进脂肪生成的基因表达来触发肝细胞内脂质堆积。Ncoa5 雄性小鼠肝内巨噬细胞的转录组与肥胖人类个体的转录组相似。PF4 高表达与 HCC 患者预后不良相关，并且在 HCC 中 M2 巨噬细胞、调节性 T 细胞和髓源性抑制细胞的浸润增加。
我们的研究结果揭示了 NCOA5 缺陷巨噬细胞引发 NAFLD/NASH 和 HCC 发生的新机制，提示巨噬细胞中的 NCOA5-PF4 轴作为预防和治疗 NAFLD/NASH 和 HCC 的潜在靶点。
