Kim Da Mi, Pan Quan, Liu Zeyu, Ai Weiqi, Han Hye Won, Banu Sakhila K, Tsai Robert Y L, Wright Gus A, Guo Shaodong, Sun Yuxiang
Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA.
Adv Sci (Weinh). 2025 Sep;12(33):e04223. doi: 10.1002/advs.202504223. Epub 2025 Jun 6.
Liver fibrosis is a severe liver disease directly linked to chronic inflammation, in which hepatic macrophages play a key role. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin that has essential functions in metabolism, inflammation, and wound-healing. However, the role of GHSR in liver fibrosis is unknown. This study uses a carbon tetrachloride (CCl)-induced liver fibrosis mouse model to investigate the role of macrophage GHSR in liver fibrosis. CCl induces macrophage accumulation and inflammatory responses, noticeably increases GHSR expression in the liver. It is found that macrophage Ghsr deletion (Ghsr-MϕKO) attenuates CCl-induced liver fibrosis and inflammation, showing reduced hepatic monocyte-derived macrophages (MDMs) and suppressed proinflammatory responses. In macrophages, transforming growth factor (TGF)-β1 expression is positively correlated with GHSR expression. GHSR-associated TGF-β1 in macrophages activates hepatic stellate cells (HSCs) by promoting the crosstalk between macrophages and HSCs. Macrophage GHSR controls inflammation and TGF-β1 expression via protein kinase A (PKA)-mediated Forkhead box protein O 1 (Foxo1) phosphorylation at S273; Foxo1-S273D mutation, mimicking constitutive phosphorylation of Foxo1 at S273, shows exacerbated CCl-induced liver inflammation and fibrosis. Thus, targeting the macrophage GHSR-Foxo1 signaling may provide a new strategy to treat liver fibrosis.
肝纤维化是一种与慢性炎症直接相关的严重肝脏疾病，其中肝巨噬细胞起着关键作用。生长激素促分泌素受体（GHSR）是营养感应激素胃饥饿素的受体，在代谢、炎症和伤口愈合中具有重要功能。然而，GHSR在肝纤维化中的作用尚不清楚。本研究使用四氯化碳（CCl）诱导的肝纤维化小鼠模型来研究巨噬细胞GHSR在肝纤维化中的作用。CCl诱导巨噬细胞积聚和炎症反应，显著增加肝脏中GHSR的表达。研究发现，巨噬细胞Ghsr基因缺失（Ghsr-MϕKO）可减轻CCl诱导的肝纤维化和炎症，表现为肝脏单核细胞衍生巨噬细胞（MDM）减少和促炎反应受到抑制。在巨噬细胞中，转化生长因子（TGF）-β1的表达与GHSR的表达呈正相关。巨噬细胞中与GHSR相关的TGF-β1通过促进巨噬细胞与肝星状细胞（HSC）之间的相互作用来激活HSC。巨噬细胞GHSR通过蛋白激酶A（PKA）介导的叉头框蛋白O 1（Foxo1）在S273位点的磷酸化来控制炎症和TGF-β1的表达；Foxo1-S273D突变模拟了Foxo1在S273位点的组成型磷酸化，显示CCl诱导的肝脏炎症和纤维化加剧。因此，靶向巨噬细胞GHSR-Foxo1信号通路可能为治疗肝纤维化提供一种新策略。
