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Adv. Sci., Jun 06 2025, | https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/advs.202504223
GHSR-Foxo1 Signaling in Macrophages Promotes Liver Fibrosis via Inflammatory Response and Hepatic Stellate Cell Activation
Da Mi Kim 1 2, Quan Pan 1, Zeyu Liu 1, Weiqi Ai 1, Hye Won Han 1, Sakhila K Banu 3, Robert Y L Tsai 4, Gus A Wright 2, Shaodong Guo 1 *, Yuxiang Sun 1 *
1Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
2Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA.
3Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, 77843, USA.
4Institute of Biosciences and Technology, Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
2Department of Veterinary Pathobiology, Texas A&M University, College Station, TX, 77843, USA.
3Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, 77843, USA.
4Institute of Biosciences and Technology, Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
*Corresponding authors: correspondence to Shaodong Guo or Yuxiang Sun
Abstract
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 (CCl4)-induced liver fibrosis mouse model to investigate the role of macrophage GHSR in liver fibrosis. CCl4 induces macrophage accumulation and inflammatory responses, noticeably increases GHSR expression in the liver. It is found that macrophage Ghsr deletion (Ghsr-MϕKO) attenuates CCl4-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 CCl4-induced liver inflammation and fibrosis. Thus, targeting the macrophage GHSR-Foxo1 signaling may provide a new strategy to treat liver fibrosis.
논문정보
- Research article
- 2025년 06월 (BRIC 등록일 2025-06-10)
- 국외 연구진
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