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GHSR‐Foxo1 Signaling in Macrophages Promotes Liver Fibrosis via Inflammatory Response and Hepatic Stellate Cell Activation
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GHSR‐Foxo1 Signaling in Macrophages Promotes Liver Fibrosis via Inflammatory Response and Hepatic Stellate Cell Activation
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Journal Article
GHSR‐Foxo1 Signaling in Macrophages Promotes Liver Fibrosis via Inflammatory Response and Hepatic Stellate Cell Activation
2025
Overview
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. Macrophage GHSR‐Foxo1 axis regulates CCl4‐induced liver fibrosis by promoting inflammation and TGF‐β1‐mediated HSC activation. GHSR activates PKA‐dependent phosphorylation of Foxo1 at serine 273, promoting macrophage pro‐inflammatory polarization to enhance the production of pro‐inflammatory cytokines that damage hepatocytes, thereby inducing liver injury. Moreover, Foxo1 induces profibrotic cytokine, TGF‐β1, in macrophages, activating HSCs and driving excess ECM accumulation, eventually contributing to liver fibrosis.
Publisher
John Wiley & Sons, Inc,Wiley
Subject
/ Animals
/ forkhead box protein o1 (Foxo1)
/ Forkhead Box Protein O1 - genetics
/ Forkhead Box Protein O1 - metabolism
/ growth hormone secretagogue receptors (GHSR)
/ Hepatic Stellate Cells - metabolism
/ Kinases
/ Liver Cirrhosis - metabolism
/ Male
/ Mice
/ Proteins
/ Receptors, Ghrelin - genetics
/ Receptors, Ghrelin - metabolism
/ Signal Transduction - physiology
