Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Inhibiting VEGFC - mediated hepatocyte - macrophage regulatory axis contributes to protective effects of naringin against high - fat diet - induced hepatic fibrosis.
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Li Jingya, Nie Ao, Li Xinyi, Chen Zheng, Xu Kai, Yan Junbin, Yao Kannan, Lin Xiaojie, Mao Wei, Chen Zhiyun, Hong Wei
Аннотация
BACKGROUND: Naringin (NAR) has shown anti-fibrotic effects. This study found it alleviates non-alcoholic steatohepatitis (NASH)-associated liver fibrosis and downregulates vascular endothelial growth factor C (VEGFC). However, the pathophysiological role of VEGFC in NASH and its contribution to NAR's protection remain unclear.
OBJECTIVE: To determine whether and how the downregulation of VEGFC contributes to the protective effect of NAR against NASH-associated hepatic fibrosis.
METHODS: A mouse model of NASH fibrosis was induced by a 24-week high-fat diet (HFD). Mice were treated concomitantly with NAR-L (25 mg/kg/day), NAR-H (50 mg/kg/day), or SAR131675 (SAR, 30 mg/kg/day) from week 9 to 24 (16 weeks). Clinical serum VEGFC levels were measured in a hospital cohort (n = 165); human hepatic VEGFC expression was analyzed in using data from Gene Expression Omnibus (GEO) datasets (GSE162694, GSE130970). Hepatocyte-specific Vegfc knockout mice (VegfcHep‑cKO) were generated by crossing Vegfcflox/flox with Alb-CreERT2 (Albumin-CreERT2) mice. In vitro, AML12 hepatocytes were pretreated (oleic acid, recombinant VEGFC, or Vegfc genetic modulation); these cells or their conditioned medium were used to stimulate bone marrow-derived macrophages to assess macrophage migration and phenotypic switching.
RESULTS: NAR and SAR131675 ameliorated liver inflammation and fibrosis in mice, downregulated VEGFC and CCL2/CCR2, reduced Ly6Chigh monocyte infiltration, and promoted Ly6Chigh-to-Ly6Clow macrophage phenotypic switch. Clinical data showed elevated VEGFC in NAFLD and NASH patients. VegfcHep‑cKO mice exhibited similar therapeutic effects. In vitro, hepatocyte-derived VEGFC promoted macrophage migration via VEGFR3 and CCL2/CCR2; inhibited phenotypic transition via regulating IL-10 or CX3CR1. NAR disrupted this axis by suppressing VEGFC in hepatocytes.
CONCLUSION: Hepatocyte-derived VEGFC is a key contributor to NASH-related liver fibrosis, functioning by regulating macrophage migration and phenotypic switch. The hepatoprotective effect of NAR is partially mediated through the inhibition of the VEGFC-mediated hepatocyte-macrophage regulatory axis.
OBJECTIVE: To determine whether and how the downregulation of VEGFC contributes to the protective effect of NAR against NASH-associated hepatic fibrosis.
METHODS: A mouse model of NASH fibrosis was induced by a 24-week high-fat diet (HFD). Mice were treated concomitantly with NAR-L (25 mg/kg/day), NAR-H (50 mg/kg/day), or SAR131675 (SAR, 30 mg/kg/day) from week 9 to 24 (16 weeks). Clinical serum VEGFC levels were measured in a hospital cohort (n = 165); human hepatic VEGFC expression was analyzed in using data from Gene Expression Omnibus (GEO) datasets (GSE162694, GSE130970). Hepatocyte-specific Vegfc knockout mice (VegfcHep‑cKO) were generated by crossing Vegfcflox/flox with Alb-CreERT2 (Albumin-CreERT2) mice. In vitro, AML12 hepatocytes were pretreated (oleic acid, recombinant VEGFC, or Vegfc genetic modulation); these cells or their conditioned medium were used to stimulate bone marrow-derived macrophages to assess macrophage migration and phenotypic switching.
RESULTS: NAR and SAR131675 ameliorated liver inflammation and fibrosis in mice, downregulated VEGFC and CCL2/CCR2, reduced Ly6Chigh monocyte infiltration, and promoted Ly6Chigh-to-Ly6Clow macrophage phenotypic switch. Clinical data showed elevated VEGFC in NAFLD and NASH patients. VegfcHep‑cKO mice exhibited similar therapeutic effects. In vitro, hepatocyte-derived VEGFC promoted macrophage migration via VEGFR3 and CCL2/CCR2; inhibited phenotypic transition via regulating IL-10 or CX3CR1. NAR disrupted this axis by suppressing VEGFC in hepatocytes.
CONCLUSION: Hepatocyte-derived VEGFC is a key contributor to NASH-related liver fibrosis, functioning by regulating macrophage migration and phenotypic switch. The hepatoprotective effect of NAR is partially mediated through the inhibition of the VEGFC-mediated hepatocyte-macrophage regulatory axis.