ArticleBiology direct2026
Activation of the TGR5/cAMP/PKA/CREB axis in cholangiocytes mediates epithelial-mesenchymal transition and fibrosis in hepatolithiasis.
Article in Biology direct, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Mechanisms underlying the role of the oral-gut-liver axis in the promotion of liver fibrosis by periodontal disease: an interacting network of inflammation, microbiota, and barrier function.Frontiers in cellular and infection microbiology · 2026Review
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5 authors.
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Abstract
backgroundThe molecular mechanisms linking bile acid signaling to biliary fibrosis in hepatolithiasis are unclear. We investigated the role of the bile acid receptor TGR5 in driving fibrotic progression.
methodsWe employed an integrated strategy. TGR5 expression was assessed in human hepatolithiasis tissues and bioinformatics databases. A hepatolithiasis mouse model was compared with TGR5-knockout (TGR5-/-) mice, analyzing lipid metabolism, cholesterol transport, and fibrosis markers via ELISA, qPCR, and immunohistochemistry. In vitro, human intrahepatic biliary epithelial cells (HIBECs) were treated with bile acids, TGR5 agonists/inhibitors, and cAMP modulators. We assessed the cAMP/PKA/CREB pathway, epithelial-mesenchymal transition (EMT), and fibrosis.
resultsTGR5 was significantly overexpressed in hepatolithiasis tissues. Genetic deletion of TGR5 in mice alleviated metabolic disturbances and markedly reduced fibrosis markers (TGF-β1, α-SMA, Collagen I). In cholangiocytes, TGR5 activation stimulated the cAMP/PKA/CREB signaling cascade, promoting EMT and fibrosis. These pro-fibrotic effects were reversed by inhibiting TGR5 or cAMP. Mechanistically, TGR5-driven cAMP signaling induced CREB phosphorylation, leading to upregulated TGF-β1 expression, which sustains the fibrotic phenotype.
conclusionThis study defines a critical pathogenic axis in hepatolithiasis, whereby TGR5 activation in cholangiocytes triggers cAMP/PKA/CREB signaling to promote EMT and biliary fibrosis via TGF-β1. Our findings directly implicate TGR5 as a central therapeutic target for mitigating fibrosis in this disease.
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