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Notch-mediated hepatocyte MCP-1 secretion causes liver fibrosis
- Source :
- JCI Insight, Vol 8, Iss 3 (2023)
- Publication Year :
- 2023
- Publisher :
- American Society for Clinical investigation, 2023.
-
Abstract
- Patients with nonalcoholic steatohepatitis (NASH) have increased expression of liver monocyte chemoattractant protein-1 (MCP-1), but its cellular source and contribution to various aspects of NASH pathophysiology remain debated. We demonstrated increased liver CCL2 (which encodes MCP-1) expression in patients with NASH, and commensurately, a 100-fold increase in hepatocyte Ccl2 expression in a mouse model of NASH, accompanied by increased liver monocyte-derived macrophage (MoMF) infiltrate and liver fibrosis. To test repercussions of increased hepatocyte-derived MCP-1, we generated hepatocyte-specific Ccl2-knockout mice, which showed reduced liver MoMF infiltrate as well as decreased liver fibrosis. Forced hepatocyte MCP-1 expression provoked the opposite phenotype in chow-fed wild-type mice. Consistent with increased hepatocyte Notch signaling in NASH, we observed a close correlation between markers of Notch activation and CCL2 expression in patients with NASH. We found that an evolutionarily conserved Notch/recombination signal binding protein for immunoglobulin kappa J region binding site in the Ccl2 promoter mediated transactivation of the Ccl2 promoter in NASH diet–fed mice. Increased liver MoMF infiltrate and liver fibrosis seen in opposite gain-of-function mice was ameliorated with concomitant hepatocyte Ccl2 knockout or CCR2 inhibitor treatment. Hepatocyte Notch activation prompts MCP-1–dependent increase in liver MoMF infiltration and fibrosis.
- Subjects :
- Gastroenterology
Metabolism
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 8
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- JCI Insight
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.893b0d435e8c4be89502dc501cc828e0
- Document Type :
- article
- Full Text :
- https://doi.org/10.1172/jci.insight.165369