biostudies-literatureKang JNIDDK NIH HHSNCI NIH HHSNational Institutes of Healthe165369https://www.ebi.ac.uk/biostudies/studies/S-EPMC9977430biostudies-literatureUnknown8(3)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 miJCI insightNotch-mediated hepatocyte MCP-1 secretion causes liver fibrosis.PMC9977430R01 DK119767P30 CA008748P30 DK063608R01 DK103818DK103818,DK119767R01 DK066525Dongiovanni PValenti LKim KDapito DHMayfield BYu JZhu CCreusot RJPajvani UBBartolome APostigo-Fernandez JMeroni MKang JFerrante AWfalseNotch-mediated hepatocyte MCP-1 secretion causes liver fibrosis.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 mi2023-01-01T00:00:00Z2023 Feb2025-04-04T20:09:37.953Z2025-04-04T20:09:37.953ZS-EPMC99774303675220610.1172/jci.insight.165369