Abstract
Monocyte chemoattractant protein-1 (MCP-1, Ccl2) expression is increased in livers of patients with nonalcoholic steatohepatitis and in murine models of steatohepatitis. Several studies in rodents indicate that MCP-1 contributes to liver steatosis induced by feeding a high-fat diet. However, the extent of MCP-1 involvement in the widely utilized methionine-choline-deficient (MCD) diet model of steatohepatitis has not been determined. We tested the hypothesis that MCP-1 contributes to steatohepatitis in mice fed the MCD diet. MCP-1-deficient mice on a C57Bl/6J background and age-matched C57Bl/6J mice were fed either MCD diet or control diet for 4 weeks. MCP-1 deficiency did not affect steatohepatitis, as indicated by liver histopathology, nor did it affect serum alanine aminotransferase activity, hepatic triglyceride levels, hepatic inflammatory gene induction, or macrophage accumulation in mice fed the MCD diet. MCP-1 deficiency reduced the expression of the profibrogenic genes, pro-collagen 1a1, connective tissue growth factor, and transforming growth factor-β, in mice fed the MCD diet. MCP-1 deficiency significantly reduced collagen deposition and α-smooth muscle actin protein levels in the livers of mice fed the MCD diet. The results indicate that MCP-1 does not contribute to liver steatosis or inflammation in the MCD diet model of steatohepatitis. Rather, the data suggest that MCP-1 contributes to fibrosis in mice fed the MCD diet, independent of effects on steatosis and inflammation.