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Article first published online: 12 OCT 2011
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 54, Issue 6, pages 2185–2197, December 2011
How to Cite
Mandrekar, P., Ambade, A., Lim, A., Szabo, G. and Catalano, D. (2011), An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: Regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology, 54: 2185–2197. doi: 10.1002/hep.24599
Potential conflict of interest: Nothing to report.
This work was supported by PHS grant #AA017545 (to P.M.) and AA017986 (to P.M.) from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) and by the resources of University of Massachusetts Medical School CFAR (grant 5P30 AI42845), and its contents are solely the responsibility of the authors and do not necessarily represent the views of the NIAAA.
- Issue published online: 30 NOV 2011
- Article first published online: 12 OCT 2011
- Accepted manuscript online: 8 AUG 2011 10:25AM EST
- Manuscript Accepted: 26 JUL 2011
- Manuscript Received: 17 FEB 2011
The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as well as hepatocytes of alcohol-fed mice. Alcohol feeding increased serum alanine aminotransferase in WT and CCR2KO, but not MCP-1KO, mice. Alcohol-induced liver steatosis and triglyceride were attenuated in alcohol-fed MCP-1KO, but high in CCR2KO mice, compared to WT, whereas serum endotoxin was high in alcohol-fed WT and MCP-1KO mice. Expression of liver proinflammatory cytokines tumor necrosis factor alpha, interleukin (IL)-1β, IL-6, KC/IL-8, intercellular adhesion molecule 1, and cluster of differentiation 68 was induced in alcohol-fed WT, but inhibited in MCP-1KO, mice independent of nuclear factor kappa light-chain enhancer of activated B cell activation in KCs. Oxidative stress, but not cytochrome P450 2E1, was prevented in chronic alcohol-fed MCP-1KO mice, compared to WT. Increased expression of peroxisome proliferator-activated receptor (PPAR)α and PPARγ was accompanied by nuclear translocation, DNA binding, and induction of fatty acid metabolism genes acyl coenzyme A oxidase and carnitine palmitoyltransferase 1A in livers of alcohol-fed MCP-1KO mice, compared to WT controls. In vitro assays uncovered an inhibitory effect of recombinant MCP-1 on PPARα messenger RNA and peroxisome proliferator response element binding in hepatocytes independent of CCR2. Conclusion: Deficiency of MCP-1 protects mice against alcoholic liver injury, independent of CCR2, by inhibition of proinflammatory cytokines and induction of genes related to fatty acid oxidation, linking chemokines to hepatic lipid metabolism. (HEPATOLOGY 2011)