PMID- 21826694
OWN - NLM
STAT- MEDLINE
DCOM- 20120207
LR  - 20211020
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 54
IP  - 6
DP  - 2011 Dec
TI  - An essential role for monocyte chemoattractant protein-1 in alcoholic liver 
      injury: regulation of proinflammatory cytokines and hepatic steatosis in mice.
PG  - 2185-97
LID - 10.1002/hep.24599 [doi]
AB  - 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)-1beta, 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)alpha and PPARgamma 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 PPARalpha 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.
CI  - Copyright (c) 2011 American Association for the Study of Liver Diseases.
FAU - Mandrekar, Pranoti
AU  - Mandrekar P
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, MA 
      01605, USA. pranoti.mandrekar@umassmed.edu
FAU - Ambade, Aditya
AU  - Ambade A
FAU - Lim, Arlene
AU  - Lim A
FAU - Szabo, Gyongyi
AU  - Szabo G
FAU - Catalano, Donna
AU  - Catalano D
LA  - eng
GR  - R01 AA017986/AA/NIAAA NIH HHS/United States
GR  - P30 AI042845/AI/NIAID NIH HHS/United States
GR  - 5P30 AI42845/AI/NIAID NIH HHS/United States
GR  - AA017545/AA/NIAAA NIH HHS/United States
GR  - R21 AA017545-01A1/AA/NIAAA NIH HHS/United States
GR  - R21 AA017545/AA/NIAAA NIH HHS/United States
GR  - AA017986/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cytokines)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Peroxisome Proliferator-Activated Receptors)
RN  - 0 (Receptors, CCR2)
RN  - EC 1.3.3.6 (Acyl-CoA Oxidase)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
MH  - Acyl-CoA Oxidase/metabolism
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/metabolism
MH  - Cell Line, Tumor
MH  - Chemokine CCL2/deficiency/*physiology
MH  - Cytokines/*physiology
MH  - Fatty Liver, Alcoholic/*physiopathology
MH  - Female
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Kupffer Cells/drug effects/metabolism
MH  - Lipopolysaccharides
MH  - Liver/*metabolism
MH  - Liver Diseases, Alcoholic/*physiopathology/prevention & control
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Oxidative Stress
MH  - Peroxisome Proliferator-Activated Receptors/metabolism
MH  - Receptors, CCR2/*physiology
PMC - PMC3342822
MID - NIHMS339225
EDAT- 2011/08/10 06:00
MHDA- 2012/02/09 06:00
PMCR- 2012/05/03
CRDT- 2011/08/10 06:00
PHST- 2011/08/10 06:00 [entrez]
PHST- 2011/08/10 06:00 [pubmed]
PHST- 2012/02/09 06:00 [medline]
PHST- 2012/05/03 00:00 [pmc-release]
AID - 10.1002/hep.24599 [doi]
PST - ppublish
SO  - Hepatology. 2011 Dec;54(6):2185-97. doi: 10.1002/hep.24599.