PMID- 25557254
OWN - NLM
STAT- MEDLINE
DCOM- 20150507
LR  - 20181113
IS  - 1096-9896 (Electronic)
IS  - 0022-3417 (Print)
IS  - 0022-3417 (Linking)
VI  - 235
IP  - 5
DP  - 2015 Apr
TI  - 22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking 
      the auto/paracrine activation of MCP-1 mediated by LXRalpha.
PG  - 710-20
LID - 10.1002/path.4494 [doi]
AB  - Chronic ethanol consumption causes hepatic steatosis and inflammation, which are 
      associated with liver hypoxia. Monocyte chemoattractant protein-1 (MCP-1) is a 
      hypoxia response factor that determines recruitment and activation of monocytes 
      to the site of tissue injury. The level of MCP-1 is elevated in the serum and 
      liver of patients with alcoholic liver disease (ALD); however, the molecular 
      details regarding the regulation of MCP-1 expression are not yet understood 
      completely. Here, we show the role of liver X receptor alpha (LXRalpha) in the regulation 
      of MCP-1 expression during the development of ethanol-induced fatty liver injury, 
      using an antagonist, 22-S-hydroxycholesterol (22-S-HC). First, administration of 
      22-S-HC attenuated the signs of liver injury with decreased levels of MCP-1 and 
      its receptor CCR2 in ethanol-fed mice. Second, hypoxic conditions or treatment 
      with the LXRalpha agonist GW3965 significantly induced the expression of MCP-1, which 
      was completely blocked by treatment with 22-S-HC or infection by shLXRalpha 
      lentivirus in the primary hepatocytes. Third, over-expression of LXRalpha or GW3965 
      treatment increased MCP-1 promoter activity by increasing the binding of 
      hypoxia-inducible factor-1alpha to the hypoxia response elements, together with LXRalpha. 
      Finally, treatment with recombinant MCP-1 increased the level of expression of 
      LXRalpha and LXRalpha-dependent lipid droplet accumulation in both hepatocytes and 
      Kupffer cells. These data show that LXRalpha and its ligand-induced up-regulation of 
      MCP-1 and MCP-1-induced LXRalpha-dependent lipogenesis play a key role in the 
      autocrine and paracrine activation of MCP-1 in the pathogenesis of alcoholic 
      fatty liver disease, and that this activation may provide a promising new target 
      for ALD therapy.
CI  - Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by 
      John Wiley & Sons, Ltd.
FAU - Na, Tae-Young
AU  - Na TY
AD  - College of Pharmacy, Seoul National University, Korea.
FAU - Han, Young-Hyun
AU  - Han YH
FAU - Ka, Na-Lee
AU  - Ka NL
FAU - Park, Han-Su
AU  - Park HS
FAU - Kang, Yun Pyo
AU  - Kang YP
FAU - Kwon, Sung Won
AU  - Kwon SW
FAU - Lee, Byung-Hoon
AU  - Lee BH
FAU - Lee, Mi-Ock
AU  - Lee MO
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150105
PL  - England
TA  - J Pathol
JT  - The Journal of pathology
JID - 0204634
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hydroxycholesterols)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Liver X Receptors)
RN  - 0 (Nr1h3 protein, mouse)
RN  - 0 (Orphan Nuclear Receptors)
RN  - 17711-16-9 (22-hydroxycholesterol)
RN  - 3K9958V90M (Ethanol)
SB  - IM
EIN - J Pathol. 2016 Apr;238(5):719. PMID: 27000438
MH  - Animals
MH  - Autocrine Communication/*drug effects
MH  - Binding Sites
MH  - Cell Hypoxia
MH  - Cells, Cultured
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Cytoprotection
MH  - Disease Models, Animal
MH  - Ethanol
MH  - Fatty Liver, Alcoholic/metabolism/pathology/*prevention & control
MH  - Hepatocytes/drug effects/metabolism/pathology
MH  - Hydroxycholesterols/*pharmacology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Kupffer Cells/drug effects/metabolism/pathology
MH  - Lipogenesis/drug effects
MH  - Liver/*drug effects/metabolism/pathology
MH  - Liver X Receptors
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Orphan Nuclear Receptors/*antagonists & inhibitors/genetics/metabolism
MH  - Paracrine Communication/*drug effects
MH  - Promoter Regions, Genetic
MH  - Signal Transduction/drug effects
MH  - Transfection
MH  - Up-Regulation
PMC - PMC6084351
OTO - NOTNLM
OT  - HIF-1
OT  - LXRalpha
OT  - MCP-1
OT  - alcoholic liver disease
EDAT- 2015/01/06 06:00
MHDA- 2015/05/08 06:00
PMCR- 2018/08/09
CRDT- 2015/01/06 06:00
PHST- 2014/07/07 00:00 [received]
PHST- 2014/11/05 00:00 [revised]
PHST- 2014/11/29 00:00 [accepted]
PHST- 2015/01/06 06:00 [entrez]
PHST- 2015/01/06 06:00 [pubmed]
PHST- 2015/05/08 06:00 [medline]
PHST- 2018/08/09 00:00 [pmc-release]
AID - PATH4494 [pii]
AID - 10.1002/path.4494 [doi]
PST - ppublish
SO  - J Pathol. 2015 Apr;235(5):710-20. doi: 10.1002/path.4494. Epub 2015 Jan 5.