title: 22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXRα.
abstract: 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 α (LXRα) 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 LXRα agonist GW3965 significantly induced the expression of MCP-1, which was completely blocked by treatment with 22-S-HC or infection by shLXRα lentivirus in the primary hepatocytes. Third, over-expression of LXRα or GW3965 treatment increased MCP-1 promoter activity by increasing the binding of hypoxia-inducible factor-1α to the hypoxia response elements, together with LXRα. Finally, treatment with recombinant MCP-1 increased the level of expression of LXRα and LXRα-dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXRα and its ligand-induced up-regulation of MCP-1 and MCP-1-induced LXRα-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.
authors.affiliation: College of Pharmacy, Seoul National University, Korea.
authors.forename: Tae-Young
authors.initials: TY
authors.lastname: Na
authors.forename: Young-Hyun
authors.initials: YH
authors.lastname: Han
authors.forename: Na-Lee
authors.initials: NL
authors.lastname: Ka
authors.forename: Han-Su
authors.initials: HS
authors.lastname: Park
authors.forename: Yun Pyo
authors.initials: YP
authors.lastname: Kang
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kwon
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects*; D001665:Binding Sites; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D019610:Cytoprotection; D004195:Disease Models, Animal; D000431:Ethanol; D005235:Fatty Liver, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006888:Hydroxycholesterols / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C497443:Hif1a protein, mouse; D006888:Hydroxycholesterols; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C003585:22-hydroxycholesterol; D000431:Ethanol
keywords: HIF-1; LXRα; MCP-1; alcoholic liver disease