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22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXR?.

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 ? (LXR?) 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 LXR? agonist GW3965 significantly induced the expression of MCP-1, which was completely blocked by treatment with 22-S-HC or infection by shLXR? lentivirus in the primary hepatocytes. Third, over-expression of LXR? or GW3965 treatment increased MCP-1 promoter activity by increasing the binding of hypoxia-inducible factor-1? to the hypoxia response elements, together with LXR?. Finally, treatment with recombinant MCP-1 increased the level of expression of LXR? and LXR?-dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXR? and its ligand-induced up-regulation of MCP-1 and MCP-1-induced LXR?-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.

SUBMITTER: Na TY

PROVIDER: S-EPMC6084351 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXRα.

Na Tae-Young TY Han Young-Hyun YH Ka Na-Lee NL Park Han-Su HS Kang Yun Pyo YP Kwon Sung Won SW Lee Byung-Hoon BH Lee Mi-Ock MO

The Journal of pathology 20150105 5

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 ...[more]

PMID: 25557254

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22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXR?.

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22-S-Hydroxycholesterol protects against ethanol-induced liver injury by blocking the auto/paracrine activation of MCP-1 mediated by LXRα.

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