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 (LXR α) 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 α agonist GW3965 significantly induced the expression of MCP‐1, which was completely blocked by treatment with 22‐S‐HC or infection by shLXR α lentivirus in the primary hepatocytes. Third, over‐expression of LXR α or GW3965 treatment increased MCP‐1 promoter activity by increasing the binding of hypoxia‐inducible factor‐1α to the hypoxia response elements, together with LXR α. Finally, treatment with recombinant MCP‐1 increased the level of expression of LXR α and LXR α‐dependent lipid droplet accumulation in both hepatocytes and Kupffer cells. These data show that LXR α and its ligand‐induced up‐regulation of MCP‐1 and MCP‐1‐induced LXR α‐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.Copyright © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

“…2b). As previous studies had verified that hepatocytes also expressed MCP-1, the most important inflammatory chemokine associated with macrophage infiltration2627, we tested the mRNA and protein expression of MCP-1 in injured hepatocytes. In contrast to the change in MIF expression, MCP-1 mRNA expression maintained a low level until 4 hours of LPS treatment, and achieved a plateau at 6 hours, with the increase amounting to approximately 40-fold.…”

“…A recent study reported that hepatocytes showed a significant increase in MCP-1 at the mRNA level in ethanol-treated HIV transgenic rats26. Additionally, protein levels of MCP-1 were significantly enhanced in hepatocytes treated with hypoxia-mimicking agents27.…”

Cytokine Changes following Acute Ethanol Intoxication in Healthy Men: A Crossover Study

“…Clearly, MCP-1 expression levels have been found to be uniquely related to blood alcohol content [21]. MCP-1 is responsible for recruitment and activation of monocytes in the process of alcohol liver disease [22]. In specific brain areas of rodents that regulate drinking behavior, MCP-1 has been found colocalized and overexpressed with Toll-like receptor 4, a potent sensor of LPS [23, 24].…”

Nuclear receptors and nonalcoholic fatty liver disease

“…However, nuclear receptors are also important in ASH, CASH, and TASH. PPAR [227], PXR [228], CAR [229], LXR [230], and FXR [231] are implicated in the pathogenesis or therapy of alcoholic liver disease. Nuclear receptor activation may also be involved in the steatohepatitis associated with atypical antipsychotic medications [232].…”