miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin

miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin

Yin Huquan; Liang Xiaomei; Jogasuria Alvin; Davidson Nicholas O; You Min

The American journal of pathology

2015

2015-05

Ethanol-mediated injury, combined with gut-derived lipopolysaccharide (LPS), provokes generation of proinflammatory cytokines in Kupffer cells, causing hepatic inflammation. Among the mediators of these effects, miR-217 aggravates ethanol-induced steatosis in hepatocytes. However, the role of miR-217 in ethanol-induced liver inflammation process is unknown. Here, we examined the role of miR-217 in the responses to ethanol, LPS, or a combination of ethanol and LPS in RAW 264.7 macrophages and in primary Kupffer cells. In macrophages, ethanol substantially exacerbated LPS-mediated induction of miR-217 and production of proinflammatory cytokines compared with LPS or ethanol alone. Consistently, ethanol administration to mice led to increases in miR-217 abundance and increased production of inflammatory cytokines in isolated primary Kupffer cells exposed to the combination of ethanol and LPS. miR-217 promoted combined ethanol and LPS-mediated inhibition of sirtuin 1 expression and activity in macrophages. Moreover, miR-217-mediated sirtuin 1 inhibition was accompanied by increased activities of two vital inflammatory regulators, NF-kappaB and the nuclear factor of activated T cells c4. Finally, adenovirus-mediated overexpression of miR-217 led to steatosis and inflammation in mice. These findings suggest that miR-217 is a pivotal regulator involved in ethanol-induced hepatic inflammation. Strategies to inhibit hepatic miR-217 could be a viable approach in attenuating alcoholic hepatitis.

Alcoholic/genetics/*metabolism; Animals; Chromatin Immunoprecipitation; Enzyme-Linked Immunosorbent Assay; Ethanol/toxicity; Fatty Liver/metabolism; Hepatitis; Immunoblotting; Inbred C57BL; Inflammation/genetics/*metabolism; Kupffer Cells/metabolism; Lipopolysaccharides/toxicity; Male; Mice; MicroRNAs/*metabolism; Nuclear Proteins/*metabolism; Phosphatidate Phosphatase/*metabolism; Real-Time Polymerase Chain Reaction; Signal Transduction/*physiology; Sirtuin 1/*metabolism; Transfection

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1286–1296

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