title: miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling.
abstract: 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-κB 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.
authors: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors: Huquan
authors: H
authors: Yin
authors: Department of Molecular Pharmacology and Physiology, University of South Florida Health Sciences Center, Tampa, Florida.
authors: Xiaomei
authors: X
authors: Liang
authors: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, College of Pharmacy, Rootstown, Ohio.
authors: Alvin
authors: A
authors: Jogasuria
authors: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri.
authors: Nicholas O
authors: NO
authors: Davidson
authors: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, College of Pharmacy, Rootstown, Ohio. Electronic address: myou@neomed.edu.
authors: Min
authors: M
authors: You
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004797:Enzyme-Linked Immunosorbent Assay; D000431:Ethanol / Q000633:toxicity; D005234:Fatty Liver / Q000378:metabolism; D006519:Hepatitis, Alcoholic / Q000235:genetics / Q000378:metabolism*; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D056564:Sirtuin 1 / Q000378:metabolism*; D014162:Transfection
chemical_list: D008070:Lipopolysaccharides; C000591813:MIRN-217 microRNA, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; D000431:Ethanol; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase; D056564:Sirtuin 1