Liu Huilin, Beier Juliane I, Arteel Gavin E, Ramsden Christopher E, Feldstein Ariel E, McClain Craig J, Kirpich Irina A
Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; College of Food Science and Engineering, Jilin Agricultural University, Changchun, China.
Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.
Am J Pathol. 2015 Jan;185(1):43-54. doi: 10.1016/j.ajpath.2014.09.007. Epub 2014 Oct 31.
Experimental alcohol-induced liver injury is exacerbated by a high polyunsaturated fat diet rich in linoleic acid. We postulated that bioactive oxidized linoleic acid metabolites (OXLAMs) play a critical role in the development/progression of alcohol-mediated hepatic inflammation and injury. OXLAMs are endogenous ligands for transient receptor potential vanilloid 1 (TRPV1). Herein, we evaluated the role of signaling through TRPV1 in an experimental animal model of alcoholic liver disease (ALD). Chronic binge alcohol administration increased plasma OXLAM levels, specifically 9- and 13-hydroxy-octadecadienoic acids. This effect was associated with up-regulation of hepatic TRPV1. Exposure of hepatocytes to these OXLAMs in vitro resulted in activation of TRPV1 signal transduction with increased intracellular Ca(2+) levels. Genetic depletion of TRPV1 did not blunt hepatic steatosis caused by ethanol, but prevented hepatic injury. TRPV1 deficiency protected from hepatocyte death and prevented the increase in proinflammatory cytokine and chemokine expression, including tumor necrosis factor-α, IL-6, macrophage inflammatory protein-2, and monocyte chemotactic protein 1. TRPV1 depletion markedly blunted ethanol-mediated induction of plasminogen activator inhibitor-1, an important alcohol-induced hepatic inflammation mediator, via fibrin accumulation. This study indicates, for the first time, that TRPV1 receptor pathway may be involved in hepatic inflammatory response in an experimental animal model of ALD. TRPV1-OXLAM interactions appear to play a significant role in hepatic inflammation/injury, further supporting an important role for dietary lipids in ALD.
富含亚油酸的高多不饱和脂肪饮食会加剧实验性酒精性肝损伤。我们推测生物活性氧化亚油酸代谢产物(OXLAMs)在酒精介导的肝脏炎症和损伤的发生/发展中起关键作用。OXLAMs是瞬时受体电位香草酸受体1(TRPV1)的内源性配体。在此,我们在酒精性肝病(ALD)的实验动物模型中评估了通过TRPV1进行信号传导的作用。长期暴饮酒精会增加血浆OXLAM水平,特别是9-和13-羟基十八碳二烯酸。这种作用与肝脏TRPV1的上调有关。体外将肝细胞暴露于这些OXLAMs会导致TRPV1信号转导激活,细胞内Ca(2+)水平升高。TRPV1基因缺失并未减轻乙醇引起的肝脏脂肪变性,但可预防肝损伤。TRPV1缺乏可保护肝细胞免于死亡,并防止促炎细胞因子和趋化因子表达增加,包括肿瘤坏死因子-α、IL-6、巨噬细胞炎性蛋白-2和单核细胞趋化蛋白1。TRPV1缺失通过纤维蛋白积累显著减弱了乙醇介导的纤溶酶原激活物抑制剂-1的诱导,纤溶酶原激活物抑制剂-1是一种重要的酒精诱导的肝脏炎症介质。本研究首次表明,TRPV1受体途径可能参与ALD实验动物模型中的肝脏炎症反应。TRPV1-OXLAM相互作用似乎在肝脏炎症/损伤中起重要作用,进一步支持了饮食脂质在ALD中的重要作用。