Dietary Fat and Alcoholic Liver Disease

 描述（由申请人提供）： 酗酒对退伍军人的健康和健康成本造成了重大影响。事实上，即使在美国有丙型肝炎的“流行病”，与酒精有关的肝损伤仍然是较高的死亡原因。退伍军人管理局的研究表明，肝硬化和酒精性肝炎叠加的患者在四年内的死亡率超过60%，其中大多数死亡发生在最初的几个月。因此，这个阶段的ALD的预后比许多常见类型的癌症，如乳腺癌，前列腺癌和结肠癌更差。不幸的是，对于ALD的任何阶段都没有FDA批准的治疗方法，这使得这项研究的必要性更加迫切。我们实验室和其他人最近的研究表明，饮食中的不饱和脂肪，特别是富含亚油酸（LA）的脂肪，在ALD的实验动物模型中加剧了酒精介导的肝脏和肠道损伤。我们的初步数据显示，在ALD动物模型中，循环氧化的LA代谢物水平升高，特别是9-和13-羟基-十八碳二烯酸（9-和13-HODE），同时肝脏12/15脂氧合酶（12/15-LO）上调，这是一种参与LA氧化的关键酶。这些发现使我们推测特定的氧化LA代谢物（OXLAMs）在ALD中起重要作用。OXLAMs是瞬时受体电位香草酸1（TRPV 1）的天然配体，TRPV 1是一种配体门控的非选择性阳离子通道，对Ca 2+具有高渗透性。最近的研究表明，Ca 2+释放在炎性小体激活中起关键作用，炎性小体是应激诱导的发病机制的关键信号平台，并且在激活后，触发高度促炎细胞因子白细胞介素-1 β（IL-1β）的释放。 和白细胞介素-18（IL-18）。IL-1β释放被认为是炎症的关键介质， 因此，作为治疗ALD中肝脏炎症的潜在治疗靶点。我们认为OXLAM通过两种主要机制参与EtOH诱导的肝脏炎症和损伤：1）OXLAM介导的线粒体功能障碍、内质网应激（ER应激）和肝细胞死亡;和2）OXLAM/TRPV 1/Ca 2+介导的炎性小体激活和IL-1β释放。拟议的研究将有助于阐明酒精诱导的肝损伤的分子机制，包括酒精-饮食相互作用，这可能导致识别新的治疗靶点和治疗ALD的潜在饮食干预措施，并有助于解释为什么只有一些重度饮酒者发展临床重要的ALD。我们的研究将通过三个具体目标来实现：目标1。在ALD动物模型中评价OXLAM是否通过诱导线粒体功能障碍、ER应激和肝细胞死亡而加重EtOH介导的肝损伤;目的2。在ALD动物模型中确定OXLAM是否通过OXLAM-TRPV 1介导的炎性小体激活和随后的IL-β释放增加而促进EtOH诱导的肝脏促炎反应。目标3：探索OXLAMs在退伍军人酒精性肝炎中单核细胞/巨噬细胞炎性小体激活中的作用。

 DESCRIPTION (provided by applicant): Alcohol abuse exacts a major toll on health and health costs in Veterans. Indeed, even though there is an "epidemic" of hepatitis C in the U.S., alcohol-related liver injury remains a higher cause of mortality. Studies from the Veterans Administration showed that patients with cirrhosis and superimposed alcoholic hepatitis had > 60% mortality over a four-year period of time, with most of those deaths occurring in the first few months. Thus, the prognosis for this stage of ALD is worse than many common types of cancer, such as breast, prostate and colon. Unfortunately, there is no FDA-approved therapy for any stage of ALD, and this makes the need for this proposed research even more compelling. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat, specifically rich in linoleic acid (LA), exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites, specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), a key enzyme involved in the oxidation of LA, in an animal model of ALD. These findings led us to postulate that specific oxidized LA metabolites (OXLAMs) play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1), a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation, which are key signaling platforms for stressor-induced pathogenesis, and which, upon activation, trigger the release of highly pro- inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). IL-1β release is thought to be a critical mediator of inflammation and thus, serves as a potential therapeutic target for treating hepatic inflammation in ALD. We propose that OXLAMs contribute to the EtOH-induced hepatic inflammation and injury via two major mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction, endoplasmic reticulum stress (ER stress) and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1β release. The proposed studies will help elucidate the molecular mechanisms of alcohol-induced liver injury, including alcohol-diet interactions, which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD, as well as help to explain why only some heavy drinkers develop clinically important ALD. Our research will be achieved through 3 specific aims: Aim 1. Evaluate whether OXLAMs exacerbate EtOH-mediated liver injury via induction of mitochondrial dysfunction, ER stress, and hepatocyte cell death in an animal model of ALD; Aim 2. Determine whether OXLAMs contribute to an EtOH-induced hepatic pro-inflammatory response via OXLAM-TRPV1-mediated inflammasome activation and subsequent increase in IL-β release in an animal model of ALD. Aim 3. Explore the role of OXLAMs in monocytes/macrophages inflammasome activation in Alcoholic Hepatitis in Veterans.