Dietary Fat and Alcoholic Liver Disease

 描述(由申请人提供)： 酒精滥用对退伍军人的健康和健康成本造成了重大损失。事实上，尽管丙型肝炎在美国“流行”，但与酒精相关的肝损伤仍然是死亡率较高的原因。退伍军人管理局的研究表明，在四年的时间里，患有肝硬变和酒精性肝炎的患者有60%的死亡率，其中大部分死亡发生在最初的几个月。因此，这一阶段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，没有FDA批准的针对ALD任何阶段的治疗方法，这使得这项拟议的研究的必要性变得更加迫切。我们实验室和其他实验室最近的研究表明，饮食中的不饱和脂肪，特别是富含亚油酸(LA)的食物，可以加重酒精介导的ALD动物模型的肝脏和肠道损伤。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-HoDES)，同时肝脏12/15脂氧合酶(12/15-LO)上调，这是参与LA氧化的关键酶。这些发现使我们假设，特定的氧化LA代谢物(OXLAM)在ALD中发挥着重要作用。OXLAM是瞬时受体电位香草素1(TRPV1)的天然配体，TRPV1是一种配体门控的非选择性阳离子通道，对钙离子具有高通透性。最近的研究表明，钙离子释放在炎症小体激活中起着关键作用，炎症小体激活是应激性致病机制的关键信号平台，激活后，会触发高度促炎细胞因子白介素1β(IL-1β)的释放。 白介素18(IL-18)。IL-1β的释放被认为是炎症和 因此，可作为治疗酒精性肝病肝脏炎症的潜在靶点。我们认为OXLAM通过两个主要机制参与乙醇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；2)OXLAM/TRPV1/Ca~(2+)介导的炎性小体激活和IL-1β的释放。拟议的研究将有助于阐明酒精诱导的肝损伤的分子机制，包括酒精与饮食的相互作用，这可能导致确定新的治疗靶点和潜在的饮食干预措施来治疗酒精性肝病，并有助于解释为什么只有一些酗酒者会患上临床上重要的酒精性肝病。我们的研究将通过三个特定的目标来实现：目的1.评估OXLAM是否通过诱导线粒体功能障碍、内质网应激和肝细胞死亡来加重乙醇介导的肝损伤；目的2.在ALD动物模型中，确定OXLAM是否通过OXLAM-TRPV1介导的炎性小体激活和随后IL-β释放的增加而参与乙醇诱导的肝脏促炎反应。目的3.探讨OXLAM在退伍军人酒精性肝炎单核/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.