Vinyl chloride-NAFLD interaction

肥胖及其代谢并发症非常普遍，是美国的主要健康问题 以及世界范围内。事实上，肥胖可能会影响个人对其他环境暴露的敏感性，例如 氯乙烯(VC)。具体地说，我们假设实验性NAFLD和某些类型的消费 膳食脂肪的含量，如多不饱和脂肪酸(PUFA)，使肝脏对VC敏感，是第二大热门。因此，我们 提示LA代谢物通过分子、细胞器和细胞增敏肝脏对VC的肝毒性。 VC效应(NAFLD机制)。目的1.评价OXLAM在VC诱导的肝细胞死亡中的作用 在NAFLD的动物模型中。具体来说，我们将：a)确定NAFLD/NAFLD的剂量反应 亚急性VC暴露后的机制以及与HF/LA饮食联合暴露的影响，b)确定 通过12/15-LO基因缺陷消融OXLAM是否减轻VC诱导的肝脏炎症和 伤害和涉及的机制。这项工作将在体内进行野生型(WT)和12/15-LO的比较 具有在药理学或遗传学上靶向12/15-LO的互补体外模型的基因敲除小鼠(例如， 原代细胞来源于12/15-LO-KO小鼠)。根据初步数据，机械终端将包括 线粒体功能障碍、肝细胞死亡(坏死与凋亡)、内质网应激和代谢/生物能量学 影响脂肪变性/细胞存活。这款R03的目标建立在我的K01研究基础上，并扩展了该项目。 然而，在这里，我们正在这个基础上利用新的问题来调查特定的 在美国流行的脂肪类型(及其氧化代谢产物)。这一焦点与我的K01截然不同 研究，但将非常适当地补充它。这项建议与NIDDK调查 肥胖的原因/后果。

Obesity and its metabolic complications are highly prevalent and are major health problems in the United States and worldwide. Indeed, obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically, we hypothesize that experimental NAFLD and the consumption of certain types of dietary fat such as poly-unsaturated fatty acids (PUFA) sensitize the liver to VC as a 2nd hit. We therefore propose that that LA metabolites sensitize the liver to VC hepatotoxicity via molecular, organelle, and cellular VC effects (NAFLD mechanisms). Aim 1. Evaluate the role of OXLAMs in VC-enhanced hepatocyte death in an animal model of NAFLD. Specifically, we will: a) determine the dose response for NAFLD/NAFLD mechanisms following sub-acute VC exposures and the impact of co-exposures with HF/LA diets, b) determine whether the ablation of OXLAMs via 12/15-LO genetic deficiency attenuates VC-induced liver inflammation and injury and the mechanisms involved. This work will be performed in vivo comparing wild-type (WT) to 12/15-LO knockout mice with complementary in vitro models that target 12/15-LO pharmacologically or genetically (e.g., primary cells derived from 12/15-LO KO mice). Mechanistic endpoints based on preliminary data will include mitochondrial dysfunction, hepatocyte death (necrosis vs. apoptosis), ER stress and metabolism/ bioenergetics impacting steatosis/cell survival. The aims of this R03 build on my K01 research and extend that project. However, here we are building on that foundation to leverage new questions in investigating the role of a specific fat type (and its oxidized metabolites) that is prevalent in the US. This focus is distinct and unique from my K01 research, but will complement it very aptly. This proposal is consistent with the goals of NIDDK to investigate the causes/consequences of obesity.