Vinyl chloride modifies the risk for nonalcoholic fatty liver disease

非酒精性脂肪肝是发达国家的一个主要健康问题，它是由肥胖和新陈代谢的流行所推动的 综合症。尽管早期NAFLD(脂肪肝)在高危人群中的患病率接近100%，但 更严重的疾病形式(NASH和GT；纤维化和GT；肝硬化和GT；肝细胞癌)要低得多，这表明其他因素 推动严重非酒精性脂肪肝的个人风险。我们假设氯乙烯(VC)就是这样一个因素。我们有 结果表明，吸入与人体环境暴露相关的浓度的VC会加剧实验 通过导致氧化应激和线粒体功能障碍导致小鼠的NAFLD。线粒体的质量和丰度， 受自噬调节，影响细胞的生物能量能力和对压力的抵抗力。线粒体也 与其他细胞器，如内质网(ER)通过线粒体相关的相互作用 膜(MAM)。这些接触点对(病理性的)生理条件敏感，适应不良。 MAM动力学的改变与线粒体功能障碍有关。重要的是，MAM的避难所钥匙 控制线粒体功能、内质网应激和自噬的组件/功能。我们假设这些 事件造成了一场“完美风暴”，它使肝细胞对非酒精性脂肪肝的生化压力敏感，这种压力由 西方风格的高脂肪、高碳水化合物饮食(WD)会加剧伤害，并提高了人们的理解 将产生新的治疗方法。目的1.研究VC和WD的交互作用对儿童心理健康的影响 线粒体/内质网动力学。亲电性VC代谢物会导致蛋白质加合物的形成，这可以诱导 线粒体与内质网应激。这种损伤可以通过改变线粒体-内质网串扰来放大 损害了细胞从损伤中新陈代谢恢复的能力。我们将直接调查 Vc暴露(±WD)对这些细胞器的损伤、功能和相互作用(通过MAM) 互补的体外模型。目的2.分析自噬在VC肝毒性中的作用。这个 自噬过程降解过剩和/或受损的细胞液成分，也是一个重要的 线粒体吞噬作用的质量控制机制。MAMs还关键地参与了自噬 流程。我们最近证明，尽管VC和WD增加了一般的自噬，但有丝分裂是 减少了。我们将研究自噬调节的作用，并检验减少有丝分裂的假设 熔剂是Vc和WD相互作用过程中的一种保护特征。将监测有丝分裂的变化，并 量化的。为了调节肝脏中的自噬，关键的自噬调节因子将被诱导或删除。目标3. 研究VC增强的NAFLD对线粒体/ER/MAM功能障碍的保护作用。 将关键成分定位于VC暴露造成的“完美风暴”，可能会保护人们免受生化反应的影响 在暴露期间应激并加重伤害。因此，通过化学伴侣缓解内质网应激，或者 通过上调内源性伴侣可能具有治疗作用，并将得到研究。同样，防止 线粒体靶向多肽SS-31对线粒体去极化的治疗效果将进行测试。

NAFLD is a major health problem in the developed world that is driven by the epidemic of obesity and metabolic syndrome. Although the prevalence of early stage NAFLD (fatty liver) is nearly 100% in at-risk individuals, the more severe form of the disease (NASH>fibrosis>cirrhosis>HCC) is much lower, indicating that other factors drive interindividual risk for severe NAFLD. We hypothesize that vinyl chloride (VC) is such a factor. We have shown that VC inhalation at concentrations relevant to human environmental exposure exacerbates experimental NAFLD in mice by causing oxidative stress and mitochondrial dysfunction. Mitochondrial quality and abundance, regulated by autophagy, affect the cell’s bioenergetic capacity and resistance to stress. Mitochondria also interact with other organelles such as the endoplasmic reticulum (ER) through mitochondrial-associated membranes (MAMs). These contact sites are sensitive to (patho)physiological conditions and maladaptive changes to MAM dynamics have been associated with mitochondrial dysfunction. Importantly, MAMs shelter key components/functions that control mitochondrial function, ER stress and autophagy. We hypothesize that these events create a ‘perfect storm,’ which sensitizes the hepatocyte to the biochemical stress of NAFLD exerted by a ‘Western’-style high-fat, high-carbohydrate diet (WD) and exacerbates injury and that improved understanding of the biology will yield novel therapies. Aim 1. To study the impact of the interaction of VC and WD on mitochondria/ER dynamics. Electrophilic VC metabolites cause formation of protein adducts, which can induce mitochondria and ER stress. This damage can then be amplified through altered mitochondrial-ER crosstalk via MAMs, impairing the cell’s ability to metabolically recover from injury. We will directly investigate the impact of VC exposure (±WD) on the damage, function and interaction (via MAMs) of these organelles in vivo and in complementary in vitro models. Aim 2. Analyze the role of autophagy in VC induced hepatotoxicity. The autophagic process degrades excess and/or damaged cytosolic components and is also an important mechanism for mitochondrial quality control through mitophagy. MAMs are also critically involved in autophagic processes. We recently demonstrated that although VC and WD increase general autophagy, mitophagy was decreased. We will investigate the role of autophagic regulation and test the hypothesis that reduced mitophagic flux is a protective feature during the interaction of VC and WD. Changes in mitophagy will be monitored and quantified. To modulate autophagy in the liver key autophagy regulators will be induced or deleted. Aim 3. Investigate the impact of protecting against mitochondria/ER/MAM dysfunction in VC-enhanced NAFLD. Targeting critical components to the ‘perfect storm’ caused by VC exposure, may protect from the biochemical stress and exacerbated injury during exposure. Therefore, alleviating ER stress with a chemical chaperone, or by upregulating endogenous chaperones may be therapeutic and will be investigated. Likewise, preventing mitochondrial depolarization with SS-31, a mitochondria-targeted peptide, will be tested for therapeutic benefit.