Vinyl chloride modifies the risk for nonalcoholic fatty liver disease

NAFLD是发达国家的一个主要健康问题，由肥胖和代谢紊乱的流行所驱动。 综合征虽然在高危人群中早期NAFLD（脂肪肝）的患病率接近100%，但 更严重形式的疾病（NASH>纤维化>肝硬化>HCC）要低得多，表明其他因素 导致严重NAFLD的个体间风险。我们假设氯乙烯（VC）是这样一个因素。我们有 表明VC吸入浓度与人类环境暴露相关， NAFLD在小鼠中通过引起氧化应激和线粒体功能障碍。线粒体的质量和丰度， 通过自噬调节，影响细胞的生物能量能力和抗应激能力。线粒体也 与其他细胞器，如内质网（ER），通过细胞相关的相互作用， 膜（MAMs）。这些接触部位对（病理性）生理条件敏感， MAM动力学的变化与线粒体功能障碍有关。重要的是，MAMs庇护所的钥匙 控制线粒体功能、ER应激和自噬的组分/功能。我们假设这些 事件产生一个“完美风暴”，使肝细胞对NAFLD的生化应激敏感， “西方”式的高脂肪，高碳水化合物饮食（WD），并加剧损伤， 将产生新的疗法。目标1。为了研究VC和WD的交互作用对 线粒体/ER动力学。亲电VC代谢物引起蛋白质加合物的形成，这可以诱导 线粒体和内质网应激。然后，这种损害可以通过改变的介电常数-ER串扰被放大， MAMs，损害细胞从损伤中代谢恢复的能力。我们将直接调查 VC暴露（±WD）对这些细胞器在体内和体内的损伤、功能和相互作用（通过MAMs） 补充体外模型。目标二。分析自噬在VC肝毒性中的作用。的 自噬过程降解过量和/或受损的胞质组分， 通过线粒体自噬进行线粒体质量控制的机制。MAMs也参与了自噬过程 流程.我们最近证明，尽管VC和WD增加了一般的自噬，但线粒体自噬是 降低我们将研究自噬调节的作用，并检验减少线粒体吞噬的假说。 在VC和WD相互作用期间，通量是保护性特征。将监测线粒体自噬的变化， 量化。为了调节肝脏中的自噬，将诱导或删除关键的自噬调节剂。目标3。 研究在VC增强的NAFLD中保护线粒体/ER/MAM功能障碍的影响。 针对关键成分的'完美风暴'造成的VC暴露，可能会保护从生化 暴露期间的压力和加重的伤害。因此，用化学伴侣减轻ER应激，或 通过上调内源性伴侣蛋白可能是治疗性的，并将进行研究。同样，预防 将测试用SS-31（一种靶向肽）进行的线粒体去极化的治疗益处。

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.