Vinyl chloride modifies the risk for nonalcoholic fatty liver disease

氯乙烯可降低非酒精性脂肪肝的风险

• 批准号: 10503659
• 负责人: Juliane I Beier
• 金额: $ 46.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503659
• 关键词: Address; Affect; Autophagocytosis; Autophagosome; Biochemical; Bioenergetics; Biology; Cancer Etiology; Carbohydrates; Cells; Chemicals; Chloroquine; Cirrhosis; Complement; Data; Diet; Disease; Endoplasmic Reticulum; Environment; Environmental Exposure; Environmental Pollutants; Event; Exposure to; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Functional disorder; Goals; Health; Hepatic; Hepatocyte; Hepatotoxicity; Human; Impairment; Individual; Inflammatory Response; Inhalation; Injury; Life Style; Liver; Liver diseases; LoxP-flanked allele; Malignant neoplasm of liver; Membrane; Meta-Analysis; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Molecular Chaperones; Monitor; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity Epidemic; Occupational; Organelles; Oxidative Stress; Peptides; Physiological; Prevalence; Process; Proteins; Quality Control; Regulation; Reporter; Resistance; Risk; Risk Factors; Role; Safety; Shelter facility; Site; Strategic Planning; Stress; Sulfhydryl Compounds; Testing; Therapeutic; Therapeutic Effect; Thinness; Toxic Environmental Substances; Toxicant exposure; Translating; Vinyl Chloride; Work; adduct; chloroacetaldehyde; diet-induced obesity; endoplasmic reticulum stress; fatty liver disease; improved; in vitro Model; in vivo; indexing; insight; liver development; liver injury; mitochondrial dysfunction; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutics; preservation; prevent; protein complex; tauroursodeoxycholic acid; therapeutic evaluation; toxicant

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.

NAFLD是发达国家的主要健康问题，它是由肥胖和代谢流行驱动的 尽管在高危个体中，早期NAFLD（脂肪肝）的患病率几乎为100％ 疾病的更严重形式（NASH>纤维化>肝硬化> HCC）要低得多，表明其他因素 驱动个人跨性别的风险。我们假设乙烯基氯化物（VC）就是这样的因素。我们有 表明，与人类环境暴露有关的浓度下的VC事故加剧了实验 小鼠中的NAFLD通过引起氧化应激和线粒体功能障碍。线粒体质量和抽象， 受自噬的调节，会影响细胞的生物能力和对压力的抵抗力。线粒体也是如此 通过线粒体相关的其他细胞器（例如内质网（ER））相互作用 膜（妈妈）。这些接触部位对（病原）生理状况和适应不良敏感 MAM动力学的变化与线粒体功能障碍有关。重要的是，妈妈庇护所钥匙 控制线粒体功能，ER应力和自噬的组件/功能。我们假设这些 事件创造了一场“完美的风暴”，它使肝细胞感知到NAFLD的生化压力 一种“西方”风格的高脂，高碳水化合物饮食（WD）和加剧了伤害，这提高了理解力 生物学将产生新的疗法。目的1。研究VC和WD的相互作用的影响 线粒体/ER动力学。亲电VC代谢产生蛋白质加合物的形成，这可以诱导 线粒体和ER应力。然后可以通过改变的线粒体 - 妈妈，损害了细胞从损伤中恢复代谢的能力。我们将直接调查 这些细胞器的损伤，功能和相互作用（通过MAMS）在体内和IN中的损害，功能和相互作用（通过MAM） 互补的体外模型。 AIM 2。分析自噬在VC诱导的肝毒性中的作用。这 自噬过程降解超过和/或损坏的胞质成分，也是重要的 线粒体质量控制的机制通过线粒体控制。妈妈也很重要地参与自噬 过程。我们最近证明，尽管VC和WD增加了一般自噬，但线粒体是 减少。我们将研究自噬调节的作用，并测试降低线索的假设 通量是VC和WD相互作用期间的受保护特征。线粒体的变化将受到监测，并 量化。要调节肝脏密钥自噬调节剂中的自噬，将被诱导或删除。目标3。 研究防止VC增强NAFLD中线粒体/ER/MAM功能障碍的影响。 将关键组件靶向由风险投资曝光引起的“完美风暴”，可以防止生化 暴露期间的压力和加剧的伤害。因此，用化学链酮减轻急诊应力，或 通过上调内源性伴侣，可能是治疗性的，并将研究。同样，防止 线粒体沉积与线粒体靶向的肽SS-31将进行治疗益处的测试。