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是发达国家的一个主要健康问题，是由肥胖和代谢的流行所驱动的