Toxic lipid intermediate accumulation and cobalamin depletion promote AHR-mediated hepatotoxicity and the progression of non-alcoholic fatty liver disease (NAFLD)-like pathologies

有毒脂质中间体积累和钴胺素消耗促进 AHR 介导的肝毒性和非酒精性脂肪肝 (NAFLD) 样病理的进展

• 批准号: 10391942
• 负责人: Timothy R. Zacharewski
• 金额: $ 156.51万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-03 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391942
• 关键词: Anabolism; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; Bile Acids; Binding; Cell Survival; Cells; Chemicals; Cobalamin; Coenzyme A; Collagen; Complex; Data; Deposition; Development; Dicarboxylic Acids; Dioxins; Disease Progression; Dose; Environmental Pollution; Enzymes; Exhibits; Family member; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Futile Cycling; Gene Expression; Genetic; Hepatic; Hepatocyte; Hepatotoxicity; Human; Hydration status; Immune; In Vitro; Infiltration; Inflammation; Interleukin-6; Knockout Mice; Lead; Ligands; Lipids; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mus; Mutase; Oleic Acids; Oxides; Palmitic Acids; Pathology; Pathway interactions; Pharmacology; Play; Population; Prevalence; Primary carcinoma of the liver cells; Propionates; Receptor Activation; Repression; Risk; Role; Serum; Severities; Steatohepatitis; Supplementation; Testing; Tetrachlorodibenzodioxin; Tissue-Specific Gene Expression; Toxic effect; Vitamin B 12; carboxylation; cofactor; dibenzo(1,4)dioxin; dibenzofuran; diphenyl; fatty acid metabolism; fatty acid oxidation; in vivo; macrophage; metabolomics; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; oxidation; propionyl-coenzyme A; stem; succinyl-coenzyme A; suicide inhibitor; transcription factor; transcriptome sequencing

Abstract: Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of pathologies which typically involves simple, reversible hepatic fat accumulation (steatosis) progressing into steatohepatitis with fibrosis that increases the risk for more complex metabolic diseases. NAFLD prevalence is projected to increase from ~83 million in 2015 to ~101 million by 2030 in the US alone. Accumulating evidence suggests environmental contaminants play an underappreciated role in NAFLD development and progression. Many chemicals induce fatty liver, but the environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and related compounds, exhibit the greatest potency. Most, if not all, of the effects induced by TCDD are mediated by the aryl hydrocarbon receptor (AHR). We have shown that TCDD induces the progression of steatosis to steatohepatitis (non- alcoholic steatohepatitis (NASH)) with fibrosis, however the underlying mechanisms are poorly understood beyond AHR activation and subsequent changes in gene expression. Our integration of preliminary RNAseq and metabolomics data suggests multiple AHR-mediated effects converge to cause to cause hepatotoxicity and the progression of NAFLD-like pathologies including the repression of hepatic fatty acid oxidation, increased bile acid levels, immune cell infiltration and decreased serum cobalamin (Cbl, aka Vitamin B12) levels. This proposal will test the hypothesis that AHR activation reprograms fatty acid metabolism causing the accumulation of toxic intermediates that contribute to hepatotoxicity and the progression of steatosis to steatohepatitis with fibrosis. In vivo and in vitro genetic and pharmacological approaches will be to further investigate the role of octenoyl-CoA, acrylyl-CoA and dicarboxylic acids (DCAs). Specific Aim 1 will use novel hepatocyte-specific AHR null mice to show that hepatic octenoyl-CoA, acrylyl-CoA and DCAs contribute to hepatotoxicity and NAFLD pathology severity. Specific Aim 2 will use (i) Cbl supplementation to protect against hepatotoxicity and NAFLF progression and (ii) Acod1 null mice to investigate the role of itaconate (Ita) in reducing Cbl levels. Specific Aim 3 will use human HepaRG cells to determine the relevance of AHR-mediated metabolic reprogramming and the accumulation of toxic intermediate metabolites. These results will establish a mechanism that involves AHR-mediated differential gene expression, metabolic reprograming and the biosynthesis of toxic metabolites that contribute to the hepatotoxicity and NAFLD progression. We will show that Cbl supplementation can protect against AHR-mediated hepatotoxicity. Cbl supplementation will also prove to be an effective countermeasure to protect exposed populations susceptible to AHR-mediated hepatotoxicity that may also be beneficial in the treatment and management of NAFLD.

抽象的： 非酒精性脂肪肝病（NAFLD）描述了一系列病理，通常涉及简单， 可逆的肝脂肪积累（脂肪变性）发展为脂肪性肝炎，纤维化增加了 风险更复杂的代谢疾病。 NAFLD患病率预计将从2015年的8300万次增加 到2030年，仅在美国就达到了约1.01亿。积累的证据表明环境污染物发挥 在NAFLD发展和进步中的作用不足。许多化学物质诱导脂肪肝，但 环境污染物，2,3,7,8-四氯迪本佐-P-二恶英（TCDD）和相关化合物，展示 最大的效力。 TCDD引起的大多数（如果不是全部）均由芳烃介导 受体（AHR）。我们已经表明，TCDD诱导了脂肪变性到脂肪性肝炎的发展（非 - 具有纤维化的酒精性脂肪性肝炎（NASH）），但是理解的基本机制 除了AHR激活以及随后的基因表达变化。我们的初步RNASEQ的整合 代谢组学数据表明，多个AHR介导的效应会导致引起肝毒性 以及NAFLD样病理的进展，包括抑制肝脂肪酸氧化， 胆汁酸水平升高，免疫细胞浸润和血清钴胺素降低（CBL，AKA维生素B12） 水平。该提案将检验以下假设：AHR激活重编程脂肪酸代谢，导致脂肪酸代谢 积累有助于肝毒性的有毒中间体和脂肪变性的进展 脂肪性肝炎伴有纤维化。体内和体外遗传和药理学方法将进一步 研究Octenoyl-COA，丙烯酰-COA和二羧酸（DCA）的作用。特定目标1将使用小说 肝细胞特异性AHR无效的小鼠表明肝coa，丙烯酰辅酶A和DCA有助于 肝毒性和NAFLD病理严重程度。特定目标2将使用（i）补充CBL来防止 肝毒性和NaFLF进展以及（ii）ACOD1 null小鼠研究Itaconate（ITA）在 降低CBL水平。特定的目标3将使用人肝细胞来确定AHR介导的相关性 代谢重编程和有毒中间代谢产物的积累。这些结果将建立一个 涉及AHR介导的差异基因表达，代谢重编程和 有助于肝毒性和NAFLD进展的有毒代谢产物的生物合成。我们将显示 补充CBL可以预防AHR介导的肝毒性。 CBL补充也将 被证明是保护易受AHR介导的暴露人群的有效对策 肝毒性也可能对NAFLD的治疗和管理有益。