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 (NAFLD) 描述了一系列病理，通常涉及简单、 可逆性肝脏脂肪堆积（脂肪变性），进展为伴有纤维化的脂肪性肝炎，增加了 更复杂的代谢疾病的风险。 NAFLD 患病率预计将从 2015 年的约 8300 万增加 到 2030 年，仅在美国就将达到约 1.01 亿。越来越多的证据表明环境污染物对 在 NAFLD 发生和进展中的作用未被充分认识。许多化学物质会诱发脂肪肝，但 环境污染物 2,3,7,8-四氯二苯并-对二恶英 (TCDD) 和相关化合物表现出 最大的效力。 TCDD 引起的大多数（如果不是全部）效应都是由芳基碳氢化合物介导的 受体（AHR）。我们已经证明 TCDD 会诱导脂肪变性进展为脂肪性肝炎（非脂肪性肝炎） 酒精性脂肪性肝炎（NASH））伴有纤维化，但其潜在机制尚不清楚 超越 AHR 激活和随后的基因表达变化。我们对初步 RNAseq 的整合 代谢组学数据表明多种 AHR 介导的效应汇聚在一起导致肝毒性 以及 NAFLD 样病理的进展，包括肝脂肪酸氧化的抑制， 胆汁酸水平增加、免疫细胞浸润和血清钴胺素（Cbl，又名维生素 B12）减少 水平。该提案将检验以下假设：AHR 激活会重新编程脂肪酸代谢，从而导致 有毒中间体的积累导致肝毒性和脂肪变性的进展 脂肪性肝炎伴纤维化。体内和体外遗传和药理学方法将进一步 研究辛烯酰辅酶 A、丙烯酰辅酶 A 和二羧酸 (DCA) 的作用。具体目标 1 将使用小说 肝细胞特异性 AHR 缺失小鼠表明，肝辛烯酰辅酶 A、丙烯酰辅酶 A 和 DCA 有助于 肝毒性和 NAFLD 病理严重程度。具体目标 2 将使用 (i) Cbl 补充剂来预防 肝毒性和 NAFLF 进展以及 (ii) Acod1 缺失小鼠研究衣康酸 (Ita) 在 降低 Cbl 水平。具体目标 3 将使用人类 HepaRG 细胞来确定 AHR 介导的相关性 代谢重编程和有毒中间代谢物的积累。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 有毒代谢物的生物合成，导致肝毒性和 NAFLD 进展。我们将展示 补充 Cbl 可以预防 AHR 介导的肝毒性。补充Cbl也会 被证明是保护易受 AHR 介导影响的暴露人群的有效对策 肝毒性也可能有益于 NAFLD 的治疗和管理。