Dysregulated Oxalate Metabolism in Cardiometabolic Diseases

项目摘要/摘要 影响全球三分之一人口的非酒精性脂肪性肝病，尚无药物治疗 非酒精性脂肪肝(NAFLD)已成为慢性肝病的主要原因。令人惊讶的是，中国的主要死因 NAFLD和更严重的非酒精性脂肪性肝炎(NASH)患者是动脉粥样硬化的心血管疾病 疾病(CVD)。这凸显出迫切需要为同时治疗确定有针对性的途径，这已经 由于对连接这两者的病理生理学和新陈代谢途径的了解有限 疾病。最近，我们和其他人发现了NAFLD和CVD中普遍存在的草酸代谢异常。 虽然草酸对肾脏的影响是众所周知的，但它们在肝细胞中还没有得到系统的研究， 负责其形成的初级细胞。此外，在NASH和相关的动脉粥样硬化中，一个致病因素 草酸的作用，其潜在的机制和针对草酸过量的治疗潜力是 未知。使用无偏见的转录组学，我们发现了限制草酸产生的基因在 来自人类和患有NASH的小鼠的肝脏。丙氨酸乙醛转氨酶(AGXT)，一种肝脏特异性酶 解毒作用使草酸前体乙醛减少，草酸显著增加。 纳什的严重程度。值得注意的是，在动脉粥样硬化的患者和小鼠中，草酸也增加了。在……里面 我们的小鼠肝脏草酸过量(Agxt-/-)模型，NASH和动脉粥样硬化都增加了 通过抑制肝脏脂肪酸β氧化(FAO)和诱导促炎途径。动脉硬化 也被外源草酸盐增强。在肝细胞中，草酸引起线粒体功能障碍和脂质 下调过氧化物酶体增殖物激活受体α(PPARα)靶标时的蓄积 上调C-C基序趋化因子配体5(CCL5)。重要的是，通过肝脏特异性限制草酸的产生 AGXT过表达作为概念验证，可以减轻NASH和动脉粥样硬化，强调了 同时处理的草酸减少。该项目将解决中心假设，即肝脏草酸 生产过剩通过线粒体功能障碍、PPARα/粮农组织受损以及 CCL5诱导，同时抑制草酸形成减少已建立的NASH和动脉粥样硬化。目标1 将利用新的小鼠确定草酸盐驱动NASH和相关动脉粥样硬化的机制 肝脏草酸过量，PPARα和CCl 5缺乏，结合饮食和药物 草酸、线粒体功能和PPARα的操作，以及体外模型。目标2将定义草酸盐 应用遗传和饮食方法减少NASH和相关动脉粥样硬化的潜在治疗 目的：限制肝脏草酸的形成，增强乙醛酸的体内外解毒作用。《目标3》将描述 用表观遗传学研究人类NASH和动脉粥样硬化中肝脏草酸的过量产生及其遗传调控， GWAs和人类肝脏样本。这项工作将描绘出一条新发现的连接NASH的代谢途径 和动脉粥样硬化，并提前翻译草酸减少作为这些疾病的同时治疗。

PROJECT SUMMARY/ABSTRACT Affecting one third of the global population, with no pharmacotherapy available, nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease. Surprisingly, the major cause of death in patients with NAFLD and the more severe nonalcoholic steatohepatitis (NASH) is atherosclerotic cardiovascular disease (CVD). This highlights a critical need to identify targetable pathways for concurrent treatment, which has been hampered by limited understanding of the pathophysiology and metabolic pathways linking these two diseases. Recently, we and others uncovered oxalate metabolism commonly dysregulated in NAFLD and CVD. While oxalate effects in the kidneys are well known, they have not been systematically studied in hepatocytes, the primary cells responsible for its formation. Moreover, in NASH and associated atherosclerosis, a causative role of oxalate, its underlying mechanisms and the therapeutic potential of targeting oxalate overproduction are unknown. Using unbiased transcriptomics, we uncovered suppression of genes that limit oxalate production in livers from humans and mice with NASH. Alanine-glyoxylate aminotransferase (AGXT), a liver-specific enzyme that detoxifies glyoxylate, the oxalate precursor, was reduced and oxalate was markedly increased in correlation with NASH severity. Remarkably, oxalate was also increased both in patients and mice with atherosclerosis. In our mouse model of hepatic oxalate overproduction (Agxt-/-), both NASH and atherosclerosis were increased with suppressed hepatic fatty acid β-oxidation (FAO) and induced proinflammatory pathways. Atherosclerosis was enhanced also by exogenous oxalate. In hepatocytes, oxalate induced mitochondrial dysfunction and lipid accumulation while downregulating peroxisome proliferator-activated receptor α (PPARα) targets and upregulating C-C motif chemokine ligand 5 (CCL5). Importantly, limiting oxalate production via liver-specific AGXT overexpression, as proof-of-concept, attenuated NASH and atherosclerosis, underscoring the potential of oxalate reduction for concurrent treatment. This project will address the central hypothesis that hepatic oxalate overproduction drives NASH and atherosclerosis via mitochondrial dysfunction, impaired PPARα/FAO, and CCL5 induction, while suppression of oxalate formation reduces established NASH and atherosclerosis. Aim 1 will determine the mechanisms by which oxalate drives NASH and associated atherosclerosis using novel mice with hepatic oxalate overproduction, PPARα and CCL5 deficiency, combined with dietary and pharmacological manipulation of oxalate, mitochondrial function and PPARα, and in vitro models. Aim 2 will define oxalate reduction as a potential therapy for NASH and associated atherosclerosis using genetic and dietary approaches to limit hepatic oxalate formation and enhance glyoxylate detoxification in vivo and in vitro. Aim 3 will characterize hepatic oxalate overproduction and its genetic regulation in human NASH and atherosclerosis using epigenetics, GWAS and human liver samples. This work will delineate a newly identified metabolic pathway linking NASH and atherosclerosis and advance translation of oxalate reduction as a concurrent treatment for these diseases.