Dysregulated Oxalate Metabolism in Cardiometabolic Diseases - 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.
