Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis. Liu et al

Published: 28 July 2021| Version 1 | DOI: 10.17632/n8nkdgd258.1
Yuhao Liu, Ying Zhao, Yousef Shukha, Haocheng Lu, Lu Wang, Zhipeng Liu, Yang Zhao, Huilun Wang, Cai Liu, Guizhen Zhao, Wenying Liang, Yanbo Fan, Lin Chang, Arif Yurdagul , Christopher Pattillo, A. Wayne Orr, Michael Aviram, Bo Wen, Minerva Garcia-Barrio, Jifeng Zhang, Wanqing Liu, Duxin Sun, Tony Hayek, Eugene Chen, Oren Rom


Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. Here we demonstrate impaired glycine and oxalate metabolism through the alanine-glyoxylate aminotransferase (AGXT) enzymatic pathway in atherosclerosis. As found in atherosclerotic patients, glycine/oxalate ratio was significantly decreased in atherosclerotic mice concomitant with suppression of AGXT. We deleted Agxt in apolipoprotein E-deficient (Apoe-/-) mice and found decreased glycine/oxalate ratio and increased atherosclerosis. Transcriptomics revealed enrichment of pro-atherogenic pathways in the liver, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages were increased. Similar findings were observed using a dietary model of oxalate overload in Apoe-/- mice. In macrophages, oxalate induced mitochondrial dysfunction and superoxide accumulation leading to increased CCL5. Conversely, adeno-associated virus-mediated overexpression of AGXT in Apoe-/- mice increased the glycine/oxalate ratio and decreased aortic superoxide, CCL5 and atherosclerosis. Collectively, we identified dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.