Dysregulated oxalate metabolism is a driver and therapeutic target in atherosclerosis
Yuhao Liu, Ying Zhao, Yousef Shukha, Haocheng Lu, Lu Wang, Zhipeng Liu, Cai Liu, Yang Zhao, Huilun Wang, Guizhen Zhao, Wenying Liang, Yanbo Fan, Lin Chang, Arif Yurdagul, Christopher B. Pattillo, A. Wayne Orr, Michael Aviram, Bo Wen, Minerva T. Garcia-Barrio, Jifeng Zhang, Wanqing Liu, Duxin Sun, Tony Hayek, Y. Eugene Chen, Oren Rom
Abstract
Dysregulated glycine metabolism is emerging as a common denominator in cardiometabolic diseases, but its contribution to atherosclerosis remains unclear. In this study, we demonstrate impaired glycine-oxalate metabolism through alanine-glyoxylate aminotransferase (AGXT) in atherosclerosis. As found in patients with atherosclerosis, the glycine/oxalate ratio is decreased in atherosclerotic mice concomitant with suppression of AGXT. Agxt deletion in apolipoprotein E-deficient ( Apoe −/− ) mice decreases the glycine/oxalate ratio and increases atherosclerosis with induction of hepatic pro-atherogenic pathways, predominantly cytokine/chemokine signaling and dysregulated redox homeostasis. Consistently, circulating and aortic C-C motif chemokine ligand 5 (CCL5) and superoxide in lesional macrophages are increased. Similar findings are observed following dietary oxalate overload in Apoe −/− mice. In macrophages, oxalate induces mitochondrial dysfunction and superoxide accumulation, leading to increased CCL5. Conversely, AGXT overexpression in Apoe −/− mice increases the glycine/oxalate ratio and decreases aortic superoxide, CCL5, and atherosclerosis. Our findings uncover dysregulated oxalate metabolism via suppressed AGXT as a driver and therapeutic target in atherosclerosis.