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
Contributors:
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

Description

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.

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