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Induction of glutathione biosynthesis by glycine-based treatment mitigates
Rom O, Liu Y, Finney AC, Ghrayeb A, Zhao Y, Shukha Y, Wang L, Rajanayake KK, Das
S, Rashdan NA, Weissman N, Delgadillo L, Wen B, Garcia-Barrio MT, Aviram M,
Kevil CG, Yurdagul A, Pattillo CB, Zhang J, Sun D, Hayek T, Gottlieb E, Mor I,
Submitted Externally on 6/21/2022
Volume : Pages
52 : 102313
Lower circulating levels of glycine are consistently reported in association
with cardiovascular disease (CVD), but the causative role and therapeutic
potential of glycine in atherosclerosis, the underlying cause of most CVDs,
remain to be established. Here, following the identification of reduced
circulating glycine in patients with significant coronary artery disease (sCAD),
we investigated a causative role of glycine in atherosclerosis by modulating
glycine availability in atheroprone mice. We further evaluated the
atheroprotective potential of DT-109, a recently identified glycine-based
compound with dual lipid/glucose-lowering properties. Glycine deficiency
enhanced, while glycine supplementation attenuated, atherosclerosis development
in apolipoprotein E-deficient (Apoe-/-) mice. DT-109 treatment showed the most
significant atheroprotective effects and lowered atherosclerosis in the whole
aortic tree and aortic sinus concomitant with reduced superoxide. In Apoe-/-
mice with established atherosclerosis, DT-109 treatment significantly reduced
atherosclerosis and aortic superoxide independent of lipid-lowering effects.
Targeted metabolomics and kinetics studies revealed that DT-109 induces
glutathione formation in mononuclear cells. In bone marrow-derived macrophages
(BMDMs), glycine and DT-109 attenuated superoxide formation induced by glycine
deficiency. This was abolished in BMDMs from glutamate-cysteine ligase modifier
subunit-deficient (Gclm-/-) mice in which glutathione biosynthesis is impaired.
Metabolic flux and carbon tracing experiments revealed that glycine deficiency
inhibits glutathione formation in BMDMs while glycine-based treatment induces de
novo glutathione biosynthesis. Through a combination of studies in patients with
CAD, in vivo studies using atherosclerotic mice and in vitro studies using
macrophages, we demonstrated a causative role of glycine in atherosclerosis and
identified glycine-based treatment as an approach to mitigate atherosclerosis
through antioxidant effects mediated by induction of glutathione biosynthesis.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
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