TY - JOUR
T1 - The nutritional supplement l-alpha glycerylphosphorylcholine promotes atherosclerosis
AU - Wang, Zeneng
AU - Hazen, Jennie
AU - Jia, Xun
AU - Org, Elin
AU - Zhao, Yongzhong
AU - Osborn, Lucas J.
AU - Nimer, Nisreen
AU - Buffa, Jennifer
AU - Culley, Miranda K.
AU - Krajcik, Daniel
AU - van den Born, Bert-Jan H.
AU - Zwinderman, Koos
AU - Levison, Bruce S.
AU - Nieuwdorp, Max
AU - Lusis, Aldons J.
AU - Didonato, Joseph A.
AU - Hazen, Stanley L.
N1 - Funding Information: Funding: This work was supported by grants R01HL130819 (ZW), R01HL144651 (AJL, ZW), R01HL103866 (SLH), and P01 HL147823 (SLH, ZW) from the National Institutes of Health and the Office of Dietary Supplements, Estonian Research Council grant PUT1371 (EO) and ZONMW VICI grant 2020 [09150182010020] (MN). S.L.H. and M.N. also note support from the Leducq Foundation (17CVD01). Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - L-alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe−/− mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides, Ruminococcus, and Bacteroides and decreased abundance of Akkermansia, Lactobacillus, and Roseburia, as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase (cutC)-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.
AB - L-alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe−/− mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides, Ruminococcus, and Bacteroides and decreased abundance of Akkermansia, Lactobacillus, and Roseburia, as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase (cutC)-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.
KW - Atherosclerosis
KW - L-alpha glycerylphosphorylcholine
KW - Microbiota
KW - Trimethylamine
KW - Trimethylamine N-oxide
UR - http://www.scopus.com/inward/record.url?scp=85121052629&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms222413477
DO - https://doi.org/10.3390/ijms222413477
M3 - Article
C2 - 34948275
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 24
M1 - 13477
ER -