PMID- 38337615
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240214
IS  - 2072-6643 (Electronic)
IS  - 2072-6643 (Linking)
VI  - 16
IP  - 3
DP  - 2024 Jan 23
TI  - Diet-Induced Severe Hyperhomocysteinemia Promotes Atherosclerosis Progression and 
      Dysregulates the Plasma Metabolome in Apolipoprotein-E-Deficient Mice.
LID - 10.3390/nu16030330 [doi]
LID - 330
AB  - Atherosclerosis and resulting cardiovascular disease are the leading causes of 
      death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the 
      intermediate amino acid homocysteine, is an independent risk factor for 
      atherosclerosis, but the intricate biological processes mediating this effect 
      remain elusive. Several factors regulate homocysteine levels, including the 
      activity of several enzymes and adequate levels of their coenzymes, including 
      pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin 
      (vitamin B12). To better understand the biological influence of HHcy on the 
      development and progression of atherosclerosis, apolipoprotein-E-deficient 
      (apoE(-/-) mice), a model for human atherosclerosis, were fed a 
      hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a 
      control diet (CD). After eight weeks, the plasma, aorta, and liver were collected 
      to quantify methylation metabolites, while plasma was also used for a broad 
      targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery 
      (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe 
      accumulation of plasma and hepatic homocysteine and an increased BCA plaque 
      burden were observed, thus confirming the atherogenic effect of the HHD. 
      Moreover, a decreased methylation capacity in the plasma and aorta, indirectly 
      assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) 
      was detected in HHD mice together with a 172-fold increase in aortic 
      cystathionine levels, indicating increased flux through the transsulfuration 
      pathway. Betaine and its metabolic precursor, choline, were significantly 
      decreased in the livers of HHD mice versus CD mice. Widespread changes in the 
      plasma metabolome of HHD mice versus CD animals were detected, including 
      alterations in acylcarnitines, amino acids, bile acids, ceramides, 
      sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional 
      lipid metabolism. This study confirms the relevance of severe HHcy in the 
      progression of vascular plaque and suggests novel metabolic pathways implicated 
      in the pathophysiology of atherosclerosis.
FAU - Andrews, Stephen G
AU  - Andrews SG
AD  - Department of Nutritional Sciences, Penn State University, University Park, PA 
      16802, USA.
FAU - Koehle, Anthony M
AU  - Koehle AM
AD  - Department of Nutritional Sciences, Penn State University, University Park, PA 
      16802, USA.
FAU - Paudel, Devendra
AU  - Paudel D
AUID- ORCID: 0000-0002-6521-9121
AD  - Department of Nutritional Sciences, Penn State University, University Park, PA 
      16802, USA.
FAU - Neuberger, Thomas
AU  - Neuberger T
AUID- ORCID: 0000-0002-3965-9780
AD  - Huck Institutes of the Life Sciences, Penn State University, University Park, PA 
      16802, USA.
AD  - Department of Biomedical Engineering, Penn State University, University Park, PA 
      16802, USA.
FAU - Ross, A Catharine
AU  - Ross AC
AUID- ORCID: 0000-0002-6180-9570
AD  - Department of Nutritional Sciences, Penn State University, University Park, PA 
      16802, USA.
FAU - Singh, Vishal
AU  - Singh V
AUID- ORCID: 0000-0003-3577-1713
AD  - Department of Nutritional Sciences, Penn State University, University Park, PA 
      16802, USA.
FAU - Bottiglieri, Teodoro
AU  - Bottiglieri T
AUID- ORCID: 0000-0002-4199-7551
AD  - Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White 
      Research Institute, Dallas, TX 75204, USA.
FAU - Castro, Rita
AU  - Castro R
AUID- ORCID: 0000-0002-4585-0741
AD  - Department of Nutritional Sciences, Penn State University, University Park, PA 
      16802, USA.
AD  - Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
LA  - eng
PT  - Journal Article
DEP - 20240123
PL  - Switzerland
TA  - Nutrients
JT  - Nutrients
JID - 101521595
RN  - 7LP2MPO46S (S-Adenosylmethionine)
RN  - 935E97BOY8 (Folic Acid)
RN  - 0 (Apolipoproteins E)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 0 (Apolipoproteins)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - *Hyperhomocysteinemia
MH  - *Atherosclerosis/metabolism
MH  - Diet
MH  - S-Adenosylmethionine/metabolism
MH  - Folic Acid/adverse effects
MH  - Apolipoproteins E/genetics/metabolism
MH  - Metabolome
MH  - Homocysteine/metabolism
MH  - Apolipoproteins/metabolism
PMC - PMC10856797
OTO - NOTNLM
OT  - atheroma
OT  - high-field MRI
OT  - hypomethylating stress
OT  - vascular disease
COIS- The authors declare no potential conflicts of interest with respect to the 
      research, authorship, and/or publication of this article.
EDAT- 2024/02/10 10:52
MHDA- 2024/02/10 10:53
PMCR- 2024/01/23
CRDT- 2024/02/10 01:04
PHST- 2023/12/03 00:00 [received]
PHST- 2023/12/30 00:00 [revised]
PHST- 2024/01/09 00:00 [accepted]
PHST- 2024/02/10 10:53 [medline]
PHST- 2024/02/10 10:52 [pubmed]
PHST- 2024/02/10 01:04 [entrez]
PHST- 2024/01/23 00:00 [pmc-release]
AID - nu16030330 [pii]
AID - nutrients-16-00330 [pii]
AID - 10.3390/nu16030330 [doi]
PST - epublish
SO  - Nutrients. 2024 Jan 23;16(3):330. doi: 10.3390/nu16030330.