{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T11:12:50Z","timestamp":1776337970861,"version":"3.51.2"},"reference-count":70,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Penn State High-Field Magnetic Resonance Imaging Facility and the Huck Institutes of the Life Sciences of the Pennsylvania State University","award":["T32DK120509"],"award-info":[{"award-number":["T32DK120509"]}]},{"name":"NIH","award":["T32DK120509"],"award-info":[{"award-number":["T32DK120509"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>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\u2212\/\u2212 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.<\/jats:p>","DOI":"10.3390\/nu16030330","type":"journal-article","created":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T04:17:40Z","timestamp":1705983460000},"page":"330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Diet-Induced Severe Hyperhomocysteinemia Promotes Atherosclerosis Progression and Dysregulates the Plasma Metabolome in Apolipoprotein-E-Deficient Mice"],"prefix":"10.3390","volume":"16","author":[{"given":"Stephen G.","family":"Andrews","sequence":"first","affiliation":[{"name":"Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA"}]},{"given":"Anthony M.","family":"Koehle","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6521-9121","authenticated-orcid":false,"given":"Devendra","family":"Paudel","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3965-9780","authenticated-orcid":false,"given":"Thomas","family":"Neuberger","sequence":"additional","affiliation":[{"name":"Huck Institutes of the Life Sciences, Penn State University, University Park, PA 16802, USA"},{"name":"Department of Biomedical Engineering, Penn State University, University Park, PA 16802, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-9570","authenticated-orcid":false,"given":"A. Catharine","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3577-1713","authenticated-orcid":false,"given":"Vishal","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4199-7551","authenticated-orcid":false,"given":"Teodoro","family":"Bottiglieri","sequence":"additional","affiliation":[{"name":"Center of Metabolomics, Institute of Metabolic Disease, Baylor Scott and White Research Institute, Dallas, TX 75204, USA"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-0741","authenticated-orcid":false,"given":"Rita","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, Penn State University, University Park, PA 16802, USA"},{"name":"Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1161\/CIRCRESAHA.115.307611","article-title":"Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease","volume":"118","author":"Herrington","year":"2016","journal-title":"Circ. 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