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Indoleamine 2,3-dioxygenase-1 (IDO1)-mediated tryptophan (Trp) metabolism has been proposed to play an immunomodulatory role in several diseases. The potential of IDO1 to be a link between NASH and cardiovascular disease has never been investigated. Using Apoe\u2212\/\u2212and Apoe\u2212\/\u2212Ido1\u2212\/\u2212 mice that were fed a high-fat, high-cholesterol diet (HFCD) to simultaneously induce NASH and atherosclerosis, we found that Ido1 deficiency significantly accelerated atherosclerosis after 7 weeks. Surprisingly, Apoe\u2212\/\u2212Ido1\u2212\/\u2212 mice did not present a more aggressive NASH phenotype, including hepatic lipid deposition, release of liver enzymes, and histopathological parameters. As expected, a lower L-kynurenine\/Trp (Kyn\/Trp) ratio was found in the plasma and arteries of Apoe\u2212\/\u2212Ido1\u2212\/\u2212 mice compared to controls. However, no difference in the hepatic Kyn\/Trp ratio was found between the groups. Hepatic transcript analyses revealed that HFCD induced a temporal increase in tryptophan 2,3-dioxygenase (Tdo2) mRNA, indicating an alternative manner to maintain Trp degradation during NASH development in both Apoe\u2212\/\u2212 and Apoe\u2212\/\u2212Ido1\u2212\/mice\u2212. Using HepG2 hepatoma cell and THP1 macrophage cultures, we found that iron, TDO2, and Trp degradation may act as important mediators of cross-communication between hepatocytes and macrophages regulating liver inflammation. In conclusion, we show that Ido1 deficiency aggravates atherosclerosis, but not liver disease, in a newly established NASH and atherosclerosis comorbidity model. Our data indicate that the overexpression of TDO2 is an important mechanism that helps in balancing the kynurenine pathway and inflammation in the liver, but not in the artery wall, which likely determined disease outcome in these two target tissues.<\/jats:p>","DOI":"10.3390\/ijms23095203","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T14:49:38Z","timestamp":1651848578000},"page":"5203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetic Deficiency of Indoleamine 2,3-dioxygenase Aggravates Vascular but Not Liver Disease in a Nonalcoholic Steatohepatitis and Atherosclerosis Comorbidity Model"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2789-2593","authenticated-orcid":false,"given":"Aastha","family":"Arora","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"},{"name":"Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense-C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Luis","family":"Tripodi","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"},{"name":"Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2528-9264","authenticated-orcid":false,"given":"Ilona","family":"Kareinen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Berg","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4907-4783","authenticated-orcid":false,"given":"Maria Josefa","family":"Forteza","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4614-8030","authenticated-orcid":false,"given":"Anton","family":"Gister\u00e5","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silke","family":"Griepke","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense-C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1117-4754","authenticated-orcid":false,"given":"Felipe Beccaria","family":"Casagrande","sequence":"additional","affiliation":[{"name":"Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2630-7038","authenticated-orcid":false,"given":"Joilson O.","family":"Martins","sequence":"additional","affiliation":[{"name":"Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dulcineia Saes Parra","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cole","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Monaco","sequence":"additional","affiliation":[{"name":"Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0087-116X","authenticated-orcid":false,"given":"Daniel F. J.","family":"Ketelhuth","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, 17164 Stockholm, Sweden"},{"name":"Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense-C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1093\/eurheartj\/ehu299","article-title":"Cardiovascular disease in Europe 2014: Epidemiological update","volume":"35","author":"Nichols","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_2","unstructured":"World Health Organization (2009). 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