Genetic Deficiency of Indoleamine 2,3-dioxygenase Aggravates Vascular but Not Liver Disease in a Nonalcoholic Steatohepatitis and Atherosclerosis Comorbidity Model

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Arora, Aastha ; Tripodi, Gustavo Luis ; Kareinen, Ilona ; Berg, Martin ; Forteza, Maria Josefa ; Gistera, Anton ; Griepke, Silke ; Casagrande, Felipe Beccaria ; Martins, Joilson O. ; Abdalla, Dulcineia Saes Parra ; Cole, Jennifer ; Monaco, Claudia ; Ketelhuth, Daniel F. J.

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 9, p. 17-pg., 2022-05-01.

Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that increases cardiovascular disease risk. 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(-/-) and Apoe(-/-)Ido1(-/-) 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(-/-)Ido1(-/-) 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(-/-)Ido1(-/-) 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(-/-) and Apoe(-/-)Ido1(-/)mice(-). 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. (AU)

• FAPESP's process: 19/13598-8 - Immunometabolism as new approach to development of "natural adjuvants" that induce regulatory responses
• Grantee: Gustavo Luis Tripodi
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 20/03175-0 - Investigating mechanisms that link angiotensins to Obesity and Diabetes
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Regular Research Grants