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.