TRα Protects Against Atherosclerosis in Male Mice: Identification of a Novel Anti-Inflammatory Property for TRα in Mice

Hypothyroidism is associated with an increased occurrence of atherosclerosis, suggesting some protective role for thyroid hormones (THs). Hypercholesterolemia is one of the major risk factor to develop this disease. Here, we show that the well-known TH cholesterol lowering effect was dependent on TH nuclear receptor (TR)beta liver activity. But most importantly, TR alpha was also shown to contribute of slowing down atherosclerosis progression via an independent mechanism. Introduction of TR alpha(0/0) deletion in the ApoE(-/-) background accelerated the appearance of plaques. Earlier cholesterol accumulation was detected in aorta macrophages, likely due to impaired cholesterol efflux. The IL-1 beta inflammatory cytokine was elevated in serum and macrophages in correlation with an activation of the AKT/nuclear factor kappa B pathway in these cells. Inhibition of AKT prevented inflammation and restored normal cholesterol efflux. Similar low-grade inflammation was identified in TR alpha(0/0) male mice. Thus, the mere absence of TR alpha is associated with elevated levels of cytokines likely responsible for cholesterol accumulation and atherosclerosis. This TR alpha protective activity should be relevant for other inflammatory pathologies.