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

• Published in: Endocrinology (Philadelphia) Vol. 155; no. 7; pp. 2735 - 2745
• Main Authors: Billon, Cyrielle, Canaple, Laurence, Fleury, Sébastien, Deloire, Alexandre, Beylot, Michel, Dombrowicz, David, del Carmine, Peggy, Samarut, Jacques, Gauthier, Karine
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.07.2014; Oxford University Press
• Subjects: Animals; Aorta - metabolism; Aorta - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - blood; Atherosclerosis - genetics; Atherosclerosis - metabolism; Blotting, Western; Bone Marrow Transplantation - methods; Cell Nucleus - metabolism; Cells, Cultured; Cholesterol - blood; Cholesterol - metabolism; Endocrinology and metabolism; Human health and pathology; Inflammation - blood; Inflammation - genetics; Inflammation - metabolism; Interleukin-1beta - blood; Interleukin-1beta - metabolism; Life Sciences; Macrophages - metabolism; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Thyroid Hormone Receptors alpha - deficiency; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormones - blood; Thyroid Hormones - metabolism
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2014-1098

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)β liver activity. But most importantly, TRα was also shown to contribute of slowing down atherosclerosis progression via an independent mechanism. Introduction of TRα0/0 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-1β inflammatory cytokine was elevated in serum and macrophages in correlation with an activation of the AKT/nuclear factor κB pathway in these cells. Inhibition of AKT prevented inflammation and restored normal cholesterol efflux. Similar low-grade inflammation was identified in TRα0/0 male mice. Thus, the mere absence of TRα is associated with elevated levels of cytokines likely responsible for cholesterol accumulation and atherosclerosis. This TRα protective activity should be relevant for other inflammatory pathologies.