Billon Cyrielle, Canaple Laurence, Fleury Sébastien, Deloire Alexandre, Beylot Michel, Dombrowicz David, Del Carmine Peggy, Samarut Jacques, Gauthier Karine
Institut de Génomique Fonctionnelle de Lyon (C.B., L.C., A.D., J.S., K.G.), Université de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique. Institut National de la Recherche Agronomique, Ecole Normale Supérieure de Lyon, 69364 Lyon, France; Inserm Unité 1011 (S.F., D.D.), University of Lille Nord de France and Institut Pasteur de Lille, 59000 Lille, France; and Inserm Equipe Région-Inserm 22/Equipe Associée 4173 (M.B.) and Anira-ANIPHY (P.d.C.), Faculté Rockefeller, Université Lyon 1, 69008 Lyon, France.
Endocrinology. 2014 Jul;155(7):2735-45. doi: 10.1210/en.2014-1098. Epub 2014 May 5.
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 TRα(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-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 TRα(0/0) 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.
甲状腺功能减退与动脉粥样硬化的发生率增加有关，这表明甲状腺激素（THs）具有一定的保护作用。高胆固醇血症是引发这种疾病的主要危险因素之一。在此，我们表明，众所周知的TH降低胆固醇的作用依赖于TH核受体（TR）β的肝脏活性。但最重要的是，TRα也被证明通过一种独立机制有助于减缓动脉粥样硬化的进展。在载脂蛋白E（ApoE）基因敲除背景下引入TRα基因敲除会加速斑块的出现。在主动脉巨噬细胞中更早地检测到胆固醇积累，这可能是由于胆固醇流出受损所致。血清和巨噬细胞中的白细胞介素-1β炎症细胞因子升高，与这些细胞中AKT/核因子κB途径的激活相关。抑制AKT可预防炎症并恢复正常的胆固醇流出。在TRα基因敲除的雄性小鼠中也发现了类似的低度炎症。因此，仅仅缺乏TRα就与可能导致胆固醇积累和动脉粥样硬化的细胞因子水平升高有关。这种TRα的保护活性可能与其他炎症性疾病相关。
