Thyroid hormone (T3) and TRβ agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats
Thyroid hormone (T3) and TRβ agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats
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DOI：
10.1096/fj.08-108464
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Columbano, Amedeo
中科院分区：
文献类型：
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作者：
Perra, Andrea;Simbula, Gabriella;Columbano, Amedeo
非酒精性脂肪性肝病是临床上最常见的非感染性肝病，并且越来越需要新的治疗方法来治疗这种肝病。在这里，我们研究了甲状腺激素三碘甲状腺原氨酸（T3）和甲状腺激素受体β亚型（TR β），GC-1的激动剂，对脂肪肝和脂肪性肝炎诱导的啮齿动物胆碱-蛋氨酸缺乏（CMD）饮食的影响。雄性Fischer 344大鼠喂食CMD饲料1周后出现明显的脂肪肝和轻度肝炎。同时给予T3可完全预防与脂肪酸线粒体和过氧化物酶体β-氧化增加相关的脂肪变化。为了研究T3是否也可以逆转完全建立的脂肪肝，大鼠喂食CMD饮食10周，然后共喂食T3 1周。同时给予T3导致肝脏脂肪变性完全消退，并伴有脂质过氧化、环氧合酶-2表达以及磷酸化STAT 3和磷酸化SAPK/JNK活化的降低。最后，额外的实验表明，GC-1对心率没有显著的副作用，可以预防和逆转CMD诱导的脂肪积累，并改善脂肪性肝炎。这些结果表明TR激动剂具有抑制或逆转由营养模型诱导的肝脂肪变性的潜力。
Nonalcoholic fatty liver disease is the most common noninfectious liver disease in clinical practice, and there is an increasing need for new therapeutic approaches for the treatment of this liver disease. Here, we examined the effect of the thyroid hormone triiodothyronine (T3) and the agonist of the thyroid hormone receptor beta isoform (TR beta), GC-1, on fatty liver and steatohepatitis induced in rodents by a choline-methionine deficient (CMD) diet. Male Fischer 344 rats fed a CMD diet for 1 wk developed a marked fatty liver and mild hepatitis. Concurrent administration of T3 resulted in a complete prevention of the fatty change associated with increased fatty acid mitochondrial and peroxisomal beta-oxidation. To investigate whether T3 could also reverse fully established fatty liver, rats were fed a CMD diet for 10 wk and then cofed T3 for 1 wk. Coadministration of T3 resulted in a complete regression of liver steatosis associated with a decrease of lipid peroxidation, cyclooxygenase-2 expression, and activation of phospho-STAT3 and phospho-SAPK/JNK. Finally, additional experiments showed that GC-1, which has no significant side effects on heart rate, prevented and reverted CMD-induced fat accumulation, and ameliorated steatohepatitis. These results indicate that TR agonists have the potential to inhibit or reverse hepatic steatosis induced by a nutritional model.