甲状腺激素调控线粒体turnover在肥胖型和非肥胖型NAFLD的发病机制研究

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Obese and non-obese NAFLD, two types of NAFLD defined with body mass index, have different risks for developing nonalcoholic steatohepatitis (NASH). Whether the pathophysiology of obese and non-obese NAFLD is different remains unknown. Using liver samples from biopsy-proven NAFLD patients, we revealed a significant negative correlation of hepatic iodothyronine deiodinase type 1 (DIO1) level with NAFLD activity score (NAS) and body mass index. Studies with NAFLD patients and animals demonstrated that DIO1 expression, as well as markers of mitochondrial turnover (mitochondrial biogenesis and mitophagy), were significantly lower in patients with obese NAFLD than non-NAFLD controls and patients with non-obese NAFLD; whereas no difference was detected in the latter two groups. Administration of a highly selective thyroid hormone receptor β (THR-β) agonist (also selective for liver) increased mitochondrial turnover, attenuated clinical and histological phenotype of obese NAFLD, but showed no effect on non-obese NAFLD. We postulate that decreased thyroid hormone signaling impairs mitochondrial turnover and accelerates the development of obese NAFLD, the molecular mechanisms remain to be determined. However, this is not the case in non-obese NAFLD, in which thyroid hormone signaling is almost normal. Based on these results, further studies will be performed to directly prove that decreased thyroid hormone signaling would aggravate NAFLD development and to explore the mechanism. We will also determine the differences of thyroid hormone signaling and mitochondrial turnover between obese and non-obese NAFLD. Our study will provide theoretical support for stratified therapy in patients with NAFLD.

非酒精性脂肪性肝病(NAFLD)是最常见的肝脏疾病。肥胖和非肥胖型NAFLD患病率均较高，但疾病进展存在差异，两者发病机制是否不同未知。我们对病理诊断NAFLD的患者研究首次发现，肝脏脱碘酶DIO1水平和病理评分及BMI显著负相关。肥胖型NAFLD肝脏DIO1、线粒体turnover(线粒体自噬和生成)低于对照和非肥胖型NAFLD，而后两者无差异。肝脏特异性甲状腺激素β受体激动剂增加肥胖型NAFLD线粒体turnover、改善其表型，而对非肥胖型无改善。我们提出肥胖和非肥胖型NAFLD甲状腺激素信号通路活性不同，该通路下调导致线粒体turnover受损，从而促进NAFLD发生，具体分子机制仍需明确。我们通过基因敲除鼠等方法证明甲状腺激素通路下调促进NAFLD发生并阐述其机制，明确甲状腺激素通路及其调控的线粒体turnover在两种NAFLD发病中的作用差异，本研究可为其分层治疗提供理依据。

非酒精性脂肪性肝病(NAFLD)是最常见的肝脏疾病。肥胖和非肥胖型NAFLD患病率均较高，但疾病进展存在差异，两者发病机制是否不同未知。我们对病理诊断NAFLD的患者研究首次发现，肝脏脱碘酶DIO1水平和病理评分及BMI显著负相关。我们在患者和小鼠中均发现，肥胖型NAFLD肝脏DIO1低于对照和非肥胖型NAFLD，而后两者无差异。肝脏特异性甲状腺激素β受体(THRβ)激动剂改善其表型，而对非肥胖型无改善。这些数据提示肥胖型和非肥胖型NAFLD存在发病机制的差异，并且甲状腺激素通路在肥胖型NAFLD中可能发挥重要的作用。为进一步探索其机制，我们检测了肥胖型NAFLD、非肥胖型NAFLD和对照组人肝脏组织的线粒体turnover(线粒体自噬和生成)的情况，发现肥胖型NAFLD肝脏组织线粒体自噬相关蛋白PINK1和生成相关蛋白PGC-1α的表达均较对照组显著降低，而非肥胖型NAFLD并未表现出这种变化。动物实验证实了上述结论。我们同时发现，THRβ激动剂增加肥胖型NAFLD线粒体turnover，而对非肥胖型NAFLD无明显作用。因此，我们首次得出肥胖和非肥胖型NAFLD甲状腺激素信号通路活性不同，该通路下调导致线粒体turnover受损，从而促进NAFLD发生的结论。我们明确了甲状腺激素通路及其调控的线粒体turnover在两种NAFLD发病中的作用差异，本研究可为其分层治疗提供理依据。