National Institute for Infectious Diseases, IRCCS "Lazzaro Spallanzani", Rome, Italy.
Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
Cell Death Dis. 2018 Feb 15;9(3):257. doi: 10.1038/s41419-018-0292-8.
Non-alcoholic fatty liver disease (NAFLD) is one of the most important liver diseases worldwide. Currently, no effective treatment is available, and NAFLD pathogenesis is incompletely understood. Transglutaminase type 2 (TG2) is a ubiquitous enzyme whose dysregulation is implicated in the pathogenesis of various human diseases. Here we examined the impact of TG2 on NAFLD progression using the high-fat-diet-induced model in both wild-type and TG2-deficient mice. Animals were fed with a standard chow diet or a high-fat diet (42% of the energy from fat) for 16 weeks. Results demonstrated that the absence of a functional enzyme, which causes the impairment of autophagy/mitophagy, leads to worsening of disease progression. Data were confirmed by pharmacological inhibition of TG2 in WT animals. In addition, the analysis of human liver samples from NAFLD patients validated the enzyme's involvement in the liver fat disease pathogenesis. Our findings strongly suggest that TG2 activation may offer protection in the context of NAFLD, thus representing a novel therapeutic target for tackling the NAFLD progression.
非酒精性脂肪性肝病 (NAFLD) 是全球最重要的肝病之一。目前尚无有效的治疗方法，且 NAFLD 的发病机制尚未完全阐明。转谷氨酰胺酶 2 (TG2) 是一种广泛存在的酶，其失调与多种人类疾病的发病机制有关。在这里，我们使用野生型和 TG2 缺陷型小鼠的高脂肪饮食诱导模型研究了 TG2 对 NAFLD 进展的影响。动物喂食标准饲料或高脂肪饮食（42%的能量来自脂肪）16 周。结果表明，缺乏一种功能酶会导致自噬/线粒体自噬受损，从而导致疾病进展恶化。WT 动物中 TG2 的药理学抑制作用证实了这一结果。此外，对来自 NAFLD 患者的人类肝脏样本的分析验证了该酶在肝脏脂肪疾病发病机制中的作用。我们的研究结果强烈表明，TG2 的激活可能在 NAFLD 中提供保护，因此代表了一种针对 NAFLD 进展的新的治疗靶点。
