HtrA2/Omi mitigates NAFLD in high-fat-fed mice by ameliorating mitochondrial dysfunction and restoring autophagic flux.
HtrA2/Omi mitigates NAFLD in high-fat-fed mice by ameliorating mitochondrial dysfunction and restoring autophagic flux.
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HtrA2/Omi 通过改善线粒体功能障碍和恢复自噬通量来减轻高脂肪喂养小鼠的 NAFLD
DOI：
10.1038/s41420-022-01022-4
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发表时间：
2022-04-21
影响因子：
7
通讯作者：
Li, Xiaonan
中科院分区：
文献类型：
--
作者：
Zhou, Wei;Deng, Xueting;Zhu, Xiaolei;Yan, Qinhui;Zhou, Nan;Du, Susu;Li, Xiaonan
非酒精性脂肪性肝病(NAFLD)是最常见的慢性肝脏代谢综合征，影响着全球数百万人。最近，改善线粒体功能和自噬能力被认为是预防NAFLD的一种手段。已有研究表明，高温需求蛋白A2(HtrA2/Omi)有利于肝细胞线粒体的动态平衡和自噬。因此，我们探讨了HtrA2/Omi在NAFLD发育过程中对线粒体功能和自噬的调节作用。建立高脂饮食(HFD)诱导的小鼠NAFLD模型和游离脂肪酸(FFAs)诱导的体外肝细胞脂肪变性模型。用体内的腺相关病毒(AAV)和体外的质粒恢复HtrA2/Omi的表达。在这项研究中，我们报道了HtrA2/Omi在HFD诱导的NAFLD模型和FFA处理的L02细胞中的表达显著降低。然而，修复HtrA2/Omi改善了肝脏脂肪变性，改善了血脂、血糖稳态、胰岛素抵抗、组织病理脂肪堆积和与脂代谢相关的基因表达。此外，HtrA2/Omi还可减轻HFD介导的线粒体功能障碍和自噬阻断。TEM分析表明，与HFD小鼠相比，HtrA2/Omi组小鼠肝脏线粒体结构和自噬小体的形成得到改善。肝脏HtrA2/OMi过表达促进线粒体脂肪酸β氧化基因表达，上调Lc3II蛋白水平，诱导Lc3斑点，降低SqSTM1/p62蛋白水平。此外，肝脏HtrA2/Omi增加了小鼠的呼吸交换率和产热。最后，HtrA2/Omi的过表达显著减少了FFA处理的L02肝细胞中的脂质堆积、线粒体功能障碍和自噬抑制。综上所述，我们证明了HtrA2/Omi通过改善线粒体功能和恢复自噬通量，是治疗NAFLD的潜在候选基因。
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver metabolic syndrome which affects millions of people worldwide. Recently, improving mitochondrial function and autophagic ability have been proposed as a means to prevent NAFLD. It has been previously described that high-temperature requirement protein A2 (HtrA2/Omi) favors mitochondrial homeostasis and autophagy in hepatocytes. Thus, we explored the effects of HtrA2/Omi on regulating mitochondrial function and autophagy during NAFLD development. High-fat diet (HFD)-induced NAFLD in mice and free fatty acids (FFAs)-induced hepatocytes steatosis in vitro were established. Adeno-associated viruses (AAV) in vivo and plasmid in vitro were used to restore HtrA2/Omi expression. In this study, we reported that HtrA2/Omi expression considerably decreased in liver tissues from the HFD-induced NAFLD model and in L02 cells with FFA-treated. However, restoring HtrA2/Omi ameliorated hepatic steatosis, confirming by improved serum lipid profiles, glucose homeostasis, insulin resistance, histopathological lipid accumulation, and the gene expression related to lipid metabolism. Moreover, HtrA2/Omi also attenuated HFD-mediated mitochondrial dysfunction and autophagic blockage. TEM analysis revealed that liver mitochondrial structure and autophagosome formation were improved in hepatic HtrA2/Omi administration mice compared to HFD mice. And hepatic HtrA2/Omi overexpression enhanced mitochondrial fatty acid β-oxidation gene expression, elevated LC3II protein levels, induced LC3 puncta, and decreased SQSTM1/p62 protein levels. Furthermore, hepatic HtrA2/Omi increased respiratory exchange ratio and heat production in mice. Finally, HtrA2/Omi overexpression by plasmid significantly diminished lipid accumulation, mitochondrial dysfunction, and autophagic inhibition in FFA-treated L02 hepatocytes. Taken together, we demonstrated that HtrA2/Omi was a potential candidate for the treatment of NAFLD via improving mitochondrial functions, as well as restoring autophagic flux.
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影响因子：
2.4
作者：
Kiourtis C;Wilczynska A;Nixon C;Clark W;May S;Bird TG
通讯作者：
Bird TG
影响因子：
5.5
作者：
Álvarez-Mercado AI;Rojano-Alfonso C;Micó-Carnero M;Caballeria-Casals A;Peralta C;Casillas-Ramírez A
通讯作者：
Casillas-Ramírez A
影响因子：
5.6
作者：
Di Ciaula A;Calamita G;Shanmugam H;Khalil M;Bonfrate L;Wang DQ;Baffy G;Portincasa P
通讯作者：
Portincasa P
Cyanidin-3-O-glucoside 通过促进 PINK1 介导的线粒体自噬改善小鼠非酒精性脂肪肝
影响因子：
7.3
作者：
Li, Xinwei;Shi, Zhen;Liu, Guowen
通讯作者：
Liu, Guowen
DOI：
10.1016/j.bbrc.2016.05.086
发表时间：
2016-08-05
影响因子：
3.1
作者：
He, Qin;Sha, Sha;Dong, Ming
通讯作者：
Dong, Ming