CREBH alleviates mitochondrial oxidative stress through SIRT3 mediating deacetylation of MnSOD and suppression of Nlrp3 inflammasome in NASH.
CREBH alleviates mitochondrial oxidative stress through SIRT3 mediating deacetylation of MnSOD and suppression of Nlrp3 inflammasome in NASH.
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CREBH 通过 SIRT3 介导 MnSOD 脱乙酰化和抑制 NASH 中的 Nlrp3 炎症小体来减轻线粒体氧化应激。
DOI：
10.1016/j.freeradbiomed.2022.07.018
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发表时间：
2022-08
期刊：
影响因子：
--
通讯作者：
Xu Keshu
中科院分区：
文献类型：
--
作者：
Zhang Junli;Zhao Yajuan;Wang Shuhan;Li Guixin;Xu Keshu
脂毒性和未解决的氧化应激是非酒精性脂肪性肝炎(NASH)代谢性炎症的关键驱动因素。CAMP反应元件结合蛋白H(CREBH)是一种肝脏特异性转录因子，调节NASH的糖脂代谢。然而，它在线粒体氧化应激中的作用及其与sirtuin 3(SIRT3)的关系仍然不清楚，sirtuin 3是线粒体蛋白质去乙酰化的主要调节因子。本研究用棕榈酸处理AML-12细胞，模拟NASH的体外病理变化，并用8周龄雄性C57BL/6J小鼠饲喂高脂(HF)饲料或蛋氨酸胆碱缺乏(MCD)饲料，建立被广泛接受的NASH体内模型。我们发现，脂质过载诱导线粒体氧化应激，并刺激CREBH和SIRT3的表达。CREBH过表达可减轻线粒体氧化应激。此外，CREBH还可促进SIRT3的表达，从而调节锰超氧化物歧化酶(MnSOD)的脱乙酰化，抑制NOD样受体PYRIN结构域含3(Nlrp3)的炎性小体激活，而抑制SIRT3则损害CREBH对线粒体氧化应激的保护作用。CREBH基因敲除小鼠对HF和MCD饮食诱导的NASH高度敏感，具有更严重的氧化应激。综上所述，我们的结果首次支持CREBH可能通过SIRT3调节MnSOD的乙酰化和Nlrp3炎症小体的激活而在NASH的进展中起到保护因子的作用。这些结果表明CREBH可能是治疗NASH的有价值的候选药物。
Lipotoxicity and unresolved oxidative stress are key drivers of metabolic inflammation in nonalcoholic steatohepatitis (NASH). cAMP-response element binding protein H(CREBH) is a liver-specific transcription factor and regulates the glucose and lipid metabolism of NASH. However, its role in mitochondrial oxidative stress and its association with sirtuin 3 (SIRT3), a master regulator of deacetylation for mitochondrial proteins, remains elusive. In this study, AML-12 cells were treated with palmitic acid to imitate the pathological changes of NASH in vitro and 8-week-old male C57BL/6J mice were fed with a high-fat (HF) diet or a methionine-choline-deficient (MCD) diet to build the widely accepted in vivo model of NASH. We found that lipid overload induced mitochondrial oxidative stress and stimulated the expression of CREBH and SIRT3. CREBH overexpression alleviated the mitochondrial oxidative stress. Moreover, CREBH promoted SIRT3 expression, which regulated the deacetylation of manganese superoxide dismutase (MnSOD) and inhibited NOD-Like Receptor Pyrin Domain Containing 3 (Nlrp3) inflammasome activation whereas suppression of SIRT3 damaged the protecting ability of CREBH in mitochondrial oxidative stress. CREBH knockout mice were highly susceptible to HF and MCD diet-induced NASH with more severe oxidative stress. Collectively, our results firstly provided the support that CREBH could serve as a protective factor in the progression of NASH by regulating the acetylation of MnSOD and the activation of Nlrp3 inflammasome through SIRT3. These results suggest that CREBH might be a valuable therapeutic candidate for NASH.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
影响因子：
5.4
作者：
Hao Y;Miao J;Liu W;Peng L;Chen Y;Zhong Q
通讯作者：
Zhong Q
影响因子：
4.6
作者：
Nakagawa Y;Satoh A;Tezuka H;Han SI;Takei K;Iwasaki H;Yatoh S;Yahagi N;Suzuki H;Iwasaki Y;Sone H;Matsuzaka T;Yamada N;Shimano H
通讯作者：
Shimano H
非酒精性脂肪肝。
DOI：
10.1136/bmj.g4596
发表时间：
2014-07-29
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Sattar N;Forrest E;Preiss D
通讯作者：
Preiss D
CREBH 敲除会加速饮食诱导的非酒精性脂肪肝小鼠模型的肝纤维化。
影响因子：
6.1
作者：
Li Guixin;Zhang Junli;Jiang Qianqian;Liu Beibei;Xu Keshu
通讯作者：
Xu Keshu