NRF2-mediated SIRT3 induction protects hepatocytes from ER stress-induced liver injury
NRF2-mediated SIRT3 induction protects hepatocytes from ER stress-induced liver injury
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DOI：
10.1096/fj.202101470r
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发表时间：
2022-03-01
期刊：
影响因子：
4.8
通讯作者：
Kim, Sang Geon
中科院分区：
文献类型：
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作者：
Kim, Ayoung;Koo, Ja Hyun;Kim, Sang Geon
肝细胞慢性内质网应激在非酒精性脂肪肝的发病机制中起作用。因此，考虑到氧化应激、线粒体功能障碍和内质网应激之间的关联，我们的研究探讨了nrf2介导的SIRT3激活在内质网应激中的作用。基于生物信息学分析和动物实验，预测SIRT3是NRF2的靶点。在Ppargc1 α和Cpt1a抑制的肝细胞中，Nrf2的去除减少了线粒体DNA的含量，而其过表达增加了氧消耗。此外，染色质免疫沉淀和荧光素酶报告基因分析表明，NRF2通过抗氧化反应元件（ARE）位点（包括-641至-631 bp和-419至-409 bp区域）诱导SIRT3。在tunicamycin诱导的内质网应激条件和内质网应激后肝损伤动物模型中，NRF2水平与SIRT3高度相关。Nrf2缺乏增强了tunicamycin介导的CHOP诱导，而Sirt3过表达则减弱了CHOP的诱导。此外，Nrf2敲除小鼠肝细胞中Sirt3的递送通过降低内质网应激阻止了tunicamycin增加死亡率。SIRT3在非酒精性肝病患者的肝脏中上调，而SIRT3的低表达与更严重的疾病状况相一致。综上所述，我们的研究结果表明，nrf2介导的SIRT3诱导可以保护肝细胞免受内质网应激诱导的损伤，这可能有助于抑制肝脏疾病的进展。
Chronic endoplasmic reticulum (ER) stress in hepatocytes plays a role in the pathogenesis of nonalcoholic fatty liver disease. Therefore, given the association between oxidative stress, mitochondrial dysfunction, and ER stress, our study investigated the role of NRF2-mediated SIRT3 activation in ER stress. SIRT3, a sirtuin, was predicted as the target of NRF2 based on bioinformatic analyses and animal experiments. Nrf2 abrogation diminished mitochondrial DNA content in hepatocytes with Ppargc1 alpha and Cpt1a inhibition, whereas its overexpression enhanced oxygen consumption. Further, chromatin immunoprecipitation and luciferase reporter assays indicated that NRF2 induced SIRT3 through the antioxidant responsive element (ARE) sites comprising the -641 to -631 bp and -419 to -409 bp regions. In tunicamycin-induced ER stress conditions and liver injury animal models following ER stress, NRF2 levels were highly correlated with SIRT3. Nrf2 deficiency enhanced the tunicamycin-mediated induction of CHOP, which was attenuated by Sirt3 overexpression. Further, Sirt3 delivery to hepatocytes in Nrf2 knockout mice prevented tunicamycin from increasing mortality by decreasing ER stress. SIRT3 was upregulated in livers of patients with nonalcoholic liver diseases, whereas lower SIRT3 expression coincided with more severe disease conditions. Taken together, our findings indicated that NRF2-mediated SIRT3 induction protects hepatocytes from ER stress-induced injury, which may contribute to the inhibition of liver disease progression.