Aims

Hepatocyte necroptosis is a critical event in the progression of non-alcoholic fatty liver disease (NAFLD). Obstructive sleep apnea hypopnea syndrome (OSAHS) and chronic intermittent hypoxia (CIH) may be linked with the pathogenesis and the severity of NAFLD. However, the potential role of necroptosis in OSAHS-associated NAFLD has not been evaluated. The present study investigated whether IH could affect NAFLD progression through promoting receptor-interacting protein kinase-3 (RIPK3)-dependent necroptosis, oxidative stress, and inflammatory response, and further elucidated the underlying molecular mechanisms.

Main methods

LO2 cells were treated with palmitic acid (PA) and subjected to IH, and necroptosis, oxidative stress, and inflammation were assessed. The high-fat choline-deficient (HFCD)-fed mouse model was also used to assess the effects of CIH in experimental NAFLD in vivo.

Key findings

In this study, we found that RIPK3-mediated necroptosis was activated both in the PA plus IH-treated LO2 cells and liver of HFCD/CIH mice, and which could trigger oxidative stress and inflammatory response by decreasing Nrf2 and increasing p-P65. RIPK3 downregulation significantly reduced hepatocyte necroptosis, and ameliorated oxidative stress and inflammation through modulating Nrf2/NFκB pathway in vitro and vivo. Similarly, pretreatment with TBHQ, an activator of Nrf2, effectively blocked the generation of oxidative productions and inflammatory cytokines. In addition, RIPK3 inhibitor GSK-872 or TBHQ administration obviously alleviated hepatic injury, including histology, transaminase activities, and triglyceride contents in vivo.

Significance

IH aggravates NAFLD via RIPK3-dependent necroptosis-modulated Nrf2/NFκB signaling pathway, and which should be considered as a potential therapeutic strategy for the treatment of NAFLD with OSASH.

中文翻译：

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间歇性缺氧通过依赖 RIPK3 的坏死性凋亡调节的 Nrf2/NFκB 信号通路加重非酒精性脂肪肝

宗旨

肝细胞坏死是非酒精性脂肪性肝病 (NAFLD) 进展中的一个关键事件。阻塞性睡眠呼吸暂停低通气综合征 (OSAHS) 和慢性间歇性缺氧 (CIH) 可能与 NAFLD 的发病机制和严重程度有关。然而，坏死性凋亡在 OSAHS 相关 NAFLD 中的潜在作用尚未得到评估。本研究调查了 IH 是否可以通过促进受体相互作用蛋白激酶 3 (RIPK3) 依赖的坏死性凋亡、氧化应激和炎症反应来影响 NAFLD 的进展，并进一步阐明潜在的分子机制。

主要方法

LO2 细胞用棕榈酸 (PA) 处理并进行 IH，并评估坏死性凋亡、氧化应激和炎症。高脂肪胆碱缺乏 (HFCD) 喂养的小鼠模型也用于评估 CIH 在体内实验性 NAFLD 中的影响。

主要发现

在这项研究中，我们发现 RIPK3 介导的坏死性凋亡在 PA 加 IH 处理的 LO2 细胞和 HFCD/CIH 小鼠的肝脏中均被激活，并且可以通过降低 Nrf2 和增加 p-P65 触发氧化应激和炎症反应。RIPK3 下调通过在体外和体内调节 Nrf2/NFκB 通路显着减少肝细胞坏死性凋亡，并改善氧化应激和炎症。类似地，用 TBHQ（Nrf2 的激活剂）预处理可有效阻止氧化产物和炎性细胞因子的产生。此外，RIPK3抑制剂GSK-872或TBHQ给药明显减轻肝损伤，包括组织学、转氨酶活性和体内甘油三酯含量。

意义

IH 通过依赖 RIPK3 的坏死性凋亡调节的 Nrf2/NFκB 信号通路加重 NAFLD，这应该被视为用 OSASH 治疗 NAFLD 的潜在治疗策略。