Kolachala Vasantha L, Palle Sirish K, Shen Ming, Shenoi Asha, Shayakhmetov Dmitry M, Gupta Nitika A
Department of Pediatrics Emory University School of Medicine Atlanta GA.
Transplant Services Children's Healthcare of Atlanta Atlanta GA.
Hepatol Commun. 2019 Apr 25;3(7):925-942. doi: 10.1002/hep4.1352. eCollection 2019 Jul.
Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3-mediated necroptosis or caspase 8 (Casp8)-mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1-mediated cell death is operational, leading to protection in RIP1 kinase-dead knock-in (RIPK1) mice and necrostatin-1s (Nec1s)-treated lean wild-type (WT) mice. However, when fed a high-fat diet (HFD), RIPK1-treated and Nec1s-treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD-fed RIPK3/Casp8 mice show protection from IRI, but HFD-fed RIPK3/Casp8 mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.
目前的认识是，受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）可导致两种不同形式的细胞死亡：RIPK3介导的坏死性凋亡或半胱天冬酶8（Casp8）介导的凋亡。在此，我们报告，在经历缺血再灌注损伤（IRI）的脂肪变性肝脏中，RIPK1信号传导对于保护免受肝细胞损伤是必不可少的，但在正常肝脏中并非如此。在正常肝脏IRI中，RIPK1介导的细胞死亡起作用，导致RIP1激酶失活敲入（RIPK1）小鼠和经坏死抑制因子-1s（Nec1s）处理的正常野生型（WT）小鼠得到保护。然而，当喂食高脂饮食（HFD）时，接受IRI的经RIPK1处理和Nec1s处理的WT小鼠表现出肝细胞损伤加剧，同时RIPK1泛素化减少。此外，我们证明喂食HFD的RIPK3/Casp8双敲除小鼠对IRI有保护作用，但喂食HFD的RIPK3/Casp8单敲除小鼠则没有。我们还表明，阻断RIPK1会导致Casp8活性增加并降低线粒体活力。尽管还需要更多的研究，但我们为RIPK1抑制在经历IRI的正常肝脏和脂肪变性肝脏中导致不同结果提供了重要的概念验证。考虑到普通人群中非酒精性脂肪性肝病（NAFLD）的发病率不断上升，在使用RIPK1抑制剂治疗患者时，解决这一关键差异将势在必行。本研究还提出了一种预防NAFLD中肝细胞损伤的药物治疗新靶点。
