小柯机器人

美国加州大学圣地亚哥分校Michael Karin和Ju Youn Kim共同合作近期取得重要工作进展，他们研究发现PIDDosom-SCAP相互作用控制着高果糖饮食依赖的从单纯性脂肪病变到脂肪性肝炎的转变。相关论文2022年8月29日在线发表于《细胞—代谢》杂志上。

研究人员揭示了控制从肝硬化到脂肪性肝炎转变的两种途径之间的调节串联。由NASH诱导饮食引起的ER应激激活IRE1并诱导PIDDosome亚基caspase-2、RAIDD和PIDD1以及INSIG2（一种SCAP依赖性SREBP激活抑制剂）的表达。PIDDosome组装激活caspase-2并维持IRE1的激活。PIDDosome消融或IRE1抑制可减弱脂肪性肝炎并减少INSIG2表达。

相反，在抑制单纯性脂肪变性的同时，SCAP消融会扩大IRE1和PIDDosome的激活以及NASH饮食动物的肝脏损伤，这些影响与ER的破坏有关，可以通过IRE1的抑制来预防。因此，PIDDosome和SCAP通路拮抗调节营养诱导的肝脏ER应激，以控制从简单脂肪变性到肝炎的非线性转变，这是NASH发病机制的关键步骤。

据介绍，甾醇缺乏会触发SCAP介导的SREBP激活，而营养过剩和ER应激会通过caspase-2激活SREBP1/2。

附：英文原文

Title: PIDDosome-SCAP crosstalk controls high-fructose-diet-dependent transition from simple steatosis to steatohepatitis

Author: Ju Youn Kim, Lily Q. Wang, Valentina C. Sladky, Tae Gyu Oh, Junlai Liu, Kaitlyn Trinh, Felix Eichin, Michael Downes, Mojgan Hosseini, Etienne D. Jacotot, Ronald M. Evans, Andreas Villunger, Michael Karin

Issue&Volume: 2022-08-29

Abstract: Sterol deficiency triggers SCAP-mediated SREBP activation, whereas hypernutritiontogether with ER stress activates SREBP1/2 via caspase-2. Whether these pathways interactand how they are selectively activated by different dietary cues are unknown. Here,we reveal regulatory crosstalk between the two pathways that controls the transitionfrom hepatosteatosis to steatohepatitis. Hepatic ER stress elicited by NASH-inducingdiets activates IRE1 and induces expression of the PIDDosome subunits caspase-2, RAIDD,and PIDD1, along with INSIG2, an inhibitor of SCAP-dependent SREBP activation. PIDDosomeassembly activates caspase-2 and sustains IRE1 activation. PIDDosome ablation or IRE1inhibition blunt steatohepatitis and diminish INSIG2 expression. Conversely, whileinhibiting simple steatosis, SCAP ablation amplifies IRE1 and PIDDosome activationand liver damage in NASH-diet-fed animals, effects linked to ER disruption and preventableby IRE1 inhibition. Thus, the PIDDosome and SCAP pathways antagonistically modulatenutrient-induced hepatic ER stress to control non-linear transition from simple steatosisto hepatitis, a key step in NASH pathogenesis.

DOI: 10.1016/j.cmet.2022.08.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00348-5

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
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