非酒精性脂肪肝是指肝脏病变，从脂肪变性到脂肪性肝炎，纤维化最终导致肝硬化和肝细胞癌。尽管已经提出了几种机制，包括胰岛素抵抗、氧化应激和炎症，但其病理生理学仍不完全清楚。在过去的十年中，由内质网（ER）应激引发的功能失调的未折叠蛋白反应（UPR）成为多种驱动因素之一。与此同时，越来越多的证据表明，胰岛素降解酶 (IDE) 是一种高度保守且普遍表达的金属肽链内切酶，最初因其在胰岛素衰减中的作用而被发现，它可能调节 ER 应激和 UPR。体外和体内，IDE 是否调节 ER 应激诱导的 UPR 和肝脏脂质积累。我们发现，IDE 缺陷的小鼠表现出较高的肝脏甘油三酯含量以及较高的肌醇需求酶 1 (IRE1) 途径激活。在体外或体内衣霉素或棕榈酸酯诱导 ER 应激后，使用其抑制剂 BDM44768 对 IDE 进行药理学抑制，主要加剧了 ER 应激诱导的 IRE1 激活并促进肝细胞中的脂质积累，而 IRE1 抑制剂 4μ8c 和基拉6。最后，我们发现 IDE 敲除促进脂肪组织中的脂肪分解并增加肝脏 CD36 表达，这可能导致脂肪变性。这些结果揭示了 IDE 在调节 ER 应激和肝脂肪变性发展中的新作用。这些发现为调节 IDE 治疗代谢疾病的创新策略铺平了道路。© 2024 英国药理学会。

Nonalcoholic fatty liver disease refers to liver pathologies, ranging from steatosis to steatohepatitis, with fibrosis ultimately leading to cirrhosis and hepatocellular carcinoma. Although several mechanisms have been suggested, including insulin resistance, oxidative stress, and inflammation, its pathophysiology remains imperfectly understood. Over the last decade, a dysfunctional unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress emerged as one of the multiple driving factors. In parallel, growing evidence suggests that insulin-degrading enzyme (IDE), a highly conserved and ubiquitously expressed metallo-endopeptidase originally discovered for its role in insulin decay, may regulate ER stress and UPR.We investigated, by genetic and pharmacological approaches, in vitro and in vivo, whether IDE modulates ER stress-induced UPR and lipid accumulation in the liver.We found that IDE-deficient mice display higher hepatic triglyceride content along with higher inositol-requiring enzyme 1 (IRE1) pathway activation. Upon induction of ER stress by tunicamycin or palmitate in vitro or in vivo, pharmacological inhibition of IDE, using its inhibitor BDM44768, mainly exacerbated ER stress-induced IRE1 activation and promoted lipid accumulation in hepatocytes, effects that were abolished by the IRE1 inhibitors 4μ8c and KIRA6. Finally, we identified that IDE knockout promotes lipolysis in adipose tissue and increases hepatic CD36 expression, which may contribute to steatosis.These results unravel a novel role for IDE in the regulation of ER stress and development of hepatic steatosis. These findings pave the way to innovative strategies modulating IDE to treat metabolic diseases.© 2024 British Pharmacological Society.