作者: Herledan, Adrien ; Enée, Emmanuelle ; Hennuyer, Nathalie ; Vallez, Emmanuelle ; Duplan, Isabelle ; Deprez, Benoit ; Loyens, Anne ; Staels, Bart ; van Endert, Peter ; Bicharel‐Leconte, Marie ; Lancel, Steve ; Andres, Marine ; Deprez‐Poulain, Rebecca ; Zibar, Khamis

Background and Purpose:

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.

Experimental Approach:

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.

Key Results:

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.

Conclusion and Implications:

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.

Nature communications1区 · 综合性期刊

Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice

1区 · 综合性期刊

ArticleOA

作者: Leroux, Florence ; Enée, Emmanuelle ; Gauriot, Marion ; Jahklal, Jouda ; Hennuyer, Nathalie ; Totobenazara, Jane ; Cantrelle, François-Xavier ; van Endert, Peter ; Lippens, Guy ; Sevin, Emmanuel ; Duplan, Isabelle ; Paquet, Charlotte ; Hermant, Paul ; Herledan, Adrien ; Charton, Julie ; Piveteau, Catherine ; Dassonneville, Sandrine ; Woitrain, Eloise ; Deprez-Poulain, Rebecca ; Landry, Valerie ; Deprez, Benoit ; Dumont, Julie ; Marechal, Xavier ; Tang, Wei-Jen ; Culot, Maxime ; Berte, Gonzague ; Bosc, Damien ; Staels, Bart ; Liang, Wenguang G ; Verdelet, Tristan

Abstract:

Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer’s disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.

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