Insulin-degrading enzyme inhibition increases the unfolded protein response and favours lipid accumulation in the liver.

Autor: Andres M; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - EGID Drugs and Molecules for Living Systems, Lille, France.; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Hennuyer N; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Zibar K; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Bicharel-Leconte M; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Duplan I; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Enée E; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France., Vallez E; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Herledan A; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - EGID Drugs and Molecules for Living Systems, Lille, France., Loyens A; Univ. Lille, UMR-S 1172-JPArc Centre de Recherche Jean-Pierre Aubert Neurosciences et Cancer, Lille, France., Staels B; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France., Deprez B; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - EGID Drugs and Molecules for Living Systems, Lille, France., van Endert P; Université Paris Cité, INSERM, CNRS, Institut Necker Enfants Malades, Paris, France.; Service immunologie biologique, AP-HP, Hôpital Universitaire Necker-Enfants Malades, Paris, France., Deprez-Poulain R; Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - EGID Drugs and Molecules for Living Systems, Lille, France.; Institut Universitaire de France (IUF), Paris, France., Lancel S; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Oct; Vol. 181 (19), pp. 3610-3626. Date of Electronic Publication: 2024 May 29.
DOI: 10.1111/bph.16436
Abstrakt: 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.
(© 2024 British Pharmacological Society.)
Databáze: MEDLINE
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