Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation.
Fiche publication
Date publication
janvier 2016
Journal
The Journal of biological chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr PAIS DE BARROS Jean-Paul, Pr MASSON David
Tous les auteurs :
Sun X, Haas ME, Miao J, Mehta A, Graham MJ, Crooke RM, Pais de Barros JP, Wang JG, Aikawa M, Masson D, Biddinger SB
Lien Pubmed
Résumé
Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxrα in mice with hepatocyte-specific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxrα produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxrα, and LXRα was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXRα to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXRα and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.
Mots clés
Animals, Crosses, Genetic, Diabetes Mellitus, Type 2, complications, Endoplasmic Reticulum Stress, Female, Gene Expression Regulation, Gene Expression Regulation, Enzymologic, Gene Knockdown Techniques, Hepatitis, complications, Insulin, metabolism, Insulin Resistance, Lipogenesis, Liver, enzymology, Liver X Receptors, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Orphan Nuclear Receptors, agonists, Phospholipids, metabolism, Receptor, Insulin, agonists, Signal Transduction
Référence
J. Biol. Chem.. 2016 Jan 15;291(3):1115-22