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Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Abstract : 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 Lxr alpha in mice with hepatocytespecific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxr alpha produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxr alpha, and LXR alpha was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXR alpha 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 LXR alpha 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.
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01391796
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : jeudi 3 novembre 2016 - 18:40:55
Dernière modification le : jeudi 13 décembre 2018 - 15:58:01

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Xiaowei Sun, Mary E. Haas, Ji Miao, Abhiruchi Mehta, Mark J. Graham, et al.. Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2016, 291 (3), pp.1115 - 1122. ⟨10.1074/jbc.M115.668269⟩. ⟨hal-01391796⟩

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