1. Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation
- Author
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Rosanne M. Crooke, Jianguo Wang, Xiaowei Sun, Jean-Paul Pais de Barros, Abhiruchi J Mehta, David Masson, Ji Miao, Mary E. Haas, Sudha B. Biddinger, Mark J. Graham, Masanori Aikawa, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Harvard Medical School [Boston] (HMS), Isis Pharmaceuticals, IBIS THERAPEUTICS-ISIS Therapeutics, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), Harvard Medical School [Boston] ( HMS ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Harvard Medical School [Boston] ( HMS ) -Brigham and Women's Hospital [Boston], and ANR-11-LABX-0021/11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du ( 2011 )
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Lipid-metabolism ,Resistance ,Biochemistry ,Hepatitis ,MESH: Hepatitis ,MESH: Endoplasmic Reticulum Stress ,polycyclic compounds ,Insulin ,Gene-expression ,Phospholipids ,Liver X Receptors ,Mice, Knockout ,biology ,MESH : Gene Expression Regulation ,Fatty-acid synthesis ,food and beverages ,Endoplasmic Reticulum Stress ,Orphan Nuclear Receptors ,Cultured-cells ,Lipids ,MESH: Gene Expression Regulation ,MESH : Endoplasmic Reticulum Stress ,Messenger-rna ,Liver ,MESH: Orphan Nuclear Receptors ,Gene Knockdown Techniques ,Lipogenesis ,Female ,lipids (amino acids, peptides, and proteins) ,Signal Transduction ,liver X receptor ,medicine.medical_specialty ,Lxr-alpha ,Mice, Transgenic ,digestive system ,Phospholipid transfer protein ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Insulin resistance ,MESH : Hepatitis ,Lysophosphatidylcholine acyltransferase ,Internal medicine ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Liver X receptor ,Molecular Biology ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Crosses, Genetic ,Endoplasmic reticulum ,Element-binding protein-1c ,MESH : Liver ,Cell Biology ,medicine.disease ,MESH : Orphan Nuclear Receptors ,Receptor, Insulin ,Mice, Inbred C57BL ,Insulin receptor ,030104 developmental biology ,Endocrinology ,Diabetes Mellitus, Type 2 ,Gene Expression Regulation ,Nuclear receptor ,biology.protein ,Unfolded protein response ,Insulin Resistance ,MESH: Liver - Abstract
IF 4.258; International audience; 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.
- Published
- 2016
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