title: Molecular mechanisms of estrogen receptors' suppression of lipogenesis in pancreatic β-cells.
abstract: The gonadal steroid, 17β-estradiol (E2), suppresses pancreatic islet fatty acid and glycerolipid synthesis and prevents β-cell failure in rodent models of type 2 diabetes. β-Cell estrogen receptors (ER) mediate these actions by suppressing the expression and enzymatic activity of fatty acid synthase (FAS). Here, we explored the mechanism of FAS suppression. We show that E2, and pharmacological agonists for ERα, ERβ, and the G protein-coupled ER, suppress mRNA and protein expression of the transcriptional regulators of FAS, namely, sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrate response element binding protein (ChREBP) in insulin-secreting INS-1 cells. ER suppress SREBP1c and ChREBP mRNA and protein expression via an extranuclear localization. Using two mouse lines with pancreas-specific null deletion of either ERα or the signal transducer and activator of transcription 3 (STAT3), we show that ERα activation in vivo reduces SREBP1c and ChREBP mRNA expression via a direct islet action involving STAT3 activation. The master regulators of lipogenesis, liver X receptor (LXR) α and β, transcriptionally up-regulate SREBP1c and ChREBP. We find that activation of ERα, ERβ, and G protein-coupled ER suppresses LXR's mRNA expression in INS-1 cells. We also observe that activation of ERα in mouse islets in vivo suppresses LXR mRNA in a STAT3-dependent manner. Finally, we show that E2 also activates and uses AMP-activated protein kinase in INS-1 cells to suppress SREBP1c protein expression. This study identifies extranuclear ER pathways involving STAT3 and AMP-activated protein kinase in the genetic control of lipogenesis with therapeutic implications to protect β-cells in type 2 diabetes.
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, 303 East Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Tiano
authors.forename: Franck
authors.initials: F
authors.lastname: Mauvais-Jarvis
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology; D050155:Lipogenesis; D051379:Mice; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D011960:Receptors, Estrogen; D050796:STAT3 Transcription Factor; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D064429:Fatty Acid Synthases; D055372:AMP-Activated Protein Kinases