Jørgen Sikkeland1, Torstein Lindstad2, Hatice Zeynep Nenseth2, Xavier Dezitter3, Su Qu2, Ridhwan M Muhumed2, Meric Erikci Ertunc4, Margaret F Gregor5, Fahri Saatcioglu6. 1. Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0310 Oslo, Norway. 2. Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway. 3. Plateforme de Binding et de Biologie Moléculaire, Institut de Chimie Pharmaceutique Albert Lespagnol, Faculté des Sciences Pharmaceutiques et Biologiques - Université de Lille, F-59006 Lille, France. 4. Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway; Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA. 5. Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA. 6. Department of Biosciences, University of Oslo, Postboks 1066 Blindern, 0316 Oslo, Norway; Institute for Cancer Genetics and Informatics, Oslo University Hospital, 0310 Oslo, Norway. Electronic address: fahris@ibv.uio.no.
Abstract
BACKGROUND: Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obese mice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. METHODS: 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. RESULTS: ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPα-mediated STAMP2 expression. CONCLUSION: These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.
BACKGROUND: Chronic ER stress and dysfunction is a hallmark of obesity and a critical contributor to metaflammation, abnormal hormone action and altered substrate metabolism in metabolic tissues, such as liver and adipocytes. Lack of STAMP2 in lean mice induces inflammation and insulin resistance on a regular diet, and it is dysregulated in the adipose tissue of obesemice and humans. We hypothesized that the regulation of STAMP2 is disrupted by ER stress. METHODS: 3T3-L1 and MEF adipocytes were treated with ER stress inducers thapsigargin and tunicamycin, and inflammation inducer TNFα. The treatments effect on STAMP2 expression and enzymatic function was assessed. In addition, 3T3-L1 adipocytes and HEK cells were utilized for Stamp2 promoter activity investigation performed with luciferase and ChIP assays. RESULTS: ER stress significantly reduced both STAMP2 mRNA and protein expression in cultured adipocytes whereas TNFα had the opposite effect. Concomitant with loss of STAMP2 expression during ER stress, intracellular localization of STAMP2 was altered and total iron reductase activity was reduced. Stamp2 promoter analysis by reporter assays and chromatin immunoprecipitation, showed that induction of ER stress disrupts C/EBPα-mediated STAMP2 expression. CONCLUSION: These data suggest a clear link between ER stress and quantitative and functional STAMP2-deficiency.
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