Regulation of Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 11β-HSD1 by CCAAT-Enhancer-Binding Protein C-EBP β Isoforms, LIP and LAPReportar como inadecuado




Regulation of Adipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 11β-HSD1 by CCAAT-Enhancer-Binding Protein C-EBP β Isoforms, LIP and LAP - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

11β-hydroxysteroid dehydrogenase type 1 11β-HSD1 catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11β-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat HF-feeding, adipose tissue 11β-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease. Transcription of 11β-HSD1 is directly regulated by members of the CCAAT-enhancer binding protein C-EBP family. Here we show that while total C-EBPβ in adipose tissue is unaltered by HF diet, the ratio of the C-EBPβ isoforms liver-enriched inhibitor protein LIP and liver-enriched activator protein LAP C-EBPβ-LIP:LAP is increased in subcutaneous adipose. This may cause changes in 11β-HSD1 expression since genetically modified C-EBPβ+-L mice, with increased C-EBPβ-LIP:LAP ratio, have decreased subcutaneous adipose 11β-HSD1 mRNA levels, whereas C-EBPβΔuORF mice, with decreased C-EBPβ-LIP:LAP ratio, show increased subcutaneous adipose 11β-HSD1. C-EBPβ-LIP:LAP ratio is regulated by endoplasmic reticulum ER stress and mTOR signalling, both of which are altered in obesity. In 3T3-L1 adipocytes, 11β-HSD1 mRNA levels were down-regulated following induction of ER stress by tunicamycin but were up-regulated following inhibition of mTOR by rapamycin. These data point to a central role for C-EBPβ and its processing to LIP and LAP in transcriptional regulation of 11β-HSD1 in adipose tissue. Down-regulation of 11β-HSD1 by increased C-EBPβ-LIP:LAP in adipocytes may be part of a nutrient-sensing mechanism counteracting nutritional stress generated by HF diet.



Autor: Cristina L. Esteves, Val Kelly, Valérie Bégay, Tak Y. Man, Nicholas M. Morton, Achim Leutz, Jonathan R. Seckl, Karen E. Chapman

Fuente: http://plos.srce.hr/



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