Nature (London), 2014-12, Vol.516 (7529), p.108-111
2014
Details
- Autor(en) / Beteiligte
- Titel
- Transcriptional regulation of autophagy by an FXR-CREB axis
- Ist Teil von
- Nature (London), 2014-12, Vol.516 (7529), p.108-111
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- EBSCOhost Psychology and Behavioral Sciences Collection
- Beschreibungen/Notizen
- Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases is well defined, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR) and the fasting transcriptional activator cAMP response element-binding protein (CREB) coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice, and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, FXR and CREB binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1 and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB-CRTC2 complex. This study identifies the new FXR-CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1038/nature13949Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4257899
- Format
- –
- Schlagworte
- Animals, Autophagy, Autophagy (Cytology), Autophagy - genetics, Bile, Cyclic AMP Response Element-Binding Protein - metabolism, Deoxyribonucleic acid, DNA, Fasting - physiology, Gene Expression Regulation - drug effects, Genes, Genetic research, Genetic transcription, Isoxazoles - pharmacology, Kinases, Liver - cytology, Liver - metabolism, Male, Metabolic disorders, Metabolites, Mice, Mice, Inbred C57BL, Physiology, Protein Binding, Receptors, Cytoplasmic and Nuclear - agonists, Receptors, Cytoplasmic and Nuclear - metabolism, Rodents