Transcriptional regulation of autophagy by an FXR–CREB axis

• Published in: Nature (London) Vol. 516; no. 7529; pp. 108 - 111
• Main Authors: Seok, Sunmi, Fu, Ting, Choi, Sung-E, Li, Yang, Zhu, Rong, Kumar, Subodh, Sun, Xiaoxiao, Yoon, Gyesoon, Kang, Yup, Zhong, Wenxuan, Ma, Jian, Kemper, Byron, Kemper, Jongsook Kim
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.12.2014; Nature Publishing Group
• Subjects: 13; 13/106; 13/51; 13/89; 14/19; 38; 45; 45/15; 631/443/163; 631/443/319/1557; 631/80/39; 64/60; 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; Humanities and Social Sciences; Isoxazoles - pharmacology; Kinases; letter; Lipids; Liver - cytology; Liver - metabolism; Male; Metabolic disorders; Metabolites; Mice; Mice, Inbred C57BL; multidisciplinary; Nutrients; Physiology; Protein Binding; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents; Science
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature13949

The FXR–CREB axis is identified as a key physiological switch that regulates autophagy during feeding/fasting cycles; in the fed state, the nuclear receptor FXR is shown to suppress autophagy in the liver by inhibiting autophagy-associated lipid breakdown triggered under fasting conditions by the transcriptional activator CREB. Control of autophagy by nuclear receptors Autophagy — the process in which a cell digests its own components in organelles known as lysosomes — comes in various forms. A basic form involves recycling nutrients upon starvation to maintain cellular homeostasis, so it is not surprising, that the signalling mediators of nutrient sensing can modulate autophagy in the short-term. Two studies now show that starvation-induced autophagy can also be regulated through long-term transcriptional control. Jongsook Kemper and colleagues find that, in the fed state, the nuclear receptor FXR suppresses autophagy in the liver. For this, FXR seems to inhibit autophagy-associated lipid breakdown triggered under fasting conditions by the transcriptional activator CREB. David Moore and colleagues also observe FXR-mediated suppression of autophagy. In addition, they find that another nuclear receptor, PPARα, which is activated in the fasted state, triggers autophagy such that PPARα and FXR compete for binding to shared sites in the promoters of autophagic genes, with opposite transcriptional outputs. Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions 1 , 2 , 3 , 4 . Acute regulation of autophagy by nutrient-sensing kinases is well defined 3 , 5 , 6 , 7 , but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR) 8 , 9 and the fasting transcriptional activator cAMP response element-binding protein (CREB) 10 , 11 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 12 , 13 , 14 , 15 , 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 16 , 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.