Transcriptional regulation of autophagy by an FXR-CREB axis.
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.
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Sunmi
S
Seok
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Ting
T
Fu
1] Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea.
Sung-E
SE
Choi
Department of Bioengineering and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Yang
Y
Li
Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA.
Rong
R
Zhu
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Subodh
S
Kumar
Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA.
Xiaoxiao
X
Sun
Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea.
Gyesoon
G
Yoon
Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea.
Yup
Y
Kang
Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA.
Wenxuan
W
Zhong
Department of Bioengineering and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Jian
J
Ma
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Byron
B
Kemper
Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Jongsook Kim
JK
Kemper
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005215:Fasting / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D017362:Cyclic AMP Response Element-Binding Protein; D007555:Isoxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064