한빛사 논문
Abstract
Sunmi Seok1*, Ting Fu1*, Sung-E Choi1,2, Yang Li3, Rong Zhu4, Subodh Kumar1, Xiaoxiao Sun4, Gyesoon Yoon2, Yup Kang2, Wenxuan Zhong4, Jian Ma3, Byron Kemper1 & Jongsook Kim Kemper1
1Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. 2Institute for Medical Science, Ajou University School of Medicine,Suwon442- 749, Korea. 3Department of Bioengineering and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. 4Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA.
Correspondence to: Jongsook Kim Kemper
*These authors contributed equally to this work.
Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions1, 2, 3, 4. Acute regulation of autophagy by nutrient-sensing kinases is well defined3, 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 data12, 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 lipophagy16, 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.
논문정보
관련 링크
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기