Transcriptional regulation of autophagy by an FXR-CREB axis

Sunmi Seok, Ting Fu, Sung E. Choi, Yang Li, Rong Zhu, Subodh Kumar, Xiaoxiao Sun, Gyesoon Yoon, Yup Kang, Wenxuan Zhong, Jian Ma, Byron Kemper, Jongsook Kim Kemper

Research output: Contribution to journalArticlepeer-review

260 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)108-111
Number of pages4
JournalNature
Volume516
Issue number729
DOIs
StatePublished - Dec 4 2014
Externally publishedYes

ASJC Scopus subject areas

  • General

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