Transcriptional regulation of autophagy by an FXR-CREB axis.

Abstract

Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions1–4. Acute regulation of autophagy by nutrient-sensing kinases is well defined3, 5–7, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor FXR8, 9 and the fasting transcriptional activator CREB10, 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 ChIP-seq data12–15, FXR and CREB binding peaks were detected at 178 and 112, respectively, of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted lipophagy, autophagic degradation of lipids16, 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 novel FXR/CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.