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 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.