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.

Suppressed translation and ULK1 degradation as potential mechanisms of autophagy limitation under prolonged starvation

“…Moreover, we revealed that the reduction of the ULK1 protein under starvation conditions in HBSS also takes place in cells with inhibited proteasomal degradation, suggesting the involvement of some additional Several recent publications have reported the transcriptional regulation of autophagy under starvation conditions. [1][2][3][4] However, not all of these studies have been focused on the effects downstream of mRNA transcription. Potentially, upregulation of transcription factor activities contributes to an increase in the mRNA level of respective ATG genes during starvation; however, many other factors may control autophagy at the posttranscriptional level under different starvation conditions.…”

“…1A). Because, based on some previous reports, several ATG proteins are transcriptionally upregulated under starvation conditions, [1][2][3][4] we checked the expression of ULK1 in cells under nitrogen-deprivation conditions. In contrast to the reduction of protein level, the level of ULK1 mRNA was significantly increased, suggesting that some other mechanism of the regulation of ULK1 protein expression during starvation is downstream of transcription (Fig.…”

“…A number of ATG genes that are transcriptionally upregulated and facilitate autophagy in response to starvation have been identified. [1][2][3][4] However, potential mechanisms and players that limit autophagy amplification under starvation conditions remain largely unknown.…”

Autophagy at the crossroads of catabolism and anabolism

“…A complementary mechanism to regulate lipid degradation involves the nuclear receptor farnesoid X receptor (FXR; also known as the bile acid receptor), which competes with PPARα for binding to shared sites in the promoter regions of autophagy genes; when bound to the promoters of autophagy genes FXR represses their transcription in fed cells to inhibit lipophagy 74 . FXR can also inhibit the formation of a complex between the transcriptional activator cAMP response element-binding protein (CREB), which is active under conditions of fasting, and its co-activator CRTC2 to inhibit lipophagy in the liver of fed mice 75 . Collectively, these studies highlight the complexity of integrated transcriptional networks in fine-tuning lipophagy.…”

The marine n-3 PUFA DHA evokes cytoprotection against oxidative stress and protein misfolding by inducing autophagy and NFE2L2 in human retinal pigment epithelial cells

“…89 Also, in addition to TFEB (transcription factor EB), 90 recent studies have pointed to CREB (cAMP responsive element binding protein) and PPARA (peroxisome proliferator-activated receptor a) important for the transcriptional regulation of autophagy. 91,92 The pathogenesis of AMD is strongly associated with oxidative stress. 10,18,20,93,94 Currently, there is no established prevention or therapy for early AMD.…”