Nutrient-sensing nuclear receptors coordinate autophagy.
Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-α (PPARα) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARα and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Jae Man
JM
Lee
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Martin
M
Wagner
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Rui
R
Xiao
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Kang Ho
KH
Kim
Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.
Dan
D
Feng
Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.
Mitchell A
MA
Lazar
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
David D
DD
Moore
D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D005215:Fasting / Q000502:physiology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D008869:Microtubule-Associated Proteins; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C480860:Map1lc3b protein, mouse