Letter | Published:

Nutrient-sensing nuclear receptors coordinate autophagy

Nature volume 516, pages 112115 (04 December 2014) | Download Citation


Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1,2,3. 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, respectively4,5. 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.

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Gene Expression Omnibus

Data deposits

PPARα ChIP-seq data sets have been deposited in the NCBI Gene Expression Omnibus with the accession number GSE61817.


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We thank N. Mizushima for the GFP-LC3Tg/+ mice; T. Yoshimori for the mRFP–GFP–LC3 plasmid; M. Komatsu for the Atg7F/F mice; D. Townley and M. Mancini for transmission electron microscopy and confocal microscopy; the members of the Moore laboratory for comments and additional support. Core facilities supported by grants U54 HD-07495-39, P30 DX56338-05A2, P39 CA125123-04 and S10RR027783-01A1. Next-generation sequencing was performed by the Functional Genomics Core of the Penn Diabetes Research Center (DK19525). This work was supported by funding from the Alkek Foundation and the Robert R. P. Doherty Jr-Welch Chair in Science to D.D.M., and R01 DK49780 and DK43806 to M.A.L.

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Author notes

    • Martin Wagner
    •  & Dan Feng

    Present addresses: Laboratory of Experimental Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, A-8036 Graz, Austria (M.W.); Stanford University School of Medicine, Palo Alto, California 94305, USA (D.F.).


  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Jae Man Lee
    • , Martin Wagner
    • , Rui Xiao
    • , Kang Ho Kim
    •  & David D. Moore
  2. 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 Feng
    •  & Mitchell A. Lazar


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J.M.L. conceived the project, designed and performed most experiments, interpreted results, and co-wrote the manuscript. M.W. performed animal experiments and participated in discussion of the results. R.X. analysed PPARα and FXR ChIP-seq data, and designed primers for PPARα ChIP-qPCR. K.H.K. performed ChIP assays and molecular cloning. D.F. performed PPARα ChIP-seq. M.A.L. supervised experimental designs. D.D.M. conceived the project, supervised experimental designs, interpreted results, and co-wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David D. Moore.

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    This file contains autophagy-related gene list.

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