Letter | Published:

Nutrient-sensing nuclear receptors coordinate autophagy

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

Abstract

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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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

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

References

  1. 1.

    , , & Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008)

  2. 2.

    & Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008)

  3. 3.

    & Autophagy and metabolism. Science 330, 1344–1348 (2010)

  4. 4.

    , & PPARs and the complex journey to obesity. Nature Med. 10, 355–361 (2004)

  5. 5.

    , & Don’t know much bile-ology. Cell 103, 1–4 (2000)

  6. 6.

    , & Regulation of glucose production by the liver. Annu. Rev. Nutr. 19, 379–406 (1999)

  7. 7.

    & mTOR signaling in growth control and disease. Cell 149, 274–293 (2012)

  8. 8.

    , & AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400 (2012)

  9. 9.

    , & AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Rev. Mol. Cell Biol. 13, 251–262 (2012)

  10. 10.

    & Lysosome: regulator of lipid degradation pathways. Trends Cell Biol. (21 July 2014)

  11. 11.

    , , & Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proc. Natl Acad. Sci. USA 89, 4653–4657 (1992)

  12. 12.

    et al. Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc. Natl Acad. Sci. USA 90, 2160–2164 (1993)

  13. 13.

    , , & Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102–1109 (2006)

  14. 14.

    , & Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3, 452–460 (2007)

  15. 15.

    , & Methods in mammalian autophagy research. Cell 140, 313–326 (2010)

  16. 16.

    et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544 (2012)

  17. 17.

    et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J. Med. Chem. 43, 2971–2974 (2000)

  18. 18.

    et al. Identification of a subtype selective human PPARα agonist through parallel-array synthesis. Bioorg. Med. Chem. Lett. 11, 1225–1227 (2001)

  19. 19.

    , , & AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nature Cell Biol. 13, 132–141 (2011)

  20. 20.

    et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J. Biol. Chem. 284, 8023–8032 (2009)

  21. 21.

    et al. Targeted disruption of the α isoform of the peroxisome proliferator- activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell. Biol. 15, 3012–3022 (1995)

  22. 22.

    et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731–744 (2000)

  23. 23.

    , , , & In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101–1111 (2004)

  24. 24.

    et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005)

  25. 25.

    et al. Genome-wide tissue-specific farnesoid X receptor binding in mouse liver and intestine. Hepatology 51, 1410–1419 (2010)

  26. 26.

    et al. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 125, 544–555 (2003)

  27. 27.

    et al. Farnesoid X receptor represses hepatic human APOA gene expression. J. Clin. Invest. 121, 3724–3734 (2011)

  28. 28.

    et al. Transcriptional regulation of autophagy by an FXR–CREB axis. Nature (this issue)

  29. 29.

    et al. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev. Cell 2, 713–720 (2002)

  30. 30.

    et al. Redundant pathways for negative feedback regulation of bile acid production. Dev. Cell 2, 721–731 (2002)

  31. 31.

    et al. MEME SUITE: tools for motif discovery and searching. Nucleic Acids Res. 37, W202–W208 (2009)

  32. 32.

    , & The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 27, 107–132 (2011)

  33. 33.

    et al. Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor. Mol. Cell 52, 769–782 (2013)

  34. 34.

    et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319 (2011)

  35. 35.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009)

  36. 36.

    et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008)

  37. 37.

    et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002)

  38. 38.

    & Autophagy: basic principles and relevance to disease. Annu. Rev. Pathol. 3, 427–455 (2008)

  39. 39.

    , & SnapShot: Selective autophagy. Cell 152, 368–368 (2013)

  40. 40.

    et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011)

  41. 41.

    et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013)

  42. 42.

    et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013)

  43. 43.

    , & The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151, 1256–1269 (2012)

  44. 44.

    et al. Genome-wide siRNA screen reveals amino acid starvation-induced autophagy requires SCOC and WAC. EMBO J. 31, 1931–1946 (2012)

  45. 45.

    A low-viscosity epoxy resin embedding medium for electron microscopy. J. Ultrastruct. Res. 26, 31–42 (1969)

  46. 46.

    Practical Methods in Electron Microscopy 143–144 (North-Holland American Elsevier, 1975)

  47. 47.

    The use of lead citrate at high pH as an electron-opaque stain in electron microscopy. J. Cell Biol. 17, 208–212 (1963)

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Acknowledgements

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.

Author information

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.).

Affiliations

  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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Contributions

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.

Extended data

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    Supplementary Information

    This file contains Supplementary Tables 1-4 and Supplementary Figure 1.

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    Supplementary Data

    This file contains autophagy-related gene list.

About this article

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DOI

https://doi.org/10.1038/nature13961

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