Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Autophagy regulates lipid metabolism

Abstract

The intracellular storage and utilization of lipids are critical to maintain cellular energy homeostasis. During nutrient deprivation, cellular lipids stored as triglycerides in lipid droplets are hydrolysed into fatty acids for energy. A second cellular response to starvation is the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. Lipolysis and autophagy share similarities in regulation and function but are not known to be interrelated. Here we show a previously unknown function for autophagy in regulating intracellular lipid stores (macrolipophagy). Lipid droplets and autophagic components associated during nutrient deprivation, and inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets. This study identifies a critical function for autophagy in lipid metabolism that could have important implications for human diseases with lipid over-accumulation such as those that comprise the metabolic syndrome.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Inhibition of autophagy leads to increased TG accumulation.
Figure 2: Inhibition of autophagy decreases TG β-oxidation and decay.
Figure 3: Lipid droplet content is delivered to lysosomes in autophagosomes.
Figure 4: Effects of starvation, HFD feeding and a hepatocyte-specific blockage of autophagy on hepatic lipid accumulation.

Similar content being viewed by others

References

  1. Martin, S. & Parton, R. G. Lipid droplets: a unified view of a dynamic organelle. Nature Rev. Mol. Cell Biol. 7, 373–378 (2006)

    Article  CAS  Google Scholar 

  2. Zechner, R., Strauss, J. G., Haemmerle, G., Lass, A. & Zimmermann, R. Lipolysis: pathway under construction. Curr. Opin. Lipidol. 16, 333–340 (2005)

    Article  CAS  Google Scholar 

  3. Finn, P. F. & Dice, J. F. Proteolytic and lipolytic responses to starvation. Nutrition 22, 830–844 (2006)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Mizushima, N., Levine, B., Cuervo, A. M. & Klionsky, D. J. Autophagy fights disease through cellular self-digestion. Nature 451, 1069–1075 (2008)

    Article  CAS  ADS  Google Scholar 

  6. Mizushima, N. & Klionsky, D. J. Protein turnover via autophagy: implications for metabolism. Annu. Rev. Nutr. 27, 19–40 (2007)

    Article  CAS  Google Scholar 

  7. Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H. & Meijer, A. J. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243, 240–246 (1997)

    Article  CAS  Google Scholar 

  8. Leclercq, I. A. et al. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J. Clin. Invest. 105, 1067–1075 (2000)

    Article  CAS  Google Scholar 

  9. Sahai, A. et al. Roles of phosphatidylinositol 3-kinase and osteopontin in steatosis and aminotransferase release by hepatocytes treated with methionine-choline-deficient medium. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G55–G62 (2006)

    Article  CAS  Google Scholar 

  10. Owen, O. E., Reichard, G. A., Patel, M. S. & Boden, G. Energy metabolism in feasting and fasting. Adv. Exp. Med. Biol. 111, 169–188 (1979)

    Article  CAS  Google Scholar 

  11. Kellner-Weibel, G., McHendry-Rinde, B., Haynes, M. P. & Adelman, S. Evidence that newly synthesized esterified cholesterol is deposited in existing cytoplasmic lipid inclusions. J. Lipid Res. 42, 768–777 (2001)

    CAS  PubMed  Google Scholar 

  12. Brasaemle, D. L. et al. Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J. Biol. Chem. 275, 38486–38493 (2000)

    Article  CAS  Google Scholar 

  13. Gocze, P. M. & Freeman, D. A. Factors underlying the variability of lipid droplet fluorescence in MA-10 Leydig tumor cells. Cytometry 17, 151–158 (1994)

    Article  CAS  Google Scholar 

  14. Wiggins, D. & Gibbons, G. F. The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas. Biochem. J. 284, 457–462 (1992)

    Article  CAS  Google Scholar 

  15. Bernales, S., McDonald, K. L. & Walter, P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4, e423 (2006)

    Article  Google Scholar 

  16. Roberts, P. et al. Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae . Mol. Biol. Cell 14, 129–141 (2003)

    Article  CAS  Google Scholar 

  17. Yorimitsu, T., Nair, U., Yang, Z. & Klionsky, D. J. Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281, 30299–30304 (2006)

    Article  CAS  Google Scholar 

  18. Cuervo, A. M. et al. Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1, 131–140 (2005)

    Article  Google Scholar 

  19. Ford, E. S., Giles, W. H. & Dietz, W. H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J. Am. Med. Assoc. 287, 356–359 (2002)

    Article  Google Scholar 

  20. Wang, Y., Schattenberg, J. M., Rigoli, R. M., Storz, P. & Czaja, M. J. Hepatocyte resistance to oxidative stress is dependent on protein kinase C-mediated down-regulation of c-Jun/AP-1. J. Biol. Chem. 279, 31089–31097 (2004)

    Article  CAS  Google Scholar 

  21. Mizushima, N. et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol. 152, 657–668 (2001)

    Article  CAS  Google Scholar 

  22. Wang, Y. et al. Loss of macroautophagy promotes or prevents fibroblast apoptosis depending on the death stimulus. J. Biol. Chem. 283, 4766–4777 (2008)

    Article  CAS  Google Scholar 

  23. Hoppel, C., DiMarco, J. P. & Tandler, B. Riboflavin and rat hepatic cell structure and function. Mitochondrial oxidative metabolism in deficiency states. J. Biol. Chem. 254, 4164–4170 (1979)

    CAS  PubMed  Google Scholar 

  24. Piva, R. et al. Ablation of oncogenic ALK is a viable therapeutic approach for anaplastic large-cell lymphomas. Blood 107, 689–697 (2006)

    Article  CAS  Google Scholar 

  25. Schattenberg, J. M., Wang, Y., Singh, R., Rigoli, R. M. & Czaja, M. J. Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling. J. Biol. Chem. 280, 9887–9894 (2005)

    Article  CAS  Google Scholar 

  26. Kaushik, S., Massey, A. C. & Cuervo, A. M. Lysosome membrane lipid microdomains: novel regulators of chaperone-mediated autophagy. EMBO J. 25, 3921–3933 (2006)

    Article  CAS  Google Scholar 

  27. Postic, C. et al. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J. Biol. Chem. 274, 305–315 (1999)

    Article  CAS  Google Scholar 

  28. Brasaemle, D. L. & Wolins, N. E. Isolation of lipid droplets from cells by density gradient centrifugation. Curr. Protoc. Cell Biol. Chapter 3, unit 3.15 (2006)

  29. Cuervo, A. M., Palmer, A., Rivett, A. J. & Knecht, E. Degradation of proteasomes by lysosomes in rat liver. Eur. J. Biochem. 227, 792–800 (1995)

    Article  CAS  Google Scholar 

  30. Goldstein, J. L., Basu, S. K. & Brown, M. S. Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. Methods Enzymol. 98, 241–260 (1983)

    Article  CAS  Google Scholar 

  31. Andersson, L. et al. PLD1 and ERK2 regulate cytosolic lipid droplet formation. J. Cell Sci. 119, 2246–2257 (2006)

    Article  CAS  Google Scholar 

  32. Dunn, W. A. Studies on the mechanisms of autophagy: maturation of the autophagic vacuole. J. Cell Biol. 110, 1935–1945 (1990)

    Article  CAS  Google Scholar 

  33. Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122 (2005)

    Article  Google Scholar 

  34. Marzella, L., Ahlberg, J. & Glaumann, H. Isolation of autophagic vacuoles from rat liver: morphological and biochemical characterization. J. Cell Biol. 93, 144–154 (1982)

    Article  CAS  Google Scholar 

  35. Millar, J. S., Cromley, D. A., McCoy, M. G., Rader, D. J. & Billheimer, J. T. Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339. J. Lipid Res. 46, 2023–2028 (2005)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Silver for his discussions, N. Mizushima for providing the Atg5-/- mouse embryonic fibroblasts, R. Stockert for the protein disulphide isomerase antibody and the personnel at the Analytical Imaging Facility for their technical assistance. This work was supported by National Institutes of Health grants from the National Institute of Diabetes and Digestive and Kidney Diseases and National Institute on Aging, a Glenn Award and an American Liver Foundation Postdoctoral Research Fellowship Award (R.S.).

Author Contributions R.S. performed biochemical analyses and immunoblots. S.K. performed the imaging studies and subcellular fractionations. Y.W. generated the shRNAs and performed immunoblotting. Y.X. performed biochemical analyses. R.S., Y.W., Y.X. and I.N. all contributed to the in vivo studies. M.K. and K.T. provided the knockout mice. A.M.C. and M.J.C. conceived and planned the study, analysed data and wrote the paper.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Ana Maria Cuervo or Mark J. Czaja.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-19 with Legends. (PDF 13944 kb)

Supplementary Movie 1

This movie shows the dynamic association of lipid droplets (stained with BODIPY 493/503; green) with lysosomes (stained with Lysotracker; red). Cells were imaged at 30 sec intervals. Arrows point to colocalization event (top) and transient association/dissociation (bottom). (AVI 7245 kb)

Supplementary Movie 2

This movie shoes the dynamic association of lipid droplets (stained with BODIPY 493/503; green) with lysosomes (stained with Lysotracker; red). Cells were imaged at 30 sec intervals. Arrow points to colocalization event with lysosomes leading to a reduced size of the lipid droplet. (AVI 1187 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Singh, R., Kaushik, S., Wang, Y. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009). https://doi.org/10.1038/nature07976

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07976

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing