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.
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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.
This file contains Supplementary Figures 1-19 with Legends. (PDF 13944 kb)
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)
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)
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Singh, R., Kaushik, S., Wang, Y. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009). https://doi.org/10.1038/nature07976
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