Lysosome: regulator of lipid degradation pathways

Carmine Settembre, Andrea Ballabio, Carmine Settembre, Andrea Ballabio

Abstract

Autophagy is a catabolic pathway that has a fundamental role in the adaptation to fasting and primarily relies on the activity of the endolysosomal system, to which the autophagosome targets substrates for degradation. Recent studies have revealed that the lysosomal-autophagic pathway plays an important part in the early steps of lipid degradation. In this review, we discuss the transcriptional mechanisms underlying co-regulation between lysosome, autophagy, and other steps of lipid catabolism, including the activity of nutrient-sensitive transcription factors (TFs) and of members of the nuclear receptor family. In addition, we discuss how the lysosome acts as a metabolic sensor and orchestrates the transcriptional response to fasting.

Keywords: Autophagy; FOXOs; TFEB; TP53; lipophagy; lysosome; mTORC1; nuclear receptors; transcription factors.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Autophagy mediates substrate catabolism during fasting. During nutrient deprivation proteins, glycogen and fat are sequestered by autophagosomes and targeted to lysosomes where they are degraded by resident hydrolases and transformed into amino acids, fatty acids, and glucose, which are then released into the cytoplasm to support cellular energetic demands. Abbreviations: AV, autophagosome; LYS, lysosome.
Figure 2
Figure 2
Proposed model of coordinated transcriptional regulation of lipid catabolism via forkhead box protein class O (FOXO), transcription factor EB (TFEB), p53, and nuclear receptors. The nuclear translocation of TFEB, p53, and FOXOs is induced under conditions of metabolic stress such as nutrient depletion and growth factor deprivation. These transcription factors (TFs) regulate directly the expression of autophagy genes and the nuclear receptor and co-receptor peroxisome proliferator-activated receptor (PPAR)α and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), respectively, which control lipid catabolism.
Figure 3
Figure 3
The lysosome as a regulator of lipid metabolism. In the fed state (upper panel), the presence of lysosomal amino acids (AA), glucose, and growth factors induces activation of mechanistic target of rapamycin complex 1 (mTORC1) on the lysosomal membrane. Active mTORC1 transcriptionally induces lipogenesis and adipogenesis by activating SREBPs and peroxisome proliferator-activated receptor (PPAR)γ transcription factors, respectively. Concomitantly, mTORC1 blocks autophagy and fatty acid oxidation via transcription factor EB (TFEB) and PPARα inhibition, respectively. In the fasted state (lower panel), lower levels of lysosomal AA, glucose, and growth factors induce mTORC1 detachment from the lysosomal membrane and its consequent inhibition. mTORC1 inhibition in turn activates TFEB and PPARα transcription factors, which leads to the transcriptional induction of lipophagy and β-oxidation, respectively. Concomitantly, SREBPs and PPARγ are no longer activated by mTORC1, therefore lipogenesis and adipogenesis are inhibited. Abbreviations: Rheb, Ras homolog enriched in brain; Rags, Ras-related small GTP-binding protein; SREBPs, sterol regulatory element-binding proteins.

References

    1. Wang T. The comparative physiology of food deprivation: from feast to famine. Annu. Rev. Physiol. 2006;68:223–251.
    1. Guo Y. Lipid droplets at a glance. J. Cell Sci. 2009;122:749–752.
    1. Reue K. A thematic review series: lipid droplet storage and metabolism: from yeast to man. J. Lipid Res. 2011;52:1865–1868.
    1. Greenberg A.S. The role of lipid droplets in metabolic disease in rodents and humans. J. Clin. Invest. 2011;121:2102–2110.
    1. Finck B.N., Kelly D.P. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J. Clin. Invest. 2006;116:615–622.
    1. Singh R., Cuervo A.M. Autophagy in the cellular energetic balance. Cell Metab. 2011;13:495–504.
    1. Rabinowitz J.D., White E. Autophagy and metabolism. Science. 2010;330:1344–1348.
    1. Singh R. Autophagy regulates lipid metabolism. Nature. 2009;458:1131–1135.
    1. Iancu T.C. What's in a name? -“Lipolysosome”: ultrastructural features of a lipid-containing organelle. Ultrastruct. Pathol. 2013;37:293–303.
    1. Yang L. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 2010;11:467–478.
    1. Jaber N. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl. Acad. Sci. U.S.A. 2012;109:2003–2008.
    1. Xiong X. The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism. J. Biol. Chem. 2012;287:39107–39114.
    1. Liu K., Czaja M.J. Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ. 2013;20:3–11.
    1. Kaushik S. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 2011;14:173–183.
    1. Dupont N. Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr. Biol. 2014;24:609–620.
    1. Lübke T. Proteomics of the lysosome. Biochim. Biophys. Acta. 2009;1793:625–635.
    1. Anderson R.A. Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc. Natl. Acad. Sci. U.S.A. 1994;91:2718–2722.
    1. Wolman M. Wolman disease and its treatment. Clin. Pediatr. (Phila.) 1995;34:207–212.
    1. Razani B. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 2012;15:534–544.
    1. Ouimet M. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 2011;13:655–667.
    1. O’Rourke E.J., Ruvkun G. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 2013;15:668–676.
    1. Morselli E. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 2011;192:615–629.
    1. Pietrocola F. Regulation of autophagy by stress-responsive transcription factors. Semin. Cancer Biol. 2013;23:310–322.
    1. Füllgrabe J. The return of the nucleus: transcriptional and epigenetic control of autophagy. Nat. Rev. Mol. Cell Biol. 2014;15:65–74.
    1. Desvergne B. Transcriptional regulation of metabolism. Physiol. Rev. 2006;86:465–514.
    1. Lapierre L.R. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr. Biol. 2011;21:1507–1514.
    1. Settembre C. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332:1429–1433.
    1. Palmieri M. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 2011;20:3852–3866.
    1. Widlund H.R., Fisher D.E. Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene. 2003;22:3035–3041.
    1. Sardiello M. A gene network regulating lysosomal biogenesis and function. Science. 2009;325:473–477.
    1. Medina D.L. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev. Cell. 2011;21:421–430.
    1. Spampanato C. Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Mol. Med. 2013;5:691–706.
    1. Martina J.A. MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy. 2012;8:903–914.
    1. Roczniak-Ferguson A. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 2012;5:ra42.
    1. Settembre C. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 2012;31:1095–1108.
    1. Settembre C. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 2013;15:647–658.
    1. Takikita S. Fiber type conversion by PGC-1α activates lysosomal and autophagosomal biogenesis in both unaffected and Pompe skeletal muscle. PLoS ONE. 2010;5:e15239.
    1. Potthoff M.J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 2012;26:312–324.
    1. Kim K.H. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 2013;19:83–92.
    1. Lapierre L.R. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 2013;4:2267.
    1. Lapierre L.R., Hansen M. Lessons from C. elegans: signaling pathways for longevity. Trends Endocrinol. Metab. 2012;23:637–644.
    1. Vousden K.H., Lane D.P. p53 in health and disease. Nat. Rev. Mol. Cell Biol. 2007;8:275–283.
    1. Goldstein I., Rotter V. Regulation of lipid metabolism by p53 – fighting two villains with one sword. Trends Endocrinol. Metab. 2012;23:567–575.
    1. Assaily W. ROS-mediated p53 induction of Lpin1 regulates fatty acid oxidation in response to nutritional stress. Mol. Cell. 2011;44:491–501.
    1. Finck B.N. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab. 2006;4:199–210.
    1. Peterson T.R. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146:408–420.
    1. Sen N. PGC-1α, a key modulator of p53, promotes cell survival upon metabolic stress. Mol. Cell. 2011;44:621–634.
    1. Crighton D. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell. 2006;126:121–134.
    1. Kenzelmann Broz D. Global genomic profiling reveals an extensive p53-regulated autophagy program contributing to key p53 responses. Genes Dev. 2013;27:1016–1031.
    1. Stambolic V. Regulation of PTEN transcription by p53. Mol. Cell. 2001;8:317–325.
    1. Park E-J. Role of p53 in the cellular response following oleic acid accumulation in Chang liver cells. Toxicol. Lett. 2014;224:114–120.
    1. Eijkelenboom A., Burgering B.M.T. FOXOs: signalling integrators for homeostasis maintenance. Nat. Rev. Mol. Cell Biol. 2013;14:83–97.
    1. Sandri M. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117:399–412.
    1. Mammucari C. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6:458–471.
    1. Warr M.R. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013;494:323–327.
    1. Zhao J. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6:472–483.
    1. Zhang J., Ney P.A. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 2009;16:939–946.
    1. Zhang H. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J. Biol. Chem. 2008;283:10892–10903.
    1. Van der Vos K.E. Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy. Nat. Cell Biol. 2012;14:829–837.
    1. Zhao Y. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat. Cell Biol. 2010;12:665–675.
    1. Barthel A. FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 2005;16:183–189.
    1. Daitoku H. Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes. 2003;52:642–649.
    1. Lettieri Barbato D. FoxO1 controls lysosomal acid lipase in adipocytes: implication of lipophagy during nutrient restriction and metformin treatment. Cell Death Dis. 2013;4:e861.
    1. Zoncu R. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science. 2011;334:678–683.
    1. Laplante M., Sabatini D.M. mTOR signaling in growth control and disease. Cell. 2012;149:274–293.
    1. Bar-Peled L., Sabatini D.M. SnapShot: mTORC1 signaling at the lysosomal surface. Cell. 2012;151:1390–1390.e1.
    1. Sengupta S. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature. 2010;468:1100–1104.
    1. Menon S. Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice. Sci. Signal. 2012;5:ra24.
    1. Pettinelli P. Enhancement in liver SREBP-1c/PPAR-α ratio and steatosis in obese patients: correlations with insulin resistance and n-3 long-chain polyunsaturated fatty acid depletion. Biochim. Biophys. Acta. 2009;1792:1080–1086.
    1. Rodriguez-Navarro J.A. Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl. Acad. Sci. U.S.A. 2012;109:E705–E714.
    1. Fraldi A. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. EMBO J. 2010;29:3607–3620.
    1. Koga H. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 2010;24:3052–3065.
    1. Martinez-Lopez N. Autophagy proteins regulate ERK phosphorylation. Nat. Commun. 2013;4:2799.
    1. Decressac M. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc. Natl. Acad. Sci. U.S.A. 2013;110:E1817–E1826.
    1. Lamb C.A. The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 2013;14:759–774.
    1. Hamasaki M. Autophagosomes form at ER-mitochondria contact sites. Nature. 2013;495:389–393.
    1. Settembre C. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 2013;14:283–296.
    1. Mizushima N. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell Dev. Biol. 2011;27:107–132.
    1. Nazio F. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat. Cell Biol. 2013;15:406–416.
    1. Kim J. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 2011;13:132–141.
    1. Egan D.F. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011;331:456–461.
    1. Russell R.C. ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat. Cell Biol. 2013;15:741–750.
    1. Wei Y. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell. 2008;30:678–688.
    1. Lefebvre P. Sorting out the roles of PPAR in energy metabolism and vascular homeostasis. J. Clin. Invest. 2006;116:571–580.

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