Autophagy is a conserved quality-control pathway that degrades cytoplasmic contents in lysosomes. Autophagy degrades lipid droplets through a process termed lipophagy. Starvation and an acute lipid stimulus increase autophagic sequestration of lipid droplets and their degradation in lysosomes. Accordingly, liver-specific deletion of the autophagy gene increases hepatic fat content, mimicking the human condition termed nonalcoholic fatty liver disease. In this review, we provide insights into the molecular regulation of lipophagy, discuss fundamental questions related to the mechanisms by which autophagosomes recognize lipid droplets and how ATG proteins regulate membrane curvature for lipid droplet sequestration, and comment on the possibility of cross talk between lipophagy and cytosolic lipases in lipid mobilization. Finally, we discuss the contribution of lipophagy to the pathophysiology of human fatty liver disease. Understanding how lipophagy clears hepatocellular lipid droplets could provide new ways to prevent fatty liver disease, a major epidemic in developed nations.


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Literature Cited

  1. Ait-Goughoulte M, Kanda T, Meyer K, Ryerse JS, Ray RB. 1.  et al. 2008. Hepatitis C virus genotype 1a growth and induction of autophagy. J. Virol. 82:2241–49 [Google Scholar]
  2. Alexaki A, Gupta SD, Majumder S, Kono M, Tuymetova G. 2.  et al. 2014. Autophagy regulates sphingolipid levels in the liver. J. Lipid Res. 55:2521–31 [Google Scholar]
  3. Amir M, Zhao E, Fontana L, Rosenberg H, Tanaka K. 3.  et al. 2013. Inhibition of hepatocyte autophagy increases tumor necrosis factor-dependent liver injury by promoting caspase-8 activation. Cell Death Differ. 20:878–87 [Google Scholar]
  4. Atwal RS, Xia J, Pinchev D, Taylor J, Epand RM. 4.  et al. 2007. Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum. Mol. Genet. 16:2600–15 [Google Scholar]
  5. Bejarano E, Girao H, Yuste A, Patel B, Marques C. 5.  et al. 2012. Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner. Mol. Biol. Cell 23:2156–69 [Google Scholar]
  6. Bejarano E, Yuste A, Patel B, Stout RF Jr, Spray DC. 6.  et al. 2014. Connexins modulate autophagosome biogenesis. Nat. Cell Biol. 16:401–14 [Google Scholar]
  7. Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M. 7.  et al. 2005. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J. Cell Biol. 171:603–14 [Google Scholar]
  8. Bjorkoy G, Lamark T, Johansen T. 8.  2006. p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy 2:138–39 [Google Scholar]
  9. Bonten EJ, Annunziata I, d'Azzo A. 9.  2014. Lysosomal multienzyme complex: pros and cons of working together. Cell Mol. Life Sci. 71:2017–32 [Google Scholar]
  10. Cho HI, Choi JW, Lee SM. 10.  2014. Impairment of autophagosome-lysosome fusion contributes to chronic ethanol-induced liver injury. Alcohol 48:717–25 [Google Scholar]
  11. Choi AM, Ryter SW, Levine B. 11.  2013. Autophagy in human health and disease. N. Engl. J. Med. 368:651–62 [Google Scholar]
  12. Cole NB, Murphy DD, Grider T, Rueter S, Brasaemle D. 12.  et al. 2002. Lipid droplet binding and oligomerization properties of the Parkinson's disease protein alpha-synuclein. J. Biol. Chem. 277:6344–52 [Google Scholar]
  13. Cuervo AM, Wong E. 13.  2014. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 24:92–104 [Google Scholar]
  14. Czaja MJ, Cuervo AM. 14.  2009. Lipases in lysosomes, what for?. Autophagy 5:866–67 [Google Scholar]
  15. Day CP. 15.  2002. Non-alcoholic steatohepatitis (NASH): Where are we now and where are we going?. Gut 50:585–88 [Google Scholar]
  16. Day CP, James OF. 16.  1998. Steatohepatitis: a tale of two “hits”?. Gastroenterology 114:842–45 [Google Scholar]
  17. de Mattos KA, Sarno EN, Pessolani MC, Bozza PT. 17.  2012. Deciphering the contribution of lipid droplets in leprosy: multifunctional organelles with roles in Mycobacterium leprae pathogenesis. Mem. Inst. Oswaldo Cruz 107:Suppl. 1156–66 [Google Scholar]
  18. Deosaran E, Larsen KB, Hua R, Sargent G, Wang Y. 18.  et al. 2013. NBR1 acts as an autophagy receptor for peroxisomes. J. Cell Sci. 126:939–52 [Google Scholar]
  19. Dice JF, Terlecky SR, Chiang HL, Olson TS, Isenman LD. 19.  et al. 1990. A selective pathway for degradation of cytosolic proteins by lysosomes. Semin. Cell Biol. 1:449–55 [Google Scholar]
  20. Dreux M, Gastaminza P, Wieland SF, Chisari FV. 20.  2009. The autophagy machinery is required to initiate hepatitis C virus replication. PNAS 106:14046–51 [Google Scholar]
  21. Dupont N, Chauhan S, Arko-Mensah J, Castillo EF, Masedunskas A. 21.  et al. 2014. Neutral lipid stores and lipase PNPLA5 contribute to autophagosome biogenesis. Curr. Biol. 24:609–20 [Google Scholar]
  22. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA. 22.  et al. 2011. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–61 [Google Scholar]
  23. Fan W, Nassiri A, Zhong Q. 23.  2011. Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L). PNAS 108:7769–74 [Google Scholar]
  24. Filipe A, McLauchlan J. 24.  2014. Hepatitis C virus and lipid droplets: finding a niche. Trends Mol. Med. 21:34–42 [Google Scholar]
  25. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S. 25.  et al. 2007. Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–25 [Google Scholar]
  26. Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E. 26.  et al. 2014. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol. Res. 44:1026–36 [Google Scholar]
  27. Greenberg AS, Coleman RA, Kraemer FB, McManaman JL, Obin MS. 27.  et al. 2011. The role of lipid droplets in metabolic disease in rodents and humans. J. Clin. Invest. 121:2102–10 [Google Scholar]
  28. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A. 28.  et al. 2013. Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–93 [Google Scholar]
  29. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y. 29.  et al. 2007. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J. Biol. Chem. 282:37298–302 [Google Scholar]
  30. Hardie DG, Carling D, Halford N. 30.  1994. Roles of the Snf1/Rkin1/AMP-activated protein kinase family in the response to environmental and nutritional stress. Semin. Cell Biol. 5:409–16 [Google Scholar]
  31. Harding TM, Hefner-Gravink A, Thumm M, Klionsky DJ. 31.  1996. Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway. J. Biol. Chem. 271:17621–24 [Google Scholar]
  32. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T. 32.  et al. 2009. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat. Cell Biol. 11:1433–37 [Google Scholar]
  33. He C, Klionsky DJ. 33.  2009. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43:67–93 [Google Scholar]
  34. Herman PK, Emr SD. 34.  1990. Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol. Cell Biol. 10:6742–54 [Google Scholar]
  35. Herman PK, Stack JH, Emr SD. 35.  1991. A genetic and structural analysis of the yeast Vps15 protein kinase: evidence for a direct role of Vps15p in vacuolar protein delivery. EMBO J. 10:4049–60 [Google Scholar]
  36. Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, Gordon R, Fiel MI. 36.  et al. 2012. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142:938–46 [Google Scholar]
  37. Huang H, Kawamata T, Horie T, Tsugawa H, Nakayama Y. 37.  et al. 2015. Bulk RNA degradation by nitrogen starvation-induced autophagy in yeast. EMBO J. 34:154–68 [Google Scholar]
  38. Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM. 38.  et al. 2010. Macroautophagy regulates energy metabolism during effector T cell activation. J. Immunol. 185:7349–57 [Google Scholar]
  39. Itakura E, Kishi C, Inoue K, Mizushima N. 39.  2008. Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19:5360–72 [Google Scholar]
  40. Itakura E, Kishi-Itakura C, Mizushima N. 40.  2012. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell 151:1256–69 [Google Scholar]
  41. Kaini RR, Sillerud LO, Zhaorigetu S, Hu CA. 41.  2012. Autophagy regulates lipolysis and cell survival through lipid droplet degradation in androgen-sensitive prostate cancer cells. Prostate 72:1412–22 [Google Scholar]
  42. Kashima J, Shintani-Ishida K, Nakajima M, Maeda H, Unuma K. 42.  et al. 2014. Immunohistochemical study of the autophagy marker microtubule-associated protein 1 light chain 3 in normal and steatotic human livers. Hepatol. Res. 44:779–87 [Google Scholar]
  43. Kaushik S, Arias E, Kwon H, Lopez NM, Athonvarangkul D. 43.  et al. 2012. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 13:258–65 [Google Scholar]
  44. Kaushik S, Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S. 44.  et al. 2011. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 14:173–83 [Google Scholar]
  45. Khaldoun SA, Emond-Boisjoly MA, Chateau D, Carriere V, Lacasa M. 45.  et al. 2014. Autophagosomes contribute to intracellular lipid distribution in enterocytes. Mol. Biol. Cell 25:118–32 [Google Scholar]
  46. Khor VK, Shen WJ, Kraemer FB. 46.  2013. Lipid droplet metabolism. Curr. Opin. Clin. Nutr. Metab. Care 16:632–37 [Google Scholar]
  47. Kim I, Rodriguez-Enriquez S, Lemasters JJ. 47.  2007. Selective degradation of mitochondria by mitophagy. Arch. Biochem. Biophys. 462:245–53 [Google Scholar]
  48. Kim J, Klionsky DJ. 48.  2000. Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu. Rev. Biochem. 69:303–42 [Google Scholar]
  49. Kim J, Kundu M, Viollet B, Guan KL. 49.  2011. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:132–41 [Google Scholar]
  50. Kimmel AR, Brasaemle DL, McAndrews-Hill M, Sztalryd C, Londos C. 50.  2010. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J. Lipid Res. 51:468–71 [Google Scholar]
  51. Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A. 51.  et al. 2012. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445–544 [Google Scholar]
  52. Koga H, Kaushik S, Cuervo AM. 52.  2010. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24:3052–65 [Google Scholar]
  53. Koga H, Kaushik S, Cuervo AM. 53.  2010. Inhibitory effect of intracellular lipid load on macroautophagy. Autophagy 6:825–27 [Google Scholar]
  54. Kovsan J, Ben-Romano R, Souza SC, Greenberg AS, Rudich A. 54.  2007. Regulation of adipocyte lipolysis by degradation of the perilipin protein: nelfinavir enhances lysosome-mediated perilipin proteolysis. J. Biol. Chem. 282:21704–11 [Google Scholar]
  55. Kraft C, Deplazes A, Sohrmann M, Peter M. 55.  2008. Mature ribosomes are selectively degraded upon starvation by an autophagy pathway requiring the Ubp3p/Bre5p ubiquitin protease. Nat. Cell Biol. 10:602–10 [Google Scholar]
  56. Kurusu T, Koyano T, Hanamata S, Kubo T, Noguchi Y. 56.  et al. 2014. OsATG7 is required for autophagy-dependent lipid metabolism in rice postmeiotic anther development. Autophagy 10:878–88 [Google Scholar]
  57. Lapierre LR, Gelino S, Melendez A, Hansen M. 57.  2011. Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr. Biol. 21:1507–14 [Google Scholar]
  58. Lee JM, Wagner M, Xiao R, Kim KH, Feng D. 58.  et al. 2014. Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–15 [Google Scholar]
  59. Lettieri Barbato D, Tatulli G, Aquilano K, Ciriolo MR. 59.  2013. FoxO1 controls lysosomal acid lipase in adipocytes: implication of lipophagy during nutrient restriction and metformin treatment. Cell Death Dis. 4:e861 [Google Scholar]
  60. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B. 60.  et al. 1999. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–76 [Google Scholar]
  61. Lin CW, Zhang H, Li M, Xiong X, Chen X. 61.  et al. 2013. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J. Hepatol. 58:993–99 [Google Scholar]
  62. Mack HI, Zheng B, Asara JM, Thomas SM. 62.  2012. AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 8:1197–214 [Google Scholar]
  63. Marcinkiewicz A, Gauthier D, Garcia A, Brasaemle DL. 63.  2006. The phosphorylation of serine 492 of perilipin A directs lipid droplet fragmentation and dispersion. J. Biol. Chem. 281:11901–9 [Google Scholar]
  64. Mari M, Tooze SA, Reggiori F. 64.  2011. The puzzling origin of the autophagosomal membrane. F1000 Biol. Rep. 3:25 [Google Scholar]
  65. Martinez-Vicente M, Talloczy Z, Wong E, Tang G, Koga H. 65.  et al. 2010. Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease. Nat. Neurosci. 13:567–76 [Google Scholar]
  66. Massey AC, Zhang C, Cuervo AM. 66.  2006. Chaperone-mediated autophagy in aging and disease. Curr. Top. Dev. Biol. 73:205–35 [Google Scholar]
  67. Masuda Y, Itabe H, Odaki M, Hama K, Fujimoto Y. 67.  et al. 2006. ADRP/adipophilin is degraded through the proteasome-dependent pathway during regression of lipid-storing cells. J. Lipid Res. 47:87–98 [Google Scholar]
  68. McLauchlan J. 68.  2009. Lipid droplets and hepatitis C virus infection. Biochim. Biophys. Acta 1791:552–59 [Google Scholar]
  69. Moore HP, Silver RB, Mottillo EP, Bernlohr DA, Granneman JG. 69.  2005. Perilipin targets a novel pool of lipid droplets for lipolytic attack by hormone-sensitive lipase. J. Biol. Chem. 280:43109–20 [Google Scholar]
  70. Murrow L, Debnath J. 70.  2013. Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu. Rev. Pathol. 8:105–37 [Google Scholar]
  71. Nair U, Jotwani A, Geng J, Gammoh N, Richerson D. 71.  et al. 2011. SNARE proteins are required for macroautophagy. Cell 146:290–302 [Google Scholar]
  72. Nath S, Dancourt J, Shteyn V, Puente G, Fong WM. 72.  et al. 2014. Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nat. Cell Biol. 16:415–24 [Google Scholar]
  73. Nazio F, Strappazzon F, Antonioli M, Bielli P, Cianfanelli V. 73.  et al. 2013. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat. Cell Biol. 15:406–16 [Google Scholar]
  74. Nguyen LN, Bormann J, Le GT, Starkel C, Olsson S. 74.  et al. 2011. Autophagy-related lipase FgATG15 of Fusarium graminearum is important for lipid turnover and plant infection. Fungal Genet. Biol. 48:217–24 [Google Scholar]
  75. Novikoff AB, Beaufay H, de Duve C. 75.  1956. Electron microscopy of lysosome-rich fractions from rat liver. J. Biophys. Biochem. Cytol. 2:179–84 [Google Scholar]
  76. O'Rourke EJ, Ruvkun G. 76.  2013. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15:668–76 [Google Scholar]
  77. Ogasawara J, Kitadate K, Nishioka H, Fujii H, Sakurai T. 77.  et al. 2012. Oligonol-induced degradation of perilipin 1 is regulated through lysosomal degradation machinery. Natural Prod. Commun. 7:1193–96 [Google Scholar]
  78. Ohsumi Y. 78.  2014. Historical landmarks of autophagy research. Cell Res. 24:9–23 [Google Scholar]
  79. Oku M, Takano Y, Sakai Y. 79.  2014. The emerging role of autophagy in peroxisome dynamics and lipid metabolism of phyllosphere microorganisms. Front. Plant Sci. 5:81 [Google Scholar]
  80. Ouimet M, Franklin V, Mak E, Liao X, Tabas I. 80.  et al. 2011. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 13:655–67 [Google Scholar]
  81. Ouimet M, Marcel YL. 81.  2012. Regulation of lipid droplet cholesterol efflux from macrophage foam cells. Arterioscler. Thromb. Vasc. Biol. 32:575–81 [Google Scholar]
  82. Palmieri M, Impey S, Kang H, di Ronza A, Pelz C. 82.  et al. 2011. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20:3852–66 [Google Scholar]
  83. Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA. 83.  et al. 2007. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282:24131–45 [Google Scholar]
  84. Papackova Z, Dankova H, Palenickova E, Kazdova L, Cahova M. 84.  2012. Effect of short- and long-term high-fat feeding on autophagy flux and lysosomal activity in rat liver. Physiol. Res. 61:Suppl. 2S67–76 [Google Scholar]
  85. Park HW, Park H, Semple IA, Jang I, Ro SH. 85.  et al. 2014. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat. Commun. 5:4834 [Google Scholar]
  86. Phadwal K, Watson AS, Simon AK. 86.  2013. Tightrope act: autophagy in stem cell renewal, differentiation, proliferation, and aging. Cell Mol. Life Sci. 70:89–103 [Google Scholar]
  87. Phillips AR, Suttangkakul A, Vierstra RD. 87.  2008. The ATG12-conjugating enzyme ATG10 is essential for autophagic vesicle formation in Arabidopsis thaliana. Genetics 178:1339–53 [Google Scholar]
  88. Polson HE, de Lartigue J, Rigden DJ, Reedijk M, Urbe S. 88.  et al. 2010. Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation. Autophagy 6:506–22 [Google Scholar]
  89. Pyo JO, Yoo SM, Jung YK. 89.  2013. The interplay between autophagy and aging. Diabetes Metab. J. 37:333–39 [Google Scholar]
  90. Raasi S, Varadan R, Fushman D, Pickart CM. 90.  2005. Diverse polyubiquitin interaction properties of ubiquitin-associated domains. Nat. Struct. Mol. Biol. 12:708–14 [Google Scholar]
  91. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. 91.  2010. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat. Cell Biol. 12:747–57 [Google Scholar]
  92. Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S. 92.  et al. 2004. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36:585–95 [Google Scholar]
  93. Reid BN, Ables GP, Otlivanchik OA, Schoiswohl G, Zechner R. 93.  et al. 2008. Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis. J. Biol. Chem. 283:13087–99 [Google Scholar]
  94. Romanov J, Walczak M, Ibiricu I, Schuchner S, Ogris E. 94.  et al. 2012. Mechanism and functions of membrane binding by the Atg5-Atg12/Atg16 complex during autophagosome formation. EMBO J. 31:4304–17 [Google Scholar]
  95. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B. 95.  et al. 2011. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell 20:131–39 [Google Scholar]
  96. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S. 96.  et al. 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303 [Google Scholar]
  97. Santambrogio L, Cuervo AM. 97.  2011. Chasing the elusive mammalian microautophagy. Autophagy 7:652–54 [Google Scholar]
  98. Sardiello M, Ballabio A. 98.  2009. Lysosomal enhancement: a CLEAR answer to cellular degradative needs. Cell Cycle 8:4021–22 [Google Scholar]
  99. Schlumpberger M, Schaeffeler E, Straub M, Bredschneider M, Wolf DH. 99.  et al. 1997. AUT1, a gene essential for autophagocytosis in the yeast Saccharomyces cerevisiae. J. Bacteriol. 179:1068–76 [Google Scholar]
  100. Schneider JL, Cuervo AM. 100.  2014. Liver autophagy: much more than just taking out the trash. Nat. Rev. Gastroenterol. Hepatol. 11:187–200 [Google Scholar]
  101. Schulze RJ, Weller SG, Schroeder B, Krueger EW, Chi S. 101.  et al. 2013. Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. J. Cell Biol. 203:315–26 [Google Scholar]
  102. Seok S, Fu T, Choi SE, Li Y, Zhu R. 102.  et al. 2014. Transcriptional regulation of autophagy by an FXR-CREB axis. Nature 516:108–11 [Google Scholar]
  103. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F. 103.  et al. 2013. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15:647–58 [Google Scholar]
  104. Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F. 104.  et al. 2011. TFEB links autophagy to lysosomal biogenesis. Science 332:1429–33 [Google Scholar]
  105. Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S. 105.  et al. 2012. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. 31:1095–108 [Google Scholar]
  106. Shibata M, Yoshimura K, Furuya N, Koike M, Ueno T. 106.  et al. 2009. The MAP1-LC3 conjugation system is involved in lipid droplet formation. Biochem. Biophys. Res. Commun. 382:419–23 [Google Scholar]
  107. Singh R, Cuervo AM. 107.  2011. Autophagy in the cellular energetic balance. Cell Metab. 13:495–504 [Google Scholar]
  108. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I. 108.  et al. 2009. Autophagy regulates lipid metabolism. Nature 458:1131–35 [Google Scholar]
  109. Sinha RA, Farah BL, Singh BK, Siddique MM, Li Y. 109.  et al. 2014. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology 59:1366–80 [Google Scholar]
  110. Sir D, Tian Y, Chen WL, Ann DK, Yen TS. 110.  et al. 2010. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. PNAS 107:4383–88 [Google Scholar]
  111. Skop V, Cahova M, Papackova Z, Palenickova E, Dankova H. 111.  et al. 2012. Autophagy-lysosomal pathway is involved in lipid degradation in rat liver. Physiol. Res. 61:287–97 [Google Scholar]
  112. Souza SC, Muliro KV, Liscum L, Lien P, Yamamoto MT. 112.  et al. 2002. Modulation of hormone-sensitive lipase and protein kinase A-mediated lipolysis by perilipin A in an adenoviral reconstituted system. J. Biol. Chem. 277:8267–72 [Google Scholar]
  113. Spandl J, Lohmann D, Kuerschner L, Moessinger C, Thiele C. 113.  2011. Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) via its G2 binding region. J. Biol. Chem. 286:5599–606 [Google Scholar]
  114. Stankov MV, Panayotova-Dimitrova D, Leverkus M, Vondran FW, Bauerfeind R. 114.  et al. 2012. Autophagy inhibition due to thymidine analogues as novel mechanism leading to hepatocyte dysfunction and lipid accumulation. AIDS 26:1995–2006 [Google Scholar]
  115. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH. 115.  et al. 2005. A human protein-protein interaction network: a resource for annotating the proteome. Cell 122:957–68 [Google Scholar]
  116. Tanida I, Tanida-Miyake E, Ueno T, Kominami E. 116.  2001. The human homolog of Saccharomyces cerevisiae Apg7p is a protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3. J. Biol. Chem. 276:1701–6 [Google Scholar]
  117. Tanida I, Ueno T, Kominami E. 117.  2004. LC3 conjugation system in mammalian autophagy. Int. J. Biochem. Cell Biol. 36:2503–18 [Google Scholar]
  118. Tasdemir E, Maiuri MC, Tajeddine N, Vitale I, Criollo A. 118.  et al. 2007. Cell cycle-dependent induction of autophagy, mitophagy and reticulophagy. Cell Cycle 6:2263–67 [Google Scholar]
  119. Thoen LF, Guimaraes EL, Dolle L, Mannaerts I, Najimi M. 119.  et al. 2011. A role for autophagy during hepatic stellate cell activation. J. Hepatol. 55:1353–60 [Google Scholar]
  120. Thurston TL, Ryzhakov G, Bloor S, von Muhlinen N, Randow F. 120.  2009. The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10:1215–21 [Google Scholar]
  121. Tooze SA, Yoshimori T. 121.  2010. The origin of the autophagosomal membrane. Nat. Cell Biol. 12:831–35 [Google Scholar]
  122. Tsukada M, Ohsumi Y. 122.  1993. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333:169–74 [Google Scholar]
  123. Tsuyuki S, Takabayashi M, Kawazu M, Kudo K, Watanabe A. 123.  et al. 2014. Detection of WIPI1 mRNA as an indicator of autophagosome formation. Autophagy 10:497–513 [Google Scholar]
  124. van Zutphen T, Todde V, de Boer R, Kreim M, Hofbauer HF. 124.  et al. 2014. Lipid droplet autophagy in the yeast Saccharomyces cerevisiae. Mol. Biol. Cell 25:290–301 [Google Scholar]
  125. Vaughan M, Berger JE, Steinberg D. 125.  1964. Hormone-sensitive lipase and monoglyceride lipase activities in adipose tissue. J. Biol. Chem. 239:401–9 [Google Scholar]
  126. Wang CW, Miao YH, Chang YS. 126.  2014. A sterol-enriched vacuolar microdomain mediates stationary phase lipophagy in budding yeast. J. Cell Biol. 206:357–66 [Google Scholar]
  127. Wang Y, Singh R, Xiang Y, Czaja MJ. 127.  2010. Macroautophagy and chaperone-mediated autophagy are required for hepatocyte resistance to oxidant stress. Hepatology 52:266–77 [Google Scholar]
  128. Webber JL, Young AR, Tooze SA. 128.  2007. Atg9 trafficking in mammalian cells. Autophagy 3:54–56 [Google Scholar]
  129. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. 129.  2008. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol. Cell 30:678–88 [Google Scholar]
  130. Welter E, Elazar Z. 130.  2015. Autophagy mediates nonselective RNA degradation in starving yeast. EMBO J. 34:131–33 [Google Scholar]
  131. Wiggins D, Gibbons GF. 131.  1992. 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:Part 2457–62 [Google Scholar]
  132. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV. 132.  et al. 2011. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–33 [Google Scholar]
  133. Wilfling F, Haas JT, Walther TC, Farese RV Jr. 133.  2014. Lipid droplet biogenesis. Curr. Opin. Cell Biol. 29:39–45 [Google Scholar]
  134. Xiong X, Tao R, DePinho RA, Dong XC. 134.  2012. 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. 287:39107–14 [Google Scholar]
  135. Xu G, Sztalryd C, Londos C. 135.  2006. Degradation of perilipin is mediated through ubiquitination-proteasome pathway. Biochim. Biophys. Acta 1761:83–90 [Google Scholar]
  136. Xu G, Sztalryd C, Lu X, Tansey JT, Gan J. 136.  et al. 2005. Post-translational regulation of adipose differentiation-related protein by the ubiquitin/proteasome pathway. J. Biol. Chem. 280:42841–47 [Google Scholar]
  137. Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ. 137.  et al. 2013. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 18:816–30 [Google Scholar]
  138. Yamada E, Singh R. 138.  2012. Mapping autophagy on to your metabolic radar. Diabetes 61:272–80 [Google Scholar]
  139. Yamada Y, Suzuki NN, Hanada T, Ichimura Y, Kumeta H. 139.  et al. 2007. The crystal structure of Atg3, an autophagy-related ubiquitin carrier protein (E2) enzyme that mediates Atg8 lipidation. J. Biol. Chem. 282:8036–43 [Google Scholar]
  140. Yan J, Kuroyanagi H, Kuroiwa A, Matsuda Y, Tokumitsu H. 140.  et al. 1998. Identification of mouse ULK1, a novel protein kinase structurally related to C. elegans UNC-51. Biochem. Biophys. Res. Commun. 246:222–27 [Google Scholar]
  141. Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. 141.  2010. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11:467–78 [Google Scholar]
  142. Yen WL, Shintani T, Nair U, Cao Y, Richardson BC. 142.  et al. 2010. The conserved oligomeric Golgi complex is involved in double-membrane vesicle formation during autophagy. J. Cell. Biol. 188:101–14 [Google Scholar]
  143. Yla-Anttila P, Vihinen H, Jokitalo E, Eskelinen EL. 143.  2009. 3D tomography reveals connections between the phagophore and endoplasmic reticulum. Autophagy 5:1180–85 [Google Scholar]
  144. Young AR, Chan EY, Hu XW, Kochl R, Crawshaw SG. 144.  et al. 2006. Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes. J. Cell Sci. 119:3888–900 [Google Scholar]
  145. Zhang C, Cuervo AM. 145.  2008. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14:959–65 [Google Scholar]
  146. Zhou J, Farah BL, Sinha RA, Wu Y, Singh BK. 146.  et al. 2014. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance. PLOS ONE 9:e87161 [Google Scholar]
  147. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R. 147.  et al. 2004. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 306:1383–86 [Google Scholar]

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