Autophagy - A key player in cellular and body metabolism

Nature Reviews Endocrinology

Volumn 10, Issue 6, 2014, Pages 322-337

  Kim, Kook Hwan ^a   Lee, Myung Shik ^a  

^a Sungkyunkwan University   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

BECLIN 1; GLYCOGEN DEBRANCHING ENZYME; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; LEUCINE TRANSFER RNA LIGASE; PHOSPHATIDYLETHANOLAMINE; PHOSPHATIDYLINOSITOL 3 PHOSPHATE; PROOPIOMELANOCORTIN; PROTEIN SERINE THREONINE KINASE; RHEB PROTEIN; TRANSCRIPTION FACTOR FKHR; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED FACTOR 6;

ADIPOSE TISSUE; ATHEROSCLEROSIS; AUTOLYSOSOME; AUTOPHAGOSOME; AUTOPHAGY; CARCINOGENESIS; CELL METABOLISM; ENERGY EXPENDITURE; ENERGY METABOLISM; ENERGY YIELD; GLUCONEOGENESIS; GLUCOSE INTOLERANCE; GLUCOSE UTILIZATION; GLYCOGEN METABOLISM; HUMAN; HYPOINSULINEMIA; HYPOTHALAMUS; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPID STORAGE; MEMBRANE STRUCTURE; METABOLIC DISORDER; METABOLIC REGULATION; NEOPLASM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; OSSIFICATION; OSTEOPOROSIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; STELLATE CELL;

AUTOPHAGY; CELLS; ENERGY METABOLISM; HUMANS; INSULIN RESISTANCE; METABOLIC DISEASES; METABOLISM;

EID: 84901346313     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2014.35     Document Type: Review

References (191)

1. Klionsky, D. J. & Emr, S. D. Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-1721 (2000).
2. Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425-434 (2005).
3. Mizushima, N., Yoshimori, T. & Ohsumi, Y. The role of Atg proteins in autophagosome formation. Annu. Rev. Cell. Dev. Biol. 27, 107-132 (2011).
4. Kroemer, G., Mariño, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280-293 (2010).
5. Hosokawa, N. et al. Nutrient-dependent mTORC1 association with the ULK1 Atg13 FIP200 complex required for autophagy. Mol. Biol. Cell 20, 1981-1991 (2009).
6. Jung, C. H. et al. ULK Atg13 FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol. Biol. Cell 20, 1992-2003 (2009).
7. Chang, Y. Y. & Neufeld, T. P. An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation. Mol. Biol. Cell 20, 2004-2014 (2009).
8. Itakura, E., Kishi, C., Inoue, K. & Mizushima, N. Beclin 1 forms two distinct phosphatidylinositol 3 kinase complexes with mammalian Atg14 and UVRAG. Mol. Biol. Cell 19, 5360-5372 (2008).
9. Di Bartolomeo, S. et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J. Cell Biol. 191, 155-168 (2010).
10. Nazio, F. et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-Association and function through AMBRA1 and TRAF6. Nat. Cell Biol. 15, 406-416 (2013).
11. Russell, R. C. et al. ULK1 induces autophagy by phosphorylating Beclin 1 and activating VPS34 lipid kinase. Nat. Cell Biol. 15, 741-750 (2013).
12. Wang, R. C. et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956-959 (2012).
13. Wei, Y. et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 154, 1269-1284 (2013).
14. Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3 phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685-701 (2008).
15. Lu, Q. et al. The WD40 repeat PtdIns(3)P-binding protein EPG 6 regulates progression of omegasomes to autophagosomes. Dev. Cell 21, 343-357 (2011).
16. Polson, H. E. et al. Mammalian Atg18 (WIPI2) localizes to omegasome-Anchored phagophores and positively regulates LC3 lipidation. Autophagy 6, 506-522 (2010).
17. Mizushima, N., Sugita, H., Yoshimori, T. & Ohsumi, Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J. Biol. Chem. 273, 33889-33892 (1998).
18. Mizushima, N. et al. A protein conjugation system essential for autophagy. Nature 395, 395-398 (1998).
19. Kuma, A., Mizushima, N., Ishihara, N. & Ohsumi, Y. Formation of the approximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, mediated by Apg16 oligomerization, is essential for autophagy in yeast. J. Biol. Chem. 277, 18619-18625 (2002).
20. Fujita, N. et al. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol. Biol. Cell 19, 2092-2100 (2008).
21. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720-5728 (2000).
22. Tanida, I. et al. HsAtg4B/HsApg4B/autophagin 1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-Associated protein light chain 3 and GABAA receptor-Associated protein-phospholipid conjugates. J. Biol. Chem. 279, 36268-36276 (2004).
23. Ichimura, Y. et al. A ubiquitin-like system mediates protein lipidation. Nature 408, 488-492 (2000).
24. Ichimura, Y. et al. Structural basis for sorting mechanism of p62 in selective autophagy. J. Biol. Chem. 283, 22847-22857 (2008).
25. Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228-233 (2011).
26. von Muhlinen, N. et al. LC3C, bound selectively by a noncanonical LIR motif in NDP52, is required for antibacterial autophagy. Mol. Cell 48, 329-342 (2012).
27. Kirkin, V. et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol. Cell 33, 505-516 (2009).
28. Filimonenko, M. et al. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol. Cell 38, 265-279 (2010).
29. Yu, L. et al. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942-946 (2010).
30. Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311-326 (2009).
31. Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448-453 (2011).
32. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521-534 (2009).
33. Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334, 678-683 (2011).
34. Bar-Peled, L., Schweitzer, L. D., Zoncu, R. & Sabatini, D. M. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196-1208 (2012).
35. Durán, A. et al. p62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol. Cell 44, 134-146 (2011).
36. Han, J. M. et al. Leucyl-TRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410-424 (2012).
37. Durán, R. V. et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol. Cell 47, 349-358 (2012).
38. Eng, C. H., Yu, K., Lucas, J., White, E. & Abraham, R. T. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci. Signal. 3, ra31 (2010).
39. van der Vos, K. E. et al. Modulation of glutamine metabolism by the PI(3)K PKB FOXO network regulates autophagy. Nat. Cell Biol. 14, 829-837 (2012).
40. Jewell, J. L., Russell, R. C. & Guan, K. L. Amino acid signalling upstream of mTOR. Nat. Rev. Mol. Cell Biol. 14, 133-139 (2013).
41. Russell, R. C., Yuan, H. X. & Guan, K. L. Autophagy regulation by nutrient signaling. Cell Res. 24, 42-57 (2013).
42. B'Chir, W. et al. The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 41, 7683-7699 (2013).
43. Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433 (2011).
44. Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647-658 (2013).
45. Lum, J. J. et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120, 237-248 (2005).
46. Onodera, J. & Ohsumi, Y. Autophagy is required for maintenance of amino acid levels and protein synthesis under nitrogen starvation. J. Biol. Chem. 280, 31582-31586 (2005).
47. Ezaki, J. et al. Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy 7, 727-736 (2011).
48. Efeyan, A. et al. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature 493, 679-683 (2013).
49. Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251-262 (2012).
50. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590 (2003).
51. Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214-226 (2008).
52. Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-Activated protein kinase connects energy sensing to mitophagy. Science 331, 456-461 (2011).
53. Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132-141 (2011).
54. Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290-303 (2013).
55. Hariharan, N. et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ. Res. 107, 1470-1482 (2010).
56. Cheong, H., Lindsten, T., Wu, J., Lu, C. & Thompson, C. B. Ammonia-induced autophagy is independent of ULK1/ULK2 kinases. Proc. Natl Acad. Sci. USA 108, 11121-11126 (2011).
57. Jiang, S. et al. Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J. Biol. Chem. 285, 34960-34971 (2010).
58. Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131-1135 (2009).
59. Skop, V. et al. Autophagy-lysosomal pathway is involved in lipid degradation in rat liver. Physiol. Res. 61, 287-297 (2012).
60. Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 13, 655-667 (2011).
61. Shibata, M. et al. The MAP1-LC3 conjugation system is involved in lipid droplet formation. Biochem. Biophys. Res. Commun. 382, 419-423 (2009).
62. Shibata, M. et al. LC3, a microtubule-Associated protein1A/B light chain3, is involved in cytoplasmic lipid droplet formation. Biochem. Biophys. Res. Commun. 393, 274-279 (2010).
63. Koga, H., Kaushik, S. & Cuervo, A. M. Altered lipid content inhibits autophagic vesicular fusion. FASEB J. 24, 3052-3065 (2010).
64. Las, G., Serada, S. B., Wikstrom, J. D., Twig, G. & Shirihai, O. S. Fatty acids suppress autophagic turnover in β cells. J. Biol. Chem. 286, 42534-42544 (2011).
65. Choi, S. E. et al. Protective role of autophagy in palmitate-induced INS 1 β cell death. Endocrinology 150, 126-134 (2009).
66. Komiya, K. et al. Free fatty acids stimulate autophagy in pancreatic β cells via JNK pathway. Biochem. Biophys. Res. Commun. 401, 561-567 (2010).
67. Shen, S. et al. Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. Mol. Cell 48, 667-680 (2012).
68. Tan, S. H. et al. Induction of autophagy by palmitic acid via protein kinase C mediated signaling pathway independent of mTOR (mammalian target of rapamycin). J. Biol. Chem. 287, 14364-14376 (2012).
69. Mei, S. et al. Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther. 339, 487-498 (2011).
70. Chavez, J. A. & Summers, S. A. A ceramide-centric view of insulin resistance. Cell Metab. 15, 585-594 (2012).
71. Guenther, G. G. et al. Ceramide starves cells to death by downregulating nutrient transporter proteins. Proc. Natl Acad. Sci. USA 105, 17402-17407 (2008).
72. Scarlatti, F. et al. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J. Biol. Chem. 279, 18384-18391 (2004).
73. Daido, S. et al. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res. 64, 4286-4293 (2004).
74. Ebato, C. et al. Autophagy is important in islet homeostasis and compensatory increase of β cell mass in response to high-fat diet. Cell Metab. 8, 325-332 (2008).
75. Jung, H. S. et al. Loss of autophagy diminishes pancreatic β cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318-324 (2008).
76. Quan, W. et al. Autophagy deficiency in β cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice. Diabetologia 55, 392-403 (2012).
77. Park, S. W. et al. The regulatory subunits of PI3K, p85α and p85β, interact with XBP 1 and increase its nuclear translocation. Nat. Med. 16, 429-437 (2010).
78. Winnay, J. N., Boucher, J., Mori, M. A., Ueki, K. & Kahn, C. R. A regulatory subunit of phosphoinositide 3 kinase increases the nuclear accumulation of X box binding protein 1 to modulate the unfolded protein response. Nat. Med. 16, 438-445 (2010).
79. Scheuner, D. et al. Control of mRNA translation preserves endoplasmic reticulum function in β cells and maintains glucose homeostasis. Nat. Med. 11, 757-764 (2005).
80. Bartolome, A., Guillen, C. & Benito, M. Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic β cell death. Autophagy 8, 1757-1768 (2012).
81. Bachar-Wikstrom, E. et al. Stimulation of autophagy improves endoplasmic reticulum stress-induced diabetes. Diabetes 62, 1227-1237 (2013).
82. Lee, Y. et al. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J. Biol. Chem. 276, 5629-5635 (2001).
83. Mizushima, N. Methods for monitoring autophagy using GFP-LC3 transgenic mice. Methods Enzymol. 452, 13-23 (2009).
84. Ni, H. M. et al. Dissecting the dynamic turnover of GFP-LC3 in the autolysosome. Autophagy 7, 188-204 (2011).
85. Masini, M. et al. Autophagy in human type 2 diabetes pancreatic β cells. Diabetologia 52, 1083-1086 (2009).
86. Kahn, S. E., Andrikopoulos, S. & Verchere, C. B. Islet amyloid: A long-recognized but underappreciated pathological feature of type 2 diabetes. Diabetes 48, 241-253 (1999).
87. Westermark, P., Andersson, A. & Westermark, G. T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol. Rev. 91, 795-826 (2011).
88. Rivera, J. F. et al. Human-IAPP disrupts the autophagy/lysosomal pathway in pancreatic β cells: Protective role of p62-positive cytoplasmic inclusions. Cell Death Differ. 18, 415-426 (2011).
89. Baron, A. D., Brechtel, G., Wallace, P. & Edelman, S. V. Rates and tissue sites of non insulin and insulin-mediated glucose uptake in humans. Am. J. Physiol. 255, E769-E774 (1988).
90. DeFronzo, R. A. & Tripathy, D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32 (Suppl. 2), S157-S163 (2009).
91. Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83-92 (2013).
92. Masiero, E. et al. Autophagy is required to maintain muscle mass. Cell Metab. 10, 507-515 (2009).
93. Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458-471 (2007).
94. Dobrowolny, G. et al. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 8, 425-436 (2008).
95. Grumati, P. et al. Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI deficient muscles. Autophagy 7, 1415-1423 (2011).
96. He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511-515 (2012).
97. Lira, V. A. et al. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 27, 4184-4193 (2013).
98. Eckardt, K., Taube, A. & Eckel, J. Obesity-Associated insulin resistance in skeletal muscle: Role of lipid accumulation and physical inactivity. Rev. Endocr. Metab. Disord. 12, 163-172 (2011).
99. Turpin, S. M. et al. Examination of 'lipotoxicity' in skeletal muscle of high-fat fed and ob/ob mice. J. Physiol. 587, 1593-1605 (2009).
100. Jaber, N. et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl Acad. Sci. USA 109, 2003-2008 (2012).
101. Ma, D. et al. Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD. Mol. Endocrinol. 27, 1643-1654 (2013).
102. Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467-478 (2010).
103. Liu, H. Y. et al. Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: Inhibition of FoxO1-dependent expression of key autophagy genes by insulin. J. Biol. Chem. 284, 31484-31492 (2009).
104. Hernández-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946 (2012).
105. Cong, M., Iwaisako, K., Jiang, C. & Kisseleva, T. Cell signals influencing hepatic fibrosis. Int. J. Hepatol. 2012, 158547 (2012).
106. Singh, R. et al. Autophagy regulates adipose mass and differentiation in mice. J. Clin. Invest. 119, 3329-3339 (2009).
107. Zhang, Y. et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. Proc. Natl Acad. Sci. USA 106, 19860-19865 (2009).
108. Martinez-Lopez, N. et al. Autophagy in Myf5+ progenitors regulates energy and glucose homeostasis through control of brown fat and skeletal muscle development. EMBO Rep. 14, 795-803 (2013).
109. Enerbäck, S. The origins of brown adipose tissue. N. Engl. J. Med. 360, 2021-2023 (2009).
110. Kovsan, J. et al. Altered autophagy in human adipose tissues in obesity. J. Clin. Endocrinol. Metab. 96, E268-E277 (2011).
111. Jansen, H. J. et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 153, 5866-5874 (2012).
112. Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457-461 (2004).
113. Zhou, L. et al. Autophagy-mediated insulin receptor down-regulation contributes to endoplasmic reticulum stress-induced insulin resistance. Mol. Pharmacol. 76, 596-603 (2009).
114. Meng, Q. & Cai, D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IκB kinase β (IKKβ)/NF-κB pathway. J. Biol. Chem. 286, 32324-32332 (2011).
115. Kaushik, S. et al. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 14, 173-183 (2011).
116. Kaushik, S. et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 13, 258-265 (2012).
117. Coupé, B. et al. Loss of autophagy in pro-opiomelanocortin neurons perturbs axon growth and causes metabolic dysregulation. Cell Metab. 15, 247-255 (2012).
118. Quan, W. et al. Role of hypothalamic proopiomelanocortin neuron autophagy in the control of appetite and leptin response. Endocrinology 153, 1817-1826 (2012).
119. Harlan, S. M. et al. Ablation of the leptin receptor in the hypothalamic arcuate nucleus abrogates leptin-induced sympathetic activation. Circ. Res. 108, 808-812 (2011).
120. Odegaard, J. I. & Chawla, A. The immune system as a sensor of the metabolic state. Immunity 38, 644-654 (2013).
121. Sell, H., Habich, C. & Eckel, J. Adaptive immunity in obesity and insulin resistance. Nat. Rev. Endocrinol. 8, 709-716 (2012).
122. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179-188 (2011).
123. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408-415 (2011).
124. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl Acad. Sci. USA 108, 15324-15329 (2011).
125. Lee, H. M. et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62, 194-204 (2013).
126. Saitoh, T. et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL 1β production. Nature 456, 264-268 (2008).
127. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222-230 (2011).
128. Harris, J. et al. Autophagy controls IL 1β secretion by targeting pro IL 1β for degradation. J. Biol. Chem. 286, 9587-9597 (2011).
129. Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL 1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255-263 (2012).
130. Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545-553 (2012).
131. Razani, B. et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 15, 534-454 (2012).
132. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357-1361 (2010).
133. Pan, F. et al. The regulation of autophagy pathway may influence Chinese stature variation: Evidence from elder adults. J. Hum. Genet. 55, 441-447 (2010).
134. Zhang, L. et al. Pathway-based genome-wide association analysis identified the importance of regulation of autophagy pathway for ultradistal radius BMD. J. Bone Miner. Res. 25, 1572-1580 (2010).
135. DeSelm, C. J. et al. Autophagy proteins regulate the secretory component of osteoclastic bone resorption. Dev. Cell 21, 966-974 (2011).
136. Onal, M. et al. Suppression of autophagy in osteocytes mimics skeletal aging. J. Biol. Chem. 288, 17432-17440 (2013).
137. Liu, F. et al. Suppression of autophagy by FIP200 deletion leads to osteopenia in mice through the inhibition of osteoblast terminal differentiation. J. Bone Miner. Res. 28, 2414-2430 (2013).
138. Lee, N. K. et al. Endocrine regulation of energy metabolism by the skeleton. Cell 130, 456-469 (2007).
139. Nomiyama, T. et al. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J. Clin. Invest. 117, 2877-2888 (2007).
140. Rached, M. T. et al. FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice. J. Clin. Invest. 120, 357-368 (2010).
141. Rubinsztein, D. C., Mariño, G. & Kroemer, G. Autophagy and aging. Cell 146, 682-695 (2011).
142. Mizushima, N. & Levine, B. Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823-830 (2010).
143. Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809-1820 (2003).
144. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077-15082 (2003).
145. Amaravadi, R. K. et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 17, 654-666 (2011).
146. Takamura, A. et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795-800 (2011).
147. He, C. et al. Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154, 1085-1099 (2013).
148. Cadwell, K. et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456, 259-263 (2008).
149. Cann, G. M. et al. Developmental expression of LC3α and β: Absence of fibronectin or autophagy phenotype in LC3β knockout mice. Dev. Dyn. 237, 187-195 (2008).
150. Mariño, G. et al. Autophagy is essential for mouse sense of balance. J. Clin. Invest. 120, 2331-2344 (2010).
151. Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).
152. Tong, Q., Ye, C. P., Jones, J. E., Elmquist, J. K. & Lowell, B. B. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat. Neurosci. 11, 998-1000 (2008).
153. Martinet, W. & De Meyer, G. R. Autophagy in atherosclerosis: A cell survival and death phenomenon with therapeutic potential. Circ. Res. 104, 304-317 (2009).
154. Saitsu, H. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45, 445-449 (2013).
155. Chen, D. et al. A novel and functional variant within the ATG5 gene promoter in sporadic Parkinson's disease. Neurosci. Lett. 538, 49-53 (2013).
156. Chen, D. et al. Genetic analysis of the ATG7 gene promoter in sporadic Parkinson's disease. Neurosci. Lett. 534, 193-198 (2013).
157. Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146-1158 (2010).
158. Kang, M. R. et al. Frameshift mutations of autophagy-related genes ATG2B, ATG5, ATG9B and ATG12 in gastric and colorectal cancers with microsatellite instability. J. Pathol. 217, 702-706 (2009).
159. Bai, H., Inoue, J., Kawano, T. & Inazawa, J. A transcriptional variant of the LC3A gene is involved in autophagy and frequently inactivated in human cancers. Oncogene 31, 4397-4408 (2012).
160. Qin, Z. et al. Potentially functional polymorphisms in ATG10 are associated with risk of breast cancer in a Chinese population. Gene 527, 491-495 (2013).
161. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207-211 (2007).
162. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830-832 (2007).
163. Henckaerts, L. et al. Genetic variation in the autophagy gene ULK1 and risk of Crohn's disease. Inflamm. Bowel Dis. 17, 1392-1397 (2011).
164. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889-894 (2007).
165. Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).
166. Gulati, P. et al. Role for the obesity-related FTO gene in the cellular sensing of amino acids. Proc. Natl Acad. Sci. USA 110, 2557-2562 (2013).
167. Aissani, B. et al. A quantitative trait locus for body fat on chromosome 1q43 in French Canadians: Linkage and association studies. Obesity (Silver Spring) 14, 1605-1615 (2006).
168. Shmulewitz, D. et al. Linkage analysis of quantitative traits for obesity, diabetes, hypertension, and dyslipidemia on the island of Kosrae, Federated States of Micronesia. Proc. Natl Acad. Sci. USA 103, 3502-3509 (2006).
169. Bischoff, P., Josset, E. & Dumont, F. J. Novel pharmacological modulators of autophagy and therapeutic prospects. Expert Opin. Ther. Pat. 22, 1053-1079 (2012).
170. Rubinsztein, D. C., Codogno, P. & Levine, B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat. Rev. Drug Discov. 11, 709-730 (2012).
171. Fang, Y. et al. Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 17, 456-462 (2013).
172. Elloso, M. M. et al. Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E deficient mice. Am. J. Transplant. 3, 562-569 (2003).
173. Verheye, S. et al. Selective clearance of macrophages in atherosclerotic plaques by autophagy. J. Am. Coll. Cardiol. 49, 706-715 (2007).
174. Valenti, R. et al. Comparison of everolimus-eluting stent with paclitaxel-eluting stent in long chronic total occlusions. Am. J. Cardiol. 107, 1768-1771 (2011).
175. Tomic, T. et al. Metformin inhibits melanoma development through autophagy and apoptosis mechanisms. Cell Death Dis. 2, e199 (2011).
176. Dowling, R. J., Zakikhani, M., Fantus, I. G., Pollak, M. & Sonenberg, N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 67, 10804-10812 (2007).
177. Kalender, A. et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11, 390-401 (2010).
178. Sharma, S., Mells, J. E., Fu, P. P., Saxena, N. K. & Anania, F. A. GLP 1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 6, e25269 (2011).
179. Montanari, G. et al. Treatment with low dose metformin in patients with peripheral vascular disease. Pharmacol. Res. 25, 63-73 (1992).
180. [No authors listed] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854-865 (1998).
181. Mafong, D. D. & Henry, R. R. Exenatide as a treatment for diabetes and obesity: Implications for cardiovascular risk reduction. Curr. Atheroscler. Rep. 10, 55-60 (2008).
182. Best, J. H. et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP 1) receptor agonist exenatide twice daily or other glucose-lowering therapies: A retrospective analysis of the LifeLink database. Diabetes Care 34, 90-95 (2011).
183. Marquié, G. Metformin action on lipid metabolism in lesions of experimental aortic atherosclerosis of rabbits. Atherosclerosis 47, 7-17 (1983).
184. Arakawa, M. et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide 1 receptor agonist, exendin 4. Diabetes 59, 1030-1037 (2010).
185. Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC 1α. Cell 127, 1109-1122 (2006).
186. Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin 1 dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).
187. Harrison, C. Patent watch: Extra exclusivity for new medical uses. Nat. Rev. Drug Discov. 11, 666 (2012).
188. Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201-206 (2013).
189. Leone, R. D. & Amaravadi, R. K. Autophagy: A targetable linchpin of cancer cell metabolism. Trends Endocrinol. Metab. 24, 209-217 (2013).
190. Inami, Y. et al. Persistent activation of Nrf2 through p62 in hepatocellular carcinoma cells. J. Cell Biol. 193, 275-284 (2011).
191. Mathew, R. et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137, 1062-1075 (2009).