Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Autophagy Dysregulation and Obesity-Associated Pathologies

  • Sim, Namkoong (Department of Molecular and Integrative Physiology, University of Michigan) ;
  • Cho, Chun-Seok (Department of Molecular and Integrative Physiology, University of Michigan) ;
  • Semple, Ian (Department of Molecular and Integrative Physiology, University of Michigan) ;
  • Lee, Jun Hee (Department of Molecular and Integrative Physiology, University of Michigan)
  • Received : 2017.09.05
  • Accepted : 2017.10.10
  • Published : 2018.01.31
Download PDF
⟨ Previous Next ⟩

Abstract

Autophagy is one of the major degradative mechanisms that can eliminate excessive nutrients, toxic protein aggregates, damaged organelles and invading microorganisms. In response to obesity and obesity-associated lipotoxic, proteotoxic and oxidative stresses, autophagy plays an essential role in maintaining physiological homeostasis. However, obesity and its associated stress insults can often interfere with the autophagic process through various mechanisms, which result in further aggravation of obesity-related metabolic pathologies in multiple metabolic organs. Paradoxically, inhibition of autophagy, within specific contexts, indirectly produces beneficial effects that can alleviate several detrimental consequences of obesity. In this minireview, we will provide a brief discussion about our current understanding of the impact of obesity on autophagy and the role of autophagy dysregulation in modulating obesity-associated pathological outcomes.

Keywords

E1BJB7_2018_v41n1_3_f0001.png 이미지

Fig. 1. Relationship between Obesity and Autoph-agy. Sophisticated interaction between autophagyand obesity-associated pathologies is schematical-ly illustrated.

References

  1. Alers, S., Loffler, A.S., Wesselborg, S., and Stork, B. (2012a). The incredible ULKs. Cell Commun. Signal. 10, 7. https://doi.org/10.1186/1478-811X-10-7
  2. Alers, S., Loffler, A.S., Wesselborg, S., and Stork, B. (2012b). Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell Biol. 32, 2-11. https://doi.org/10.1128/MCB.06159-11
  3. Arruda, A.P., and Hotamisligil, G.S. (2015). Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metab. 22, 381-397. https://doi.org/10.1016/j.cmet.2015.06.010
  4. Bartolome, A., Guillen, C., and Benito, M. (2012). Autophagy plays a protective role in endoplasmic reticulum stress-mediated pancreatic beta cell death. Autophagy 8, 1757-1768. https://doi.org/10.4161/auto.21994
  5. Basseri, S., and Austin, R.C. (2008). ER stress and lipogenesis: a slippery slope toward hepatic steatosis. Dev. Cell 15, 795-796. https://doi.org/10.1016/j.devcel.2008.11.013
  6. Bernales, S., Schuck, S., and Walter, P. (2007). ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3, 285-287. https://doi.org/10.4161/auto.3930
  7. Bournat, J.C., and Brown, C.W. (2010). Mitochondrial dysfunction in obesity. Curr. Opin. Endocrinol. Diabetes Obes. 17, 446-452. https://doi.org/10.1097/MED.0b013e32833c3026
  8. Brookheart, R.T., Michel, C.I., and Schaffer, J.E. (2009). As a matter of fat. Cell Metab. 10, 9-12. https://doi.org/10.1016/j.cmet.2009.03.011
  9. Browning, J.D., and Horton, J.D. (2004). Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147-152. https://doi.org/10.1172/JCI200422422
  10. Cerda, C., Sanchez, C., Climent, B., Vazquez, A., Iradi, A., El Amrani, F., Bediaga, A., and Saez, G.T. (2014). Oxidative stress and DNA damage in obesity-related tumorigenesis. Adv. Exp. Med. Biol. 824, 5-17.
  11. Cho, C.S., Lombard, D.B., and Lee, J.H. (2017). SIRT3 as a regulator of hepatic autophagy. Hepatology 66, 700-702. https://doi.org/10.1002/hep.29271
  12. Choi, A.M., Ryter, S.W., and Levine, B. (2013). Autophagy in human health and disease. N Engl. J. Med. 368, 651-662. https://doi.org/10.1056/NEJMra1205406
  13. Collaborators, G.B.D.O., Afshin, A., Forouzanfar, M.H., Reitsma, M.B., Sur, P., Estep, K., Lee, A., Marczak, L., Mokdad, A.H., Moradi-Lakeh, M., et al. (2017). Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl. J. Med. 377, 13-27. https://doi.org/10.1056/NEJMoa1614362
  14. Cooke, M.S., Evans, M.D., Dizdaroglu, M., and Lunec, J. (2003). Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17, 1195-1214. https://doi.org/10.1096/fj.02-0752rev
  15. Czaja, M.J. (2015). A new mechanism of lipotoxicity: Calcium channel blockers as a treatment for nonalcoholic steatohepatitis? Hepatology 62, 312-314. https://doi.org/10.1002/hep.27858
  16. Dann, S.G., Selvaraj, A., and Thomas, G. (2007). mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol. Med. 13, 252-259. https://doi.org/10.1016/j.molmed.2007.04.002
  17. Ding, W.X., Li, M., Chen, X., Ni, H.M., Lin, C.W., Gao, W., Lu, B., Stolz, D.B., Clemens, D.L., and Yin, X.M. (2010). Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology 139, 1740-1752. https://doi.org/10.1053/j.gastro.2010.07.041
  18. Duran, A., Hernandez, E.D., Reina-Campos, M., Castilla, E.A., Subramaniam, S., Raghunandan, S., Roberts, L.R., Kisseleva, T., Karin, M., Diaz-Meco, M.T., et al. (2016). p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell 30, 595-609. https://doi.org/10.1016/j.ccell.2016.09.004
  19. Ebato, C., Uchida, T., Arakawa, M., Komatsu, M., Ueno, T., Komiya, K., Azuma, K., Hirose, T., Tanaka, K., Kominami, E., et al. (2008). Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet. Cell Metab. 8, 325-332. https://doi.org/10.1016/j.cmet.2008.08.009
  20. Ezaki, J., Matsumoto, N., Takeda-Ezaki, M., Komatsu, M., Takahashi, K., Hiraoka, Y., Taka, H., Fujimura, T., Takehana, K., Yoshida, M., et al. (2011). Liver autophagy contributes to the maintenance of blood glucose and amino acid levels. Autophagy 7, 727-736. https://doi.org/10.4161/auto.7.7.15371
  21. Feng, Y., He, D., Yao, Z., and Klionsky, D.J. (2014). The machinery of macroautophagy. Cell Res. 24, 24-41. https://doi.org/10.1038/cr.2013.168
  22. Filomeni, G., De Zio, D., and Cecconi, F. (2015). Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 22, 377-388. https://doi.org/10.1038/cdd.2014.150
  23. Fu, S., Yang, L., Li, P., Hofmann, O., Dicker, L., Hide, W., Lin, X., Watkins, S.M., Ivanov, A.R., and Hotamisligil, G.S. (2011). Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528-531. https://doi.org/10.1038/nature09968
  24. Galluzzi, L., Pietrocola, F., Levine, B., and Kroemer, G. (2014). Metabolic control of autophagy. Cell 159, 1263-1276. https://doi.org/10.1016/j.cell.2014.11.006
  25. Goldberg, I.J., Trent, C.M., and Schulze, P.C. (2012). Lipid metabolism and toxicity in the heart. Cell Metab. 15, 805-812. https://doi.org/10.1016/j.cmet.2012.04.006
  26. Gonzalez-Rodriguez, A., Mayoral, R., Agra, N., Valdecantos, M.P., Pardo, V., Miquilena-Colina, M.E., Vargas-Castrillon, J., Lo Iacono, O., Corazzari, M., Fimia, G.M., et al. (2014). Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 5, e1179. https://doi.org/10.1038/cddis.2014.162
  27. Hara, T., Takamura, A., Kishi, C., Iemura, S., Natsume, T., Guan, J.L., and Mizushima, N. (2008). FIP200, a ULK-interacting protein, is required for autophagosome formation in mammalian cells. J. Cell Biol. 181, 497-510. https://doi.org/10.1083/jcb.200712064
  28. Hauck, A.K., and Bernlohr, D.A. (2016). Oxidative stress and lipotoxicity. J. Lipid Res. 57, 1976-1986. https://doi.org/10.1194/jlr.R066597
  29. Hernandez-Gea, V., Ghiassi-Nejad, Z., Rozenfeld, R., Gordon, R., Fiel, M.I., Yue, Z., Czaja, M.J., and Friedman, S.L. (2012). Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938-946. https://doi.org/10.1053/j.gastro.2011.12.044
  30. Hill, J.O., Wyatt, H.R., Reed, G.W., and Peters, J.C. (2003). Obesity and the environment: where do we go from here? Science 299, 853-855. https://doi.org/10.1126/science.1079857
  31. Hill, J.O., Wyatt, H.R., and Peters, J.C. (2012). Energy balance and obesity. Circulation 126, 126-132. https://doi.org/10.1161/CIRCULATIONAHA.111.087213
  32. Holzer, R.G., Park, E.J., Li, N., Tran, H., Chen, M., Choi, C., Solinas, G., and Karin, M. (2011). Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 147, 173-184. https://doi.org/10.1016/j.cell.2011.08.034
  33. Hotamisligil, G.S. (2010). Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917. https://doi.org/10.1016/j.cell.2010.02.034
  34. Jansen, H.J., van Essen, P., Koenen, T., Joosten, L.A., Netea, M.G., Tack, C.J., and Stienstra, R. (2012). Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 153, 5866-5874. https://doi.org/10.1210/en.2012-1625
  35. Jewell, J.L., and Guan, K.L. (2013). Nutrient signaling to mTOR and cell growth. Trends Biochem. Sci. 38, 233-242. https://doi.org/10.1016/j.tibs.2013.01.004
  36. Ji, C., and Kaplowitz, N. (2006). ER stress: can the liver cope? J. Hepatol. 45, 321-333. https://doi.org/10.1016/j.jhep.2006.06.004
  37. Jung, H.S., Chung, K.W., Won Kim, J., Kim, J., Komatsu, M., Tanaka, K., Nguyen, Y.H., Kang, T.M., Yoon, K.H., Kim, J.W., et al. (2008). Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318-324. https://doi.org/10.1016/j.cmet.2008.08.013
  38. Kamada, Y., Funakoshi, T., Shintani, T., Nagano, K., Ohsumi, M., and Ohsumi, Y. (2000). Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J. Cell Biol. 150, 1507-1513. https://doi.org/10.1083/jcb.150.6.1507
  39. Kaur, J., and Debnath, J. (2015). Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461-472. https://doi.org/10.1038/nrm4024
  40. Kaushik, S., and Cuervo, A.M. (2012). Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407-417. https://doi.org/10.1016/j.tcb.2012.05.006
  41. Kennedy, A., Martinez, K., Chuang, C.C., LaPoint, K., and McIntosh, M. (2009). Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. J. Nutr. 139, 1-4. https://doi.org/10.3945/jn.108.098269
  42. Kim, K.H., and Lee, M.S. (2014). Autophagy--a key player in cellular and body metabolism. Nat. Rev. Endocrinol. 10, 322-337. https://doi.org/10.1038/nrendo.2014.35
  43. Kim, K.H., Jeong, Y.T., Oh, H., Kim, S.H., Cho, J.M., Kim, Y.N., Kim, S.S., Kim, D.H., Hur, K.Y., Kim, H.K., et al. (2013). Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83-92. https://doi.org/10.1038/nm.3014
  44. Kim, M., Ho, A., and Lee, J.H. (2017). Autophagy and human neurodegenerative diseases-A fly's perspective. Int. J. Mol. Sci. 18, pii: E1596.
  45. Klionsky, D.J., Cregg, J.M., Dunn, W.A., Jr., Emr, S.D., Sakai, Y., Sandoval, I.V., Sibirny, A., Subramani, S., Thumm, M., Veenhuis, M., et al. (2003). A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539-545. https://doi.org/10.1016/S1534-5807(03)00296-X
  46. Klionsky, D.J., Abdelmohsen, K., Abe, A., Abedin, M.J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C.M., Adams, P.D., Adeli, K., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222. https://doi.org/10.1080/15548627.2015.1100356
  47. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., et al. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425-434. https://doi.org/10.1083/jcb.200412022
  48. Komatsu, M., Waguri, S., Koike, M., Sou, Y.S., Ueno, T., Hara, T., Mizushima, N., Iwata, J., Ezaki, J., Murata, S., et al. (2007). Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149-1163. https://doi.org/10.1016/j.cell.2007.10.035
  49. Kopelman, P.G. (2000). Obesity as a medical problem. Nature 404, 635-643. https://doi.org/10.1038/35007508
  50. Kovsan, J., Bluher, M., Tarnovscki, T., Kloting, N., Kirshtein, B., Madar, L., Shai, I., Golan, R., Harman-Boehm, I., Schon, M.R., et al. (2011). Altered autophagy in human adipose tissues in obesity. J. Clin. Endocrinol. Metab. 96, E268-277. https://doi.org/10.1210/jc.2010-1681
  51. Kroemer, G., Marino, G., and Levine, B. (2010). Autophagy and the integrated stress response. Mol. Cell 40, 280-293. https://doi.org/10.1016/j.molcel.2010.09.023
  52. Las, G., Serada, S.B., Wikstrom, J.D., Twig, G., and Shirihai, O.S. (2011). Fatty acids suppress autophagic turnover in beta-cells. J. Biol. Chem. 286, 42534-42544. https://doi.org/10.1074/jbc.M111.242412
  53. Lelliott, C., and Vidal-Puig, A.J. (2004). Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int. J. Obes. Relat. Metab. Disord. 28 Suppl 4, S22-28. https://doi.org/10.1038/sj.ijo.0802854
  54. Li, Y., Ge, M., Ciani, L., Kuriakose, G., Westover, E.J., Dura, M., Covey, D.F., Freed, J.H., Maxfield, F.R., Lytton, J., et al. (2004). Enrichment of endoplasmic reticulum with cholesterol inhibits sarcoplasmicendoplasmic reticulum calcium ATPase-2b activity in parallel with increased order of membrane lipids: implications for depletion of endoplasmic reticulum calcium stores and apoptosis in cholesterolloaded macrophages. J. Biol. Chem. 279, 37030-37039. https://doi.org/10.1074/jbc.M405195200
  55. Li, S., Dou, X., Ning, H., Song, Q., Wei, W., Zhang, X., Shen, C., Li, J., Sun, C., and Song, Z. (2017). Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity. Hepatology 66, 936-952. https://doi.org/10.1002/hep.29229
  56. Liao, X., Sluimer, J.C., Wang, Y., Subramanian, M., Brown, K., Pattison, J.S., Robbins, J., Martinez, J., and Tabas, I. (2012). Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545-553. https://doi.org/10.1016/j.cmet.2012.01.022
  57. Lim, Y.M., Lim, H., Hur, K.Y., Quan, W., Lee, H.Y., Cheon, H., Ryu, D., Koo, S.H., Kim, H.L., Kim, J., et al. (2014). Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat. Commun. 5, 4934. https://doi.org/10.1038/ncomms5934
  58. Lin, C.W., Zhang, H., Li, M., Xiong, X., Chen, X., Chen, X., Dong, X.C., and Yin, X.M. (2013). Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J. Hepatol. 58, 993-999. https://doi.org/10.1016/j.jhep.2013.01.011
  59. Liu, H.Y., Han, J., Cao, S.Y., Hong, T., Zhuo, D., Shi, J., Liu, Z., and Cao, W. (2009). 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. https://doi.org/10.1074/jbc.M109.033936
  60. Liu, K., Zhao, E., Ilyas, G., Lalazar, G., Lin, Y., Haseeb, M., Tanaka, K.E., and Czaja, M.J. (2015). Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 11, 271-284. https://doi.org/10.1080/15548627.2015.1009787
  61. Lupi, R., Dotta, F., Marselli, L., Del Guerra, S., Masini, M., Santangelo, C., Patane, G., Boggi, U., Piro, S., Anello, M., et al. (2002). Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51, 1437-1442. https://doi.org/10.2337/diabetes.51.5.1437
  62. Ma, D., Molusky, M.M., Song, J., Hu, C.R., Fang, F., Rui, C., Mathew, A.V., Pennathur, S., Liu, F., Cheng, J.X., et al. (2013). Autophagy deficiency by hepatic FIP200 deletion uncouples steatosis from liver injury in NAFLD. Mol. Endocrinol. 27, 1643-1654. https://doi.org/10.1210/me.2013-1153
  63. Martino, L., Masini, M., Novelli, M., Beffy, P., Bugliani, M., Marselli, L., Masiello, P., Marchetti, P., and De Tata, V. (2012). Palmitate activates autophagy in INS-1E beta-cells and in isolated rat and human pancreatic islets. PLoS One 7, e36188. https://doi.org/10.1371/journal.pone.0036188
  64. Matsuura, A., Tsukada, M., Wada, Y., and Ohsumi, Y. (1997). Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192, 245-250. https://doi.org/10.1016/S0378-1119(97)00084-X
  65. Mauvezin, C., and Neufeld, T.P. (2015). Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy 11, 1437-1438. https://doi.org/10.1080/15548627.2015.1066957
  66. Mauvezin, C., Nagy, P., Juhasz, G., and Neufeld, T.P. (2015). Autophagosome-lysosome fusion is independent of V-ATPasemediated acidification. Nat. Commun. 6, 7007. https://doi.org/10.1038/ncomms8007
  67. Mei, S., Ni, H.M., Manley, S., Bockus, A., Kassel, K.M., Luyendyk, J.P., Copple, B.L., and Ding, W.X. (2011). Differential roles of unsaturated and saturated fatty acids on autophagy and apoptosis in hepatocytes. J. Pharmacol. Exp. Ther. 339, 487-498. https://doi.org/10.1124/jpet.111.184341
  68. Menzies, F.M., Fleming, A., Caricasole, A., Bento, C.F., Andrews, S.P., Ashkenazi, A., Fullgrabe, J., Jackson, A., Jimenez Sanchez, M., Karabiyik, C., et al. (2017). Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93, 1015-1034. https://doi.org/10.1016/j.neuron.2017.01.022
  69. Mir, S.U., George, N.M., Zahoor, L., Harms, R., Guinn, Z., and Sarvetnick, N.E. (2015). Inhibition of autophagic turnover in betacells by fatty acids and glucose leads to apoptotic cell death. J. Biol. Chem. 290, 6071-6085. https://doi.org/10.1074/jbc.M114.605345
  70. Mizushima, N., and Levine, B. (2010). Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823-830. https://doi.org/10.1038/ncb0910-823
  71. Mizushima, N., Yoshimori, T., and Levine, B. (2010). Methods in mammalian autophagy research. Cell 140, 313-326. https://doi.org/10.1016/j.cell.2010.01.028
  72. Mulakkal, N.C., Nagy, P., Takats, S., Tusco, R., Juhasz, G., and Nezis, I.P. (2014). Autophagy in Drosophila: from historical studies to current knowledge. Biomed. Res. Int. 2014, 273473.
  73. Murrow, L., and Debnath, J. (2013). Autophagy as a stress-response and quality-control mechanism: implications for cell injury and human disease. Annu. Rev. Pathol. 8, 105-137. https://doi.org/10.1146/annurev-pathol-020712-163918
  74. Netea-Maier, R.T., Plantinga, T.S., van de Veerdonk, F.L., Smit, J.W., and Netea, M.G. (2016). Modulation of inflammation by autophagy: Consequences for human disease. Autophagy 12, 245-260. https://doi.org/10.1080/15548627.2015.1071759
  75. Ng, M., Fleming, T., Robinson, M., Thomson, B., Graetz, N., Margono, C., Mullany, E.C., Biryukov, S., Abbafati, C., Abera, S.F., et al. (2014). Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 384, 766-781. https://doi.org/10.1016/S0140-6736(14)60460-8
  76. Nunez, C.E., Rodrigues, V.S., Gomes, F.S., Moura, R.F., Victorio, S.C., Bombassaro, B., Chaim, E.A., Pareja, J.C., Geloneze, B., Velloso, L.A., et al. (2013). Defective regulation of adipose tissue autophagy in obesity. Int. J. Obes. (Lond). 37, 1473-1480. https://doi.org/10.1038/ijo.2013.27
  77. Ogata, M., Hino, S., Saito, A., Morikawa, K., Kondo, S., Kanemoto, S., Murakami, T., Taniguchi, M., Tanii, I., Yoshinaga, K., et al. (2006). Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell Biol. 26, 9220-9231. https://doi.org/10.1128/MCB.01453-06
  78. Ost, A., Svensson, K., Ruishalme, I., Brannmark, C., Franck, N., Krook, H., Sandstrom, P., Kjolhede, P., and Stralfors, P. (2010). Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol. Med. 16, 235-246. https://doi.org/10.1007/s00894-009-0539-5
  79. Ota, T., Gayet, C., and Ginsberg, H.N. (2008). Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J. Clin. Invest. 118, 316-332. https://doi.org/10.1172/JCI32752
  80. Ozcan, U., Cao, Q., Yilmaz, E., Lee, A.H., Iwakoshi, N.N., Ozdelen, E., Tuncman, G., Gorgun, C., Glimcher, L.H., and Hotamisligil, G.S. (2004). Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457-461. https://doi.org/10.1126/science.1103160
  81. Ozcan, U., Yilmaz, E., Ozcan, L., Furuhashi, M., Vaillancourt, E., Smith, R.O., Gorgun, C.Z., and Hotamisligil, G.S. (2006). Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137-1140. https://doi.org/10.1126/science.1128294
  82. Park, H.W., and Lee, J.H. (2014). Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies. Autophagy 10, 2385-2386. https://doi.org/10.4161/15548627.2014.984268
  83. Park, H.W., Park, H., Ro, S.H., Jang, I., Semple, I.A., Kim, D.N., Kim, M., Nam, M., Zhang, D., Yin, L., et al. (2014a). Hepatoprotective role of Sestrin2 against chronic ER stress. Nat. Commun. 5, 4233.
  84. Park, H.W., Park, H., Semple, I.A., Jang, I., Ro, S.H., Kim, M., Cazares, V.A., Stuenkel, E.L., Kim, J.J., Kim, J.S., et al. (2014b). Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers. Nat. Commun. 5, 4834. https://doi.org/10.1038/ncomms5834
  85. Pyo, J.O., Yoo, S.M., Ahn, H.H., Nah, J., Hong, S.H., Kam, T.I., Jung, S., and Jung, Y.K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300.
  86. Qian, M., Fang, X., and Wang, X. (2017). Autophagy and inflammation. Clin. Transl. Med. 6, 24. https://doi.org/10.1186/s40169-017-0154-5
  87. Qin, L., Wang, Z., Tao, L., and Wang, Y. (2010). ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy 6, 239-247. https://doi.org/10.4161/auto.6.2.11062
  88. Quan, W., Hur, K.Y., Lim, Y., Oh, S.H., Lee, J.C., Kim, K.H., Kim, G.H., Kim, S.W., Kim, H.L., Lee, M.K., et al. (2012). Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice. Diabetologia 55, 392-403. https://doi.org/10.1007/s00125-011-2350-y
  89. Rashid, H.O., Yadav, R.K., Kim, H.R., and Chae, H.J. (2015). ER stress: autophagy induction, inhibition and selection. Autophagy 11, 1956-1977. https://doi.org/10.1080/15548627.2015.1091141
  90. Razani, B., Feng, C., Coleman, T., Emanuel, R., Wen, H., Hwang, S., Ting, J.P., Virgin, H.W., Kastan, M.B., and Semenkovich, C.F. (2012). Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 15, 534-544. https://doi.org/10.1016/j.cmet.2012.02.011
  91. Rodriguez-Navarro, J.A., and Cuervo, A.M. (2012). Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms. Autophagy 8, 1152-1154. https://doi.org/10.4161/auto.20649
  92. Rodriguez-Navarro, J.A., Kaushik, S., Koga, H., Dall'Armi, C., Shui, G., Wenk, M.R., Di Paolo, G., and Cuervo, A.M. (2012). Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc. Natl. Acad. Sci. USA 109, E705-714. https://doi.org/10.1073/pnas.1113036109
  93. Ross, C.A., and Poirier, M.A. (2004). Protein aggregation and neurodegenerative disease. Nat. Med. 10 Suppl, S10-17. https://doi.org/10.1038/nm1066
  94. Sarparanta, J., Garcia-Macia, M., and Singh, R. (2017). Autophagy and mitochondria in obesity and type 2 diabetes. Curr. Diabetes Rev. 13, 352-369.
  95. Schenk, S., Saberi, M., and Olefsky, J.M. (2008). Insulin sensitivity: modulation by nutrients and inflammation. J. Clin. Invest. 118, 2992-3002. https://doi.org/10.1172/JCI34260
  96. Senft, D., and Ronai, Z.A. (2015). UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci. 40, 141-148. https://doi.org/10.1016/j.tibs.2015.01.002
  97. Settembre, C., De Cegli, R., Mansueto, G., Saha, P.K., Vetrini, F., Visvikis, O., Huynh, T., Carissimo, A., Palmer, D., Klisch, T.J., et al. (2013). TFEB controls cellular lipid metabolism through a starvationinduced autoregulatory loop. Nat. Cell Biol. 15, 647-658. https://doi.org/10.1038/ncb2718
  98. Shi, H., Kokoeva, M.V., Inouye, K., Tzameli, I., Yin, H., and Flier, J.S. (2006). TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015-3025. https://doi.org/10.1172/JCI28898
  99. Singh, R., and Cuervo, A.M. (2012). Lipophagy: connecting autophagy and lipid metabolism. Int. J. Cell Biol. 2012, 282041.
  100. Singh, R., Kaushik, S., Wang, Y., Xiang, Y., Novak, I., Komatsu, M., Tanaka, K., Cuervo, A.M., and Czaja, M.J. (2009a). Autophagy regulates lipid metabolism. Nature 458, 1131-1135. https://doi.org/10.1038/nature07976
  101. Singh, R., Xiang, Y., Wang, Y., Baikati, K., Cuervo, A.M., Luu, Y.K., Tang, Y., Pessin, J.E., Schwartz, G.J., and Czaja, M.J. (2009b). Autophagy regulates adipose mass and differentiation in mice. J. Clin. Invest. 119, 3329-3339.
  102. Stubbs, C.O., and Lee, A.J. (2004). The obesity epidemic: both energy intake and physical activity contribute. Med. J. Aust. 181, 489-491.
  103. Takabatake, Y., Yamamoto, T., and Isaka, Y. (2017). Stagnation of autophagy: A novel mechanism of renal lipotoxicity. Autophagy 13, 775-776. https://doi.org/10.1080/15548627.2017.1283084
  104. Tan, S.H., Shui, G., Zhou, J., Li, J.J., Bay, B.H., Wenk, M.R., and Shen, H.M. (2012). 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. https://doi.org/10.1074/jbc.M111.294157
  105. Tanaka, S., Hikita, H., Tatsumi, T., Sakamori, R., Nozaki, Y., Sakane, S., Shiode, Y., Nakabori, T., Saito, Y., Hiramatsu, N., et al. (2016). Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology 64, 1994-2014. https://doi.org/10.1002/hep.28820
  106. Tooze, S.A., and Dikic, I. (2016). Autophagy Captures the Nobel Prize. Cell 167, 1433-1435. https://doi.org/10.1016/j.cell.2016.11.023
  107. Um, S.H., Frigerio, F., Watanabe, M., Picard, F., Joaquin, M., Sticker, M., Fumagalli, S., Allegrini, P.R., Kozma, S.C., Auwerx, J., et al. (2004). Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200-205. https://doi.org/10.1038/nature02866
  108. Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M.T., Brickey, W.J., and Ting, J.P. (2011). Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408-415. https://doi.org/10.1038/ni.2022
  109. Yamamoto, T., Takabatake, Y., Takahashi, A., Kimura, T., Namba, T., Matsuda, J., Minami, S., Kaimori, J.Y., Matsui, I., Matsusaka, T., et al. (2017). High-Fat Diet-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney. J. Am. Soc. Nephrol. 28, 1534-1551. https://doi.org/10.1681/ASN.2016070731
  110. Yang, L., Li, P., Fu, S., Calay, E.S., and Hotamisligil, G.S. (2010). Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467-478. https://doi.org/10.1016/j.cmet.2010.04.005
  111. Zhang, Y., Goldman, S., Baerga, R., Zhao, Y., Komatsu, M., and Jin, S. (2009). Adipose-specific deletion of autophagy-related gene 7 (atg7). in mice reveals a role in adipogenesis. Proc. Natl. Acad. Sci. USA 106, 19860-19865. https://doi.org/10.1073/pnas.0906048106
  112. Zhang, K., Wang, S., Malhotra, J., Hassler, J.R., Back, S.H., Wang, G., Chang, L., Xu, W., Miao, H., Leonardi, R., et al. (2011). The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J. 30, 1357-1375. https://doi.org/10.1038/emboj.2011.52
  113. Zheng, Z., Zhang, C., and Zhang, K. (2010). Role of unfolded protein response in lipogenesis. World J. Hepatol. 2, 203-207. https://doi.org/10.4254/wjh.v2.i6.203

Cited by

  1. Autophagy in Metabolic Age-Related Human Diseases vol.7, pp.10, 2018, https://doi.org/10.3390/cells7100149
  2. Overview of the Minireviews on Autophagy vol.41, pp.1, 2018, https://doi.org/10.14348/molcells.2018.0400
  3. Oxidative stress, lysosomal damage and dysfunctional autophagy in molluscan hepatopancreas (digestive gland) induced by chemical contaminants vol.152, pp.None, 2018, https://doi.org/10.1016/j.marenvres.2019.104825
  4. Neutrophil Extracellular Traps (NETs) and Damage-Associated Molecular Patterns (DAMPs): Two Potential Targets for COVID-19 Treatment vol.2020, pp.None, 2018, https://doi.org/10.1155/2020/7527953
  5. Autophagy in metabolic syndrome: breaking the wheel by targeting the renin–angiotensin system vol.11, pp.2, 2020, https://doi.org/10.1038/s41419-020-2275-9
  6. High-fat diet-induced and genetically inherited obesity differentially alters DNA methylation profile in the germline of adult male rats vol.12, pp.1, 2018, https://doi.org/10.1186/s13148-020-00974-7
  7. Multiple Mechanisms Converging on Transcription Factor EB Activation by the Natural Phenol Pterostilbene vol.2021, pp.None, 2018, https://doi.org/10.1155/2021/7658501
  8. Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus vol.13, pp.4, 2018, https://doi.org/10.3390/nu13041303
  9. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications vol.101, pp.4, 2018, https://doi.org/10.1152/physrev.00030.2020
  10. Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications vol.101, pp.4, 2018, https://doi.org/10.1152/physrev.00030.2020
  11. Roles of IκB kinases and TANK-binding kinase 1 in hepatic lipid metabolism and nonalcoholic fatty liver disease vol.53, pp.11, 2018, https://doi.org/10.1038/s12276-021-00712-w
  12. The Epstein-Barr virus deubiquitinase BPLF1 targets SQSTM1/p62 to inhibit selective autophagy vol.17, pp.11, 2021, https://doi.org/10.1080/15548627.2021.1874660