Browse > Article
http://dx.doi.org/10.14348/molcells.2018.2213

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)
Publication Information
Molecules and Cells / v.41, no.1, 2018 , pp. 3-10 More about this Journal
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
autophagy; diabetes; metabolism; obesity; stress;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Kopelman, P.G. (2000). Obesity as a medical problem. Nature 404, 635-643.   DOI
2 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.   DOI
3 Kroemer, G., Marino, G., and Levine, B. (2010). Autophagy and the integrated stress response. Mol. Cell 40, 280-293.   DOI
4 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.   DOI
5 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.   DOI
6 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.   DOI
7 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.   DOI
8 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.   DOI
9 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.   DOI
10 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.   DOI
11 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.   DOI
12 Hill, J.O., Wyatt, H.R., and Peters, J.C. (2012). Energy balance and obesity. Circulation 126, 126-132.   DOI
13 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.   DOI
14 Hotamisligil, G.S. (2010). Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140, 900-917.   DOI
15 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.   DOI
16 Jewell, J.L., and Guan, K.L. (2013). Nutrient signaling to mTOR and cell growth. Trends Biochem. Sci. 38, 233-242.   DOI
17 Ji, C., and Kaplowitz, N. (2006). ER stress: can the liver cope? J. Hepatol. 45, 321-333.   DOI
18 Kaur, J., and Debnath, J. (2015). Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461-472.   DOI
19 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.   DOI
20 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.   DOI
21 Kaushik, S., and Cuervo, A.M. (2012). Chaperone-mediated autophagy: a unique way to enter the lysosome world. Trends Cell Biol. 22, 407-417.   DOI
22 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.   DOI
23 Kim, K.H., and Lee, M.S. (2014). Autophagy--a key player in cellular and body metabolism. Nat. Rev. Endocrinol. 10, 322-337.   DOI
24 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.   DOI
25 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.
26 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.   DOI
27 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.   DOI
28 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.   DOI
29 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.   DOI
30 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.   DOI
31 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.   DOI
32 Feng, Y., He, D., Yao, Z., and Klionsky, D.J. (2014). The machinery of macroautophagy. Cell Res. 24, 24-41.   DOI
33 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.   DOI
34 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.   DOI
35 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.   DOI
36 Galluzzi, L., Pietrocola, F., Levine, B., and Kroemer, G. (2014). Metabolic control of autophagy. Cell 159, 1263-1276.   DOI
37 Goldberg, I.J., Trent, C.M., and Schulze, P.C. (2012). Lipid metabolism and toxicity in the heart. Cell Metab. 15, 805-812.   DOI
38 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.   DOI
39 Hauck, A.K., and Bernlohr, D.A. (2016). Oxidative stress and lipotoxicity. J. Lipid Res. 57, 1976-1986.   DOI
40 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.   DOI
41 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.   DOI
42 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.   DOI
43 Basseri, S., and Austin, R.C. (2008). ER stress and lipogenesis: a slippery slope toward hepatic steatosis. Dev. Cell 15, 795-796.   DOI
44 Choi, A.M., Ryter, S.W., and Levine, B. (2013). Autophagy in human health and disease. N Engl. J. Med. 368, 651-662.   DOI
45 Browning, J.D., and Horton, J.D. (2004). Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147-152.   DOI
46 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.
47 Cho, C.S., Lombard, D.B., and Lee, J.H. (2017). SIRT3 as a regulator of hepatic autophagy. Hepatology 66, 700-702.   DOI
48 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.   DOI
49 Alers, S., Loffler, A.S., Wesselborg, S., and Stork, B. (2012a). The incredible ULKs. Cell Commun. Signal. 10, 7.   DOI
50 Bernales, S., Schuck, S., and Walter, P. (2007). ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3, 285-287.   DOI
51 Bournat, J.C., and Brown, C.W. (2010). Mitochondrial dysfunction in obesity. Curr. Opin. Endocrinol. Diabetes Obes. 17, 446-452.   DOI
52 Brookheart, R.T., Michel, C.I., and Schaffer, J.E. (2009). As a matter of fat. Cell Metab. 10, 9-12.   DOI
53 Takabatake, Y., Yamamoto, T., and Isaka, Y. (2017). Stagnation of autophagy: A novel mechanism of renal lipotoxicity. Autophagy 13, 775-776.   DOI
54 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.   DOI
55 Cooke, M.S., Evans, M.D., Dizdaroglu, M., and Lunec, J. (2003). Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17, 1195-1214.   DOI
56 Czaja, M.J. (2015). A new mechanism of lipotoxicity: Calcium channel blockers as a treatment for nonalcoholic steatohepatitis? Hepatology 62, 312-314.   DOI
57 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.
58 Stubbs, C.O., and Lee, A.J. (2004). The obesity epidemic: both energy intake and physical activity contribute. Med. J. Aust. 181, 489-491.
59 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.   DOI
60 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.   DOI
61 Tooze, S.A., and Dikic, I. (2016). Autophagy Captures the Nobel Prize. Cell 167, 1433-1435.   DOI
62 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.   DOI
63 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.   DOI
64 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.   DOI
65 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.   DOI
66 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.
67 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.   DOI
68 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.   DOI
69 Zheng, Z., Zhang, C., and Zhang, K. (2010). Role of unfolded protein response in lipogenesis. World J. Hepatol. 2, 203-207.   DOI
70 Qian, M., Fang, X., and Wang, X. (2017). Autophagy and inflammation. Clin. Transl. Med. 6, 24.   DOI
71 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.   DOI
72 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.   DOI
73 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.   DOI
74 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.   DOI
75 Sarparanta, J., Garcia-Macia, M., and Singh, R. (2017). Autophagy and mitochondria in obesity and type 2 diabetes. Curr. Diabetes Rev. 13, 352-369.
76 Rodriguez-Navarro, J.A., and Cuervo, A.M. (2012). Dietary lipids and aging compromise chaperone-mediated autophagy by similar mechanisms. Autophagy 8, 1152-1154.   DOI
77 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.   DOI
78 Ross, C.A., and Poirier, M.A. (2004). Protein aggregation and neurodegenerative disease. Nat. Med. 10 Suppl, S10-17.   DOI
79 Schenk, S., Saberi, M., and Olefsky, J.M. (2008). Insulin sensitivity: modulation by nutrients and inflammation. J. Clin. Invest. 118, 2992-3002.   DOI
80 Senft, D., and Ronai, Z.A. (2015). UPR, autophagy, and mitochondria crosstalk underlies the ER stress response. Trends Biochem. Sci. 40, 141-148.   DOI
81 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.   DOI
82 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.   DOI
83 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.   DOI
84 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.   DOI
85 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.
86 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.   DOI
87 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.   DOI
88 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.   DOI
89 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.   DOI
90 Singh, R., and Cuervo, A.M. (2012). Lipophagy: connecting autophagy and lipid metabolism. Int. J. Cell Biol. 2012, 282041.
91 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.   DOI
92 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.   DOI
93 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.   DOI
94 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.   DOI
95 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.   DOI
96 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.
97 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.   DOI
98 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.   DOI
99 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.   DOI
100 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.   DOI
101 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.   DOI
102 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.   DOI
103 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.   DOI
104 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.   DOI
105 Mauvezin, C., Nagy, P., Juhasz, G., and Neufeld, T.P. (2015). Autophagosome-lysosome fusion is independent of V-ATPasemediated acidification. Nat. Commun. 6, 7007.   DOI
106 Mizushima, N., and Levine, B. (2010). Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823-830.   DOI
107 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.   DOI
108 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.   DOI
109 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.   DOI
110 Mizushima, N., Yoshimori, T., and Levine, B. (2010). Methods in mammalian autophagy research. Cell 140, 313-326.   DOI
111 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.   DOI
112 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.   DOI
113 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.   DOI