Essential role of Nrf2 in the protective effect of lipoic acid against lipoapoptosis in hepatocytes

Free Radical Biology and Medicine

Volumn 84, Issue , 2015, Pages 263-278

  Pilar Valdecantos, M ^a,b   Prieto Hontoria, Pedro Luis ^c   Pardo, Virginia ^a,d   Módol, Teresa ^c   Santamaría, Beatriz ^a,b,d   Weber, Minéia ^d,e   Herrero, Laura ^d,e   Serra, Dolors ^d,e   Muntané, Jordi ^d,f   Cuadrado, Antonio ^a,b,d   Moreno Aliaga, María Jesús ^c,d   Alfredo Martinez J ^c,d   Valverde, Ángela M ^a,b,d  

^a INSTITUTO DE INVESTIGACIONES BIOMÉDICAS ALBERTO SOLS   (Spain)

^b HOSPITAL UNIVERSITARIO LA PAZ IDIPAZ   (Spain)

^c UNIVERSITY OF NAVARRA   (Spain)

^d INSTITUTO DE SALUD CARLOS III   (Spain)

^e UNIVERSITY OF BARCELONA   (Spain)

^f HOSPITAL UNIVERSITARIO VIRGEN MACARENA   (Spain)

Author keywords

Antioxidant; Endoplasmic reticulum stress; Free radicals; Lipoapoptosis; Lipoic acid; Lipophagy; Nonalcoholic fatty liver disease; Nrf2; Palmitic acid; Reactive oxygen species

Indexed keywords

BIM PROTEIN; CASPASE 3; CATALASE; CD36 ANTIGEN; FATTY ACID; GLUTATHIONE; GLUTATHIONE DISULFIDE; GLUTATHIONE PEROXIDASE 1; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 153; HEME OXYGENASE 1; INITIATION FACTOR 2ALPHA; KETONE BODY; MANGANESE SUPEROXIDE DISMUTASE; MITOGEN ACTIVATED PROTEIN KINASE P38; PALMITIC ACID; PROTEIN BAX; PROTEIN BCL XL; PUMA PROTEIN; REACTIVE OXYGEN METABOLITE; SMALL INTERFERING RNA; STRESS ACTIVATED PROTEIN KINASE; SUPEROXIDE; THIOCTIC ACID; TRANSCRIPTION FACTOR NRF2; TRIACYLGLYCEROL; ANTIOXIDANT; NFE2L2 PROTEIN, HUMAN;

ANIMAL CELL; ANIMAL EXPERIMENT; APOPTOSIS; ARTICLE; AUTOPHAGOSOME; CELL PROLIFERATION; CELL VIABILITY; CELLULAR DISTRIBUTION; CONTROLLED STUDY; ENDOPLASMIC RETICULUM STRESS; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; FATTY ACID TRANSPORT; HUMAN; HUMAN CELL; HUMAN TISSUE; LIPID DIET; LIPID STORAGE; LIPOAPOPTOSIS; LIPOLYSIS; LIPOPHAGOCYTOSIS; LIPOTOXICITY; LIVER CELL; MALE; MITOCHONDRIAL MEMBRANE POTENTIAL; MOUSE; NONHUMAN; OXIDATION; OXIDATIVE STRESS; PRIORITY JOURNAL; PROTEIN CONTENT; PROTEIN PHOSPHORYLATION; RAT; TRIACYLGLYCEROL BLOOD LEVEL; TUNEL ASSAY; UNFOLDED PROTEIN RESPONSE; WHITE ADIPOSE TISSUE; ACTIVE TRANSPORT; ADVERSE EFFECTS; ANIMAL; ANTIOXIDANT RESPONSIVE ELEMENT; CELL CULTURE; METABOLISM; NONALCOHOLIC FATTY LIVER; PHYSIOLOGY; WISTAR RAT;

RATTUS;

ACTIVE TRANSPORT, CELL NUCLEUS; ANIMALS; ANTIOXIDANT RESPONSE ELEMENTS; ANTIOXIDANTS; APOPTOSIS; CELLS, CULTURED; DIET, HIGH-FAT; HEPATOCYTES; HUMANS; MALE; MEMBRANE POTENTIAL, MITOCHONDRIAL; NF-E2-RELATED FACTOR 2; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; PALMITIC ACID; RATS, WISTAR; REACTIVE OXYGEN SPECIES; THIOCTIC ACID;

EID: 84929082829     PISSN: 08915849     EISSN: 18734596     Source Type: Journal    
DOI: 10.1016/j.freeradbiomed.2015.03.019     Document Type: Article

References (83)

1. A Berlanga, E Guiu-Jurado, JA. Porras, and T. Auguet Molecular pathways in non-alcoholic fatty liver disease Clin. Exp. Gastroenterol 7 2014 221 239
2. CP Day, and S. Saksena Non-alcoholic steatohepatitis: definitions and pathogenesis J. Gastroenterol. Hepatol. 17 Suppl. 3 2002 S377 S384
3. C Garcia-Monzon, O Lo Iacono, R Mayoral, A Gonzalez-Rodriguez, ME Miquilena-Colina, T Lozano-Rodriguez, L. Garcia-Pozo, J Vargas-Castrillon, M Casado, L Bosca, AM Valverde, and P. Martin-Sanz Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C J. Hepatol 54 2011 142 152
4. E Vanni, E Bugianesi, A Kotronen, S De Minicis, H Yki-Jarvinen, and G. Svegliati-Baroni From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis 42 2010 320 330
5. AE Feldstein, A Canbay, P Angulo, M Taniai, LJ Burgart, KD Lindor, and GJ. Gores Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis Gastroenterology 125 2003 437 443
6. RH Unger, and L. Orci Lipoapoptosis: its mechanism and its diseases Biochim. Biophys. Acta 1585 2002 202 212
7. SC Cazanave, and GJ. Gores Mechanisms and clinical implications of hepatocyte lipoapoptosis Clin. Lipidol 5 2010 71 85
8. L Yuzefovych, G Wilson, and L. Rachek Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress Am. J. Physiol. Endocrinol. Metab. 299 2010 E1096 E1105
9. LV Yuzefovych, VA Solodushko, GL Wilson, and LI. Rachek Protection from palmitate-induced mitochondrial DNA damage prevents from mitochondrial oxidative stress, mitochondrial dysfunction, apoptosis, and impaired insulin signaling in rat L6 skeletal muscle cells Endocrinology 153 2012 92 100
10. K Begriche, A Igoudjil, D Pessayre, and B. Fromenty Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it Mitochondrion 6 2006 1 28
11. DW Jun, WK Cho, JH Jun, HJ Kwon, KS Jang, HJ Kim, HJ Jeon, KN Lee, HL Lee, OY Lee, BC Yoon, HS Choi, JS Hahm, and MH. Lee Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction Liver Int. 31 2011 1315 1324
12. D Pessayre, and B. Fromenty NASH: A mitochondrial disease J. Hepatol. 42 2005 928 940
13. H Kamata, S Honda, S Maeda, L Chang, H Hirata, and M. Karin Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases Cell 120 2005 649 661
14. Y Song, X Li, Y Li, N Li, X Shi, H Ding, Y Zhang, G Liu, and Z. Wang Non-esterified fatty acids activate the ROS-p38-p53/Nrf2 signaling pathway to induce bovine hepatocyte apoptosis in vitro Apoptosis 19 2014 984 997
15. Y Akazawa, S Cazanave, JL Mott, N Elmi, SF Bronk, S Kohno, MR Charlton, and GJ. Gores Palmitoleate attenuates palmitate-induced Bim and PUMA up-regulation and hepatocyte lipoapoptosis J. Hepatol. 52 2010 586 593
16. SC Cazanave, JL Mott, NA Elmi, SF Bronk, NW Werneburg, Y Akazawa, A Kahraman, SP Garrison, GP Zambetti, MR Charlton, and GJ. Gores JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis J. Biol. Chem. 284 2009 26591 26602
17. SC Cazanave, X Wang, H Zhou, M Rahmani, S Grant, DE Durrant, CD Klaassen, M Yamamoto, and AJ. Sanyal Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis Cell Death Differ. 21 2014 1303 1312
18. S Nakamura, T Takamura, N Matsuzawa-Nagata, H Takayama, H Misu, H Noda, S Nabemoto, S Kurita, T Ota, H Ando, K Miyamoto, and S. Kaneko Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria J. Biol. Chem. 284 2009 14809 14818
19. J Cao, DL Dai, L Yao, HH Yu, B Ning, Q Zhang, J Chen, WH Cheng, W Shen, and ZX. Yang Saturated fatty acid induction of endoplasmic reticulum stress and apoptosis in human liver cells via the PERK/ATF4/CHOP signaling pathway Mol. Cell. Biochem. 364 2012 115 129
20. KT Pfaffenbach, CL Gentile, AM Nivala, D Wang, Y Wei, and MJ. Pagliassotti Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death Am. J. Physiol. Endocrinol. Metab. 298 2010 E1027 E1035
21. D Wang, Y Wei, and MJ. Pagliassotti Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis Endocrinology 147 2006 943 951
22. Y Wei, D Wang, CL Gentile, and MJ. Pagliassotti Reduced endoplasmic reticulum luminal calcium links saturated fatty acid-mediated endoplasmic reticulum stress and cell death in liver cells Mol. Cell. Biochem. 331 2009 31 40
23. IG Ganley, PM Wong, and X. Jiang Thapsigargin distinguishes membrane fusion in the late stages of endocytosis and autophagy Autophagy 7 2011 1397 1399
24. MW Greene, CM Burrington, MS Ruhoff, AK Johnson, T Chongkrairatanakul, and A. Kangwanpornsiri PKC{delta} is activated in a dietary model of steatohepatitis and regulates endoplasmic reticulum stress and cell death J. Biol. Chem. 285 2010 42115 42129
25. ME Rinella, MS Siddiqui, K Gardikiotes, J Gottstein, M Elias, and RM. Green Dysregulation of the unfolded protein response in db/db mice with diet-induced steatohepatitis Hepatology 54 2011 1600 1609
26. A Gonzalez-Rodriguez, R Mayoral, N Agra, MP Valdecantos, V Pardo, ME Miquilena-Colina, J Vargas-Castrillon, O Lo Iacono, M Corazzari, GM Fimia, M Piacentini, J Muntane, L Bosca, C Garcia-Monzon, P Martin-Sanz, and AM. Valverde Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD Cell Death Dis 5 2014 e1179
27. P Puri, F Mirshahi, O Cheung, R Natarajan, JW Maher, JM Kellum, and AJ. Sanyal Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease Gastroenterology 134 2008 568 576
28. NR Kitteringham, A Abdullah, J Walsh, L Randle, RE Jenkins, R Sison, CE Goldring, H Powell, C Sanderson, S Williams, L Higgins, M Yamamoto, J Hayes, and BK. Park Proteomic analysis of Nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary Nrf2-dependent pathways in the liver J. Proteomics 73 2010 1612 1631
29. C Deng, Z Sun, G Tong, W Yi, L Ma, B Zhao, L Cheng, J Zhang, F Cao, and D. Yi alpha-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway PLoS One 8 2013 e58371
30. SG Huerta-Olvera, J Macias-Barragan, ME Ramos-Marquez, J Armendariz-Borunda, F Diaz-Barriga, and F. Siller-Lopez Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells Environ. Toxicol. Pharmacol. 29 2010 144 149
31. A Lau, SA Whitman, MC Jaramillo, and DD. Zhang Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway J. Biochem. Mol. Toxicol. 27 2013 99 105
32. SM Elshazly, MA El-Moselhy, and W. Barakat Insights in the mechanism underlying the protective effect of alpha-lipoic acid against acetaminophen-hepatotoxicity Eur. J. Pharmacol. 726 2014 116 123
33. PL Prieto-Hontoria, P Perez-Matute, M Fernandez-Galilea, A Barber, JA Martinez, and MJ. Moreno-Aliaga Lipoic acid prevents body weight gain induced by a high fat diet in rats: effects on intestinal sugar transport J. Physiol. Biochem. 65 2009 43 50
34. MP Valdecantos, P Perez-Matute, P Gonzalez-Muniesa, PL Prieto-Hontoria, MJ Moreno-Aliaga, and JA. Martinez Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3 Obesity (Silver Spring) 20 2012 1974 1983
35. SD Wollin, Y Wang, S Kubow, and PJ. Jones Effects of a medium chain triglyceride oil mixture and alpha-lipoic acid diet on body composition, antioxidant status, and plasma lipid levels in the Golden Syrian hamster J. Nutr. Biochem. 15 2004 402 410
36. F Bertolotto, and A. Massone Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy Drugs R&D 12 2012 29 34
37. C Haritoglou, J Gerss, HP Hammes, A Kampik, MW Ulbig, and RS. Group Alpha-lipoic acid for the prevention of diabetic macular edema Ophthalmologica 226 2011 127 137
38. M Cicek, A Yildirir, K Okyay, AC Yazici, A Aydinalp, S Kanyilmaz, and H. Muderrisoglu Use of alpha-lipoic acid in prevention of contrast-induced nephropathy in diabetic patients Renal Failure 35 2013 748 753
39. N Noori, H Tabibi, F Hosseinpanah, M Hedayati, and M. Nafar Effects of combined lipoic acid and pyridoxine on albuminuria, advanced glycation end-products, and blood pressure in diabetic nephropathy Int. J. Vitam. Nutr. Res. 83 2013 77 85
40. MN Stankovic, D Mladenovic, M Ninkovic, I Ethuricic, S Sobajic, B Jorgacevic, S. de Luka, RJ Vukicevic, and TS. Radosavljevic The effects of alpha-lipoic acid on liver oxidative stress and free fatty acid composition in methionine-choline deficient diet-induced NAFLD J. Med. Food 17 2014 254 261
41. AK Min, MK Kim, HS Kim, HY Seo, KU Lee, JG Kim, KG Park, and IK. Lee Alpha-lipoic acid attenuates methionine choline deficient diet-induced steatohepatitis in C57BL/6 mice Life Sci. 90 2012 200 205
42. PL Prieto-Hontoria, P Perez-Matute, M Fernandez-Galilea, JA Martinez, and MJ. Moreno-Aliaga Lipoic acid inhibits leptin secretion and Sp1 activity in adipocytes Mol. Nutr. Food Res. 55 2011 1059 1069
43. MP Valdecantos, P Perez-Matute, P Gonzalez-Muniesa, PL Prieto-Hontoria, MJ Moreno-Aliaga, and JA. Martinez Lipoic acid administration prevents nonalcoholic steatosis linked to long-term high-fat feeding by modulating mitochondrial function J. Nutr. Biochem. 23 2012 1676 1684
44. L Pichard, E Raulet, G Fabre, JB Ferrini, JC Ourlin, and P. Maurel Human hepatocyte culture Methods Mol. Biol. 320 2006 283 293
45. AM Valverde, I Fabregat, DJ Burks, MF White, and M. Benito IRS-2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes Hepatology 40 2004 1285 1294
46. JM Orellana-Gavalda, L Herrero, MI Malandrino, A Paneda, M Sol Rodriguez-Pena, H Petry, G Asins, S Van Deventer, FG Hegardt, and D. Serra Molecular therapy for obesity and diabetes based on a long-term increase in hepatic fatty-acid oxidation Hepatology 53 2011 821 832
47. I Rahman, A Kode, and SK. Biswas Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method Nat. Protoc. 1 2006 3159 3165
48. HT Kuo, HW Chen, HH Hsiao, and HC. Chen Heat shock response protects human peritoneal mesothelial cells from dialysate-induced oxidative stress and mitochondrial injury Nephrol. Dial. Transplant. 24 2009 1799 1809
49. T Modol, N Brice, M Ruiz de Galarreta, A. Garcia Garzon, MJ Iraburu, JJ Martinez-Irujo, and MJ. Lopez-Zabalza Fibronectin peptides as potential regulators of hepatic fibrosis through apoptosis of hepatic stellate cells J. Cell. Physiol. 230 2015 546 553
50. R Singh, S Kaushik, Y Wang, Y Xiang, I Novak, M Komatsu, K Tanaka, AM Cuervo, and MJ. Czaja Autophagy regulates lipid metabolism Nature 458 2009 1131 1135
51. R Singh, and AM. Cuervo Autophagy in the cellular energetic balance Cell Metab. 13 2011 495 504
52. MA Mobasher, and AM. Valverde Signalling pathways involved in paracetamol-induced hepatotoxicity: new insights on the role of protein tyrosine phosphatase 1B Arch. Physiol. Biochem. 120 2014 51 63
53. GA Michelotti, MV Machado, and AM. Diehl NAFLD, NASH and liver cancer Nat. Rev. Gastroenterol. Hepatol 10 2013 656 665
54. EM. Brunt Pathology of nonalcoholic steatohepatitis Hepatol. Res. 33 2005 68 71
55. EM. Brunt Histopathology of non-alcoholic fatty liver disease Clin. Liver Dis 13 2009 533 544
56. EM Brunt, DE Kleiner, LA Wilson, A Unalp, CE Behling, JE Lavine, and BA. Neuschwander-Tetri Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): a histologic marker of advanced NAFLD-clinicopathologic correlations from the Nonalcoholic Steatohepatitis Clinical Research Network Hepatology 49 2009 809 820
57. MM Richardson, JR Jonsson, EE Powell, EM Brunt, BA Neuschwander-Tetri, PS Bhathal, JB Dixon, MD Weltman, H Tilg, AR Moschen, DM Purdie, AJ Demetris, and AD. Clouston Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction Gastroenterology 133 2007 80 90
58. MD Lewis, and BJ. Roberts Role of CYP2E1 activity in endoplasmic reticulum ubiquitination, proteasome association, and the unfolded protein response Arch. Biochem. Biophys. 436 2005 237 245
59. Y Yang, W Li, Y Liu, Y Sun, Y Li, Q Yao, J Li, Q Zhang, Y Gao, L Gao, and J. Zhao Alpha-lipoic acid improves high-fat diet-induced hepatic steatosis by modulating the transcription factors SREBP-1, FoxO1 and Nrf2 via the SIRT1/LKB1/AMPK pathway J. Nutr. Biochem. 25 2014 1207 1217
60. F Kaya-Dagistanli, G Tanriverdi, A Altinok, S Ozyazgan, and M. Ozturk The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids Food Chem. Toxicol. 53 2013 84 93
61. S Golbidi, M Badran, and I. Laher Diabetes and alpha lipoic acid Front. Pharmacol 2 2011 69
62. M Fernandez-Galilea, P Perez-Matute, PL Prieto-Hontoria, M Houssier, MA Burrell, D Langin, JA Martinez, and M. Moreno-Aliaga J. alpha-Lipoic acid treatment increases mitochondrial biogenesis and promotes beige adipose features in subcutaneous adipocytes from overweight/obese subjects Biochim. Biophys. Acta 1851 2015 273 281
63. AE Huerta, S Navas-Carretero, PL Prieto-Hontoria, JA Martinez, and MJ. Moreno-Aliaga Effects of alpha-lipoic acid and eicosapentaenoic acid in overweight and obese women during weight loss Obesity (Silver Spring) 23 2015 313 321
64. V Gianturco, A Bellomo, E D, V. Formosa, A Iori, M Mancinella, G. Troisi, and V. Marigliano Impact of therapy with alpha-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: a possible preventive way against the organ dysfunction? Arch. Gerontol. Geriatr 49 Suppl. 1 2009 129 133
65. C Nevado, M Benito, and AM. Valverde Role of insulin receptor and balance in insulin receptor isoforms A and B in regulation of apoptosis in simian virus 40-immortalized neonatal hepatocytes Mol. Biol. Cell 19 2008 1185 1198
66. SC Cazanave, NA Elmi, Y Akazawa, SF Bronk, JL Mott, and GJ. Gores CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis Am. J. Physiol. Gastrointest. Liver Physiol. 299 2010 G236 G243
67. KP Shay, AJ Michels, W Li, AN Kong, and TM. Hagen Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response Biochim. Biophys. Acta 1823 2012 1102 1109
68. M McMahon, K Itoh, M Yamamoto, and JD. Hayes Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression J. Biol. Chem. 278 2003 21592 21600
69. HR Lee, JM Cho, DH Shin, CS Yong, HG Choi, N Wakabayashi, and MK. Kwak Adaptive response to GSH depletion and resistance to L-buthionine-(S,R)-sulfoximine: involvement of Nrf2 activation Mol. Cell. Biochem. 318 2008 23 31
70. CL Jung, HJ Kim, JH Park, AN Kong, CH Lee, and JS. Kim Synergistic activation of the Nrf2-signaling pathway by glyceollins under oxidative stress induced by glutathione depletion J. Agric. Food Chem. 61 2013 4072 4078
71. AJ Chia, CE Goldring, NR Kitteringham, SQ Wong, P Morgan, and BK. Park Differential effect of covalent protein modification and glutathione depletion on the transcriptional response of Nrf2 and NF-kappaB Biochem. Pharmacol. 80 2010 410 421
72. AC Brewer, TV Murray, M Arno, M Zhang, NP Anilkumar, GE Mann, and AM. Shah Nox4 regulates Nrf2 and glutathione redox in cardiomyocytes in vivo Free Radic. Biol. Med. 51 2011 205 215
73. V Zambo, L Simon-Szabo, P Szelenyi, E Kereszturi, G Banhegyi, and M. Csala Lipotoxicity in the liver World J. Hepatol 5 2013 550 557
74. M Csala, E Margittai, and G. Banhegyi Redox control of endoplasmic reticulum function Antioxid. Redox Signaling 13 2010 77 108
75. PJ Meakin, S Chowdhry, RS Sharma, FB Ashford, SV Walsh, RJ McCrimmon, AT Dinkova-Kostova, JF Dillon, JD Hayes, and ML. Ashford Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance Mol. Cell. Biol. 34 2014 3305 3320
76. YT Kuo, TH Lin, WL Chen, and HM. Lee Alpha-lipoic acid induces adipose triglyceride lipase expression and decreases intracellular lipid accumulation in HepG2 cells Eur. J. Pharmacol. 692 2012 10 18
77. RA Egnatchik, AK Leamy, Y Noguchi, M Shiota, and JD. Young Palmitate-induced activation of mitochondrial metabolism promotes oxidative stress and apoptosis in H4IIEC3 rat hepatocytes Metabolism 63 2014 283 295
78. S Seok, T Fu, SE Choi, Y Li, R Zhu, S Kumar, X Sun, G Yoon, Y Kang, W Zhong, J Ma, B Kemper, and JK. Kemper Transcriptional regulation of autophagy by an FXR-CREB axis Nature 516 2014 108 111
79. JM Lee, M Wagner, R Xiao, KH Kim, D Feng, MA Lazar, and DD. Moore Nutrient-sensing nuclear receptors coordinate autophagy Nature 516 2014 112 115
80. S Fu, SM Watkins, and GS. Hotamisligil The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling Cell Metab. 15 2012 623 634
81. NJ Hancer, W Qiu, C Cherella, Y Li, KD Copps, and MF. White Insulin and metabolic stress stimulate multisite serine/threonine phosphorylation of insulin receptor substrate 1 and inhibit tyrosine phosphorylation J. Biol. Chem. 289 2014 12467 12484
82. Y Qi, Z Xu, Q Zhu, C Thomas, R Kumar, H Feng, DE Dostal, MF White, KM Baker, and S. Guo Myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38alpha MAPK during insulin resistance Diabetes 62 2013 3887 3900
83. B Diesel, S Kulhanek-Heinze, M Holtje, B Brandt, HD Holtje, AM Vollmar, and AK. Kiemer Alpha-lipoic acid as a directly binding activator of the insulin receptor: protection from hepatocyte apoptosis Biochemistry 46 2007 2146 2155