Role of mitochondria in nonalcoholic fatty liver disease

International Journal of Molecular Sciences

Volumn 15, Issue 5, 2014, Pages 8713-8742

  Nassir, Fatiha ^a   Ibdah, Jamal A ^a  

^a University of Missouri   (United States)

Author keywords

Fatty acid oxidation; Liver; Mitochondria; NAFLD; NASH; PGC 1 ; Sirtuin 1 (SIRT1); Sirtuin 3 (SIRT3); Steatosis

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ALPHA TOCOPHEROL; BERBERINE; BIGUANIDE; CD36 ANTIGEN; ISOQUINOLINE; METFORMIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; PIOGLITAZONE; RESVERATROL; SIRTUIN; SIRTUIN 1; SIRTUIN 3; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN; FATTY ACID; PPARGC1A PROTEIN, HUMAN; TRANSCRIPTION FACTOR;

DIABETES MELLITUS; DIET; EXERCISE; FATTY ACID OXIDATION; FATTY ACID TRANSPORT; HUMAN; INSULIN RESISTANCE; LIPID METABOLISM; LIPOGENESIS; LIPOLYSIS; LIVER CIRRHOSIS; LIVER FIBROSIS; MITOCHONDRION; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PATHOGENESIS; REVIEW; WEIGHT REDUCTION; CHEMISTRY; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; PATHOLOGY;

FATTY ACIDS; HUMANS; MITOCHONDRIA; NON-ALCOHOLIC FATTY LIVER DISEASE; OXIDATIVE STRESS; SIRTUIN 1; SIRTUIN 3; TRANSCRIPTION FACTORS;

EID: 84900851950     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms15058713     Document Type: Review

References (197)

1. Milic, S.; Stimac, D. Nonalcoholic fatty liver disease/steatohepatitis: Epidemiology, pathogenesis, clinical presentation and treatment. Dig. Dis. (Basel, Switz.) 2012, 30, 158-162.
2. Nassir, F.; Adewole, O.L.; Brunt, E.M.; Abumrad, N.A. CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice. J. Lipid Res. 2013, 54, 2988-2997.
3. Cohen, J.C.; Horton, J.D.; Hobbs, H.H. Human fatty liver disease: Old questions and new insights. Science 2011, 332, 1519-1523.
4. Fabbrini, E.; Sullivan, S.; Klein, S. Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology (Baltim., Md.) 2010, 51, 679-689.
5. Grattagliano, I.; Russmann, S.; Diogo, C.; Bonfrate, L.; Oliveira, P.J.; Wang, D.Q.; Portincasa, P. Mitochondria in chronic liver disease. Curr. Drug Targets 2011, 12, 879-893.
6. Szczepaniak, L.S.; Nurenberg, P.; Leonard, D.; Browning, J.D.; Reingold, J.S.; Grundy, S.; Hobbs, H.H.; Dobbins, R.L. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am. J. Physiol. Endocrinol. Metab. 2005, 288, E462-E468.
7. Scaglioni, F.; Ciccia, S.; Marino, M.; Bedogni, G.; Bellentani, S. ASH and NASH. Dig. Dis. (Basel, Switz.) 2011, 29, 202-210.
8. Chalasani, N.; Younossi, Z.; Lavine, J.E.; Diehl, A.M.; Brunt, E.M.; Cusi, K.; Charlton, M.; Sanyal, A.J. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology (Baltim., Md.) 2012, 55, 2005-2023.
9. Adams, L.A.; Lymp, J.F.; St Sauver J.; Sanderson, S.O.; Lindor, K.D.; Feldstein, A.; Angulo, P. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Gastroenterology 2005, 129, 113-121.
10. Vernon, G.; Baranova, A.; Younossi, Z.M. Systematic review: The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment. Pharmacol. Therap. 2011, 34, 274-285.
11. Tetri, L.H.; Basaranoglu, M.; Brunt, E.M.; Yerian, L.M.; Neuschwander-Tetri, B.A. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 295, G987-G995.
12. Alisi A.; Manco M.; Panera N.; Nobili V. Association between type two diabetes and non-alcoholic fatty liver disease in youth. Ann. Hepatol. 2009, 8 (Suppl. 1), S44-S50.
13. Parikh, R.M.; Mohan, V. Changing definitions of metabolic syndrome. Indian J. Endocrinol. Metab. 2012, 16, 7-12.
14. Rahman, R.; Hammoud, G.M.; Almashhrawi, A.A.; Ahmed, K.T.; Ibdah, J.A. Primary hepatocellular carcinoma and metabolic syndrome: An update. World J. Gastrointest. Oncol. 2013, 5, 186-194.
15. Clark, J.M.; Brancati, F.L.; Diehl, A.M. Nonalcoholic fatty liver disease. Gastroenterology 2002, 122, 1649-1657.
16. Machado, M.; Marques-Vidal, P.; Cortez-Pinto, H. Hepatic histology in obese patients undergoing bariatric surgery. J. Hepatol. 2006, 45, 600-606.
17. Loria, P.; Lonardo, A.; Anania, F. Liver and diabetes: A vicious circle. Hepatol. Res. 2013, 43, 51-64.
18. Takamura, T.; Misu, H.; Ota, T.; Kaneko, S. Fatty liver as a consequence and cause of insulin resistance: Lessons from type 2 diabetic liver. Endocr. J. 2012, 59, 745-763.
19. Younossi, Z.M.; Gramlich, T.; Matteoni, C.A.; Boparai, N.; McCullough, A.J. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin. Gastroenterol. Hepatol. 2004, 2, 262-265.
20. Abdelmalek, M.; Ludwig, J.; Lindor, K.D. Two cases from the spectrum of nonalcoholic steatohepatitis. J. Clin. Gastroenterol. 1995, 20, 127-130.
21. Bacon, B.R.; Farahvash, M.J.; Janney, C.G.; Neuschwander-Tetri, B.A. Nonalcoholic steatohepatitis: An expanded clinical entity. Gastroenterology 1994, 107, 1103-1109.
22. Teli, M.R.; James, O.F.; Burt, A.D.; Bennett, M.K.; Day, C.P. The natural history of nonalcoholic fatty liver: A follow-up study. Hepatology (Baltim., Md.) 1995, 22, 1714-1719.
23. Guerrero, R.; Vega, G.L.; Grundy, S.M.; Browning, J.D. Ethnic differences in hepatic steatosis: An insulin resistance paradox? Hepatology (Baltim., Md.) 2009, 49, 791-801.
24. Lewis, J.R.; Mohanty, S.R. Nonalcoholic fatty liver disease: A review and update. Dig. Dis. Sci. 2010, 55, 560-578.
25. Day, C.P.; James, O.F. Steatohepatitis: A tale of two "hits"? Gastroenterology 1998, 114, 842-845.
26. Tilg, H.; Moschen, A.R. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology (Baltim., Md.) 2010, 52, 1836-1846.
27. Lonardo, A.; Bellentani, S.; Ratziu, V.; Loria, P. Insulin resistance in nonalcoholic steatohepatitis: Necessary but not sufficient-Death of a dogma from analysis of therapeutic studies? Expert Rev. Gastroenterol. Hepatol. 2011, 5, 279-289.
28. Yilmaz, Y. Review article: Is non-alcoholic fatty liver disease a spectrum, or are steatosis and non-alcoholic steatohepatitis distinct conditions? Aliment. Pharmacol. Therap. 2012, 36, 815-823.
29. Amaro, A.; Fabbrini, E.; Kars, M.; Yue, P.; Schechtman, K.; Schonfeld, G.; Klein, S. Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 2010, 139, 149-153.
30. Kantartzis, K.; Machicao, F.; Machann, J.; Schick, F.; Fritsche, A.; Haring, H.U.; Stefan, N. The DGAT2 gene is a candidate for the dissociation between fatty liver and insulin resistance in humans. Clin. Sci. (Lond., Engl.) 2009, 116, 531-537.
31. Kantartzis, K.; Peter, A.; Machicao, F.; Machann, J.; Wagner, S.; Konigsrainer, I.; Konigsrainer, A.; Schick, F.; Fritsche, A.; Haring H. U; et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009, 58, 2616-2623.
32. Stefan, N.; Staiger, H.; Haring, H.U. Dissociation between fatty liver and insulin resistance: The role of adipose triacylglycerol lipase. Diabetologia 2011, 54, 7-9.
33. Brumbaugh, D.E.; Friedman, J.E. Developmental origins of nonalcoholic fatty liver disease. Pediatr. Res. 2014, 75, 140-147.
34. Nestel, P.J.; Havel, R.J.; Bezman, A. Sites of initial removal of chylomicron triglyceride fatty acids from the blood. J. Clin. Investig. 1962, 41, 1915-1921.
35. Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343-1351.
36. Lafontan, M.; Langin, D. Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid Res. 2009, 48, 275-297.
37. Ferre, P.; Foufelle, F. Hepatic steatosis: A role for de novo lipogenesis and the transcription factor SREBP-1c. Diabetes, Obes. Metab. 2010, 12 (Suppl. 2), 83-92.
38. Horton, J.D.; Goldstein, J.L.; Brown, M.S. SREBPs: Transcriptional mediators of lipid homeostasis. Cold Spring Harb. Symp. Quant. Biol. 2002, 67, 491-498.
39. Kazantzis, M.; Stahl, A. Fatty acid transport proteins, implications in physiology and disease. Biochim. Biophys. Acta 2012, 1821, 852-857.
40. Doege, H.; Baillie, R.A.; Ortegon, A.M.; Tsang, B.; Wu, Q.; Punreddy, S.; Hirsch, D.; Watson, N.; Gimeno, R.E.; Stahl, A. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: Alterations in hepatic lipid homeostasis. Gastroenterology 2006, 130, 1245-1258.
41. Doege, H.; Grimm, D.; Falcon, A.; Tsang, B.; Storm, T.A.; Xu, H.; Ortegon, A.M.; Kazantzis, M.; Kay, M.A.; Stahl, A. Silencing of hepatic fatty acid transporter protein 5 in vivo reverses diet-induced non-alcoholic fatty liver disease and improves hyperglycemia. J. Biol. Chem. 2008, 283, 22186-22192.
42. Falcon, A.; Doege, H.; Fluitt, A.; Tsang, B.; Watson, N.; Kay, M.A.; Stahl, A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long-chain acyl-CoA synthetase. Am. J. Physiol. Endocrinol. Metab. 2010, 299, E384-E393.
43. Fernandez, M.A.; Albor, C.; Ingelmo-Torres, M.; Nixon, S.J.; Ferguson, C.; Kurzchalia, T.; Tebar, F.; Enrich, C.; Parton, R.G.; Pol, A. Caveolin-1 is essential for liver regeneration. Science 2006, 313, 1628-1632.
44. Su, X.; Abumrad, N.A. Cellular fatty acid uptake: A pathway under construction. Trends Endocrinol. Metab. 2009, 20, 72-77.
45. Koonen, D.P.Y.; Jacobs, R.L.; Febbraio, M.; Young, M.E.; Soltys, C.-L.M.; Ong, H.; Vance, D.E.; Dyck, J.R.B. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 2007, 56, 2863-2871.
46. Miquilena-Colina, M.E.; Lima-Cabello, E.; Sanchez-Campos, S.; Garcia-Mediavilla, M.V.; Fernandez-Bermejo, M.; Lozano-Rodriguez, T.; Vargas-Castrillon, J.; Buque, X.; Ochoa, B.; Aspichueta P.; et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis, C. Gut 2011, 60, 1394-1402.
47. Zhou, D.; Samovski, D.; Okunade, A.L.; Stahl, P.D.; Abumrad, N.A.; Su, X. CD36 level and trafficking are determinants of lipolysis in adipocytes. FASEB J. 2012, 26, 4733-4742.
48. Fabbrini, E.; Magkos, F.; Mohammed, B.S.; Pietka, T.; Abumrad, N.A.; Patterson, B.W.; Okunade, A.; Klein, S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc. Natl. Acad. Sci. USA 2009, 106, 15430-15435.
49. Stremmel, W.; Pohl, L.; Ring, A.; Herrmann, T. A new concept of cellular uptake and intracellular trafficking of long-chain fatty acids. Lipids 2001, 36, 981-989.
50. Storch, J.; Corsico, B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu. Rev. Nutr. 2008, 28, 73-95.
51. Newberry, E.P.; Xie, Y.; Kennedy, S.; Han, X.; Buhman, K.K.; Luo, J.; Gross, R.W.; Davidson, N.O. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. J. Biol. Chem. 2003, 278, 51664-51672.
52. Wolins, N.E.; Brasaemle, D.L.; Bickel, P.E. A proposed model of fat packaging by exchangeable lipid droplet proteins. FEBS Lett. 2006, 580, 5484-5491.
53. Schonfeld, G. Familial hypobetalipoproteinemia: A review. J. Lipid Res. 2003, 44, 878-883.
54. Sen, D.; Dagdelen, S.; Erbas, T. Hepatosteatosis with hypobetalipoproteinemia. J. Natl. Med. Assoc. 2007, 99, 284-286.
55. Ginsberg, H.N.; Fisher, E.A. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J. Lipid Res. 2009, 50 (Suppl.), S162-S166.
56. Tarugi, P.; Lonardo, A.; Ballarini, G.; Grisendi, A.; Pulvirenti, M.; Bagni, A.; Calandra, S. Fatty liver in heterozygous hypobetalipoproteinemia caused by a novel truncated form of apolipoprotein, B. Gastroenterology 1996, 111, 1125-1133.
57. Welty, F.K. Hypobetalipoproteinemia and abetalipoproteinemia. Curr. Opin. Lipidol. 2014, 25, 161-168.
58. Wolfrum, C.; Stoffel, M. Coactivation of Foxa2 through Pgc-1β promotes liver fatty acid oxidation and triglyceride/VLDL secretion. Cell Metab. 2006, 3, 99-110.
59. Choi, S.H.; Ginsberg, H.N. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol. Metab. 2011, 22, 353-363.
60. Van der Poorten, D.; Samer, C.F.; Ramezani-Moghadam, M.; Coulter, S.; Kacevska, M.; Schrijnders, D.; Wu, L.E.; McLeod, D.; Bugianesi, E.; Komuta M.; et al. Hepatic fat loss in advanced nonalcoholic steatohepatitis: Are alterations in serum adiponectin the cause? Hepatology (Baltim., Md.) 2013, 57, 2180-2188.
61. Begriche, K.; Massart, J.; Robin, M.A.; Bonnet, F.; Fromenty, B. Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease. Hepatology (Baltim., Md.) 2013, 58, 1497-1507.
62. Eaton, S.; Bartlett, K.; Pourfarzam, M. Mammalian mitochondrial β-oxidation. Biochem. J. 1996, 320, 345-357.
63. McGarry, J.D.; Foster, D.W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu. Rev. Biochem. 1980, 49, 395-420.
64. Sidossis, L.S.; Stuart, C.A.; Shulman, G.I.; Lopaschuk, G.D.; Wolfe, R.R. Glucose plus insulin regulate fat oxidation by controlling the rate of fatty acid entry into the mitochondria. J. Clin. Investig. 1996, 98, 2244-2250.
65. Longuet, C.; Sinclair, E.M.; Maida, A.; Baggio, L.L.; Maziarz, M.; Charron, M.J.; Drucker, D.J. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab. 2008, 8, 359-371.
66. Mandard, S.; Muller, M.; Kersten, S. Peroxisome proliferator-activated receptor α target genes. Cell. Mol. Life Sci. 2004, 61, 393-416.
67. Potthoff, M.J.; Inagaki, T.; Satapati, S.; Ding, X.; He, T.; Goetz, R.; Mohammadi, M.; Finck, B.N.; Mangelsdorf, D.J.; Kliewer S.A; et al. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc. Natl. Acad. Sci. USA 2009, 106, 10853-10858.
68. Pellicoro, A.; Ramachandran, P.; Iredale, J.P.; Fallowfield, J.A. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 2014, 14, 181-194.
69. Wang, K. Molecular mechanisms of hepatic apoptosis. Cell Death Dis. 2014, 5, e996.
70. Malaguarnera, M.; di Rosa, M.; Nicoletti, F.; Malaguarnera, L. Molecular mechanisms involved in NAFLD progression. J. Mol. Med. (Berl., Ger.) 2009, 87, 679-695.
71. Musso, G.; Gambino, R.; Cassader, M. Obesity, diabetes, and gut microbiota: The hygiene hypothesis expanded? Diabetes Care 2010, 33, 2277-2284.
72. Calvo, S.E.; Mootha, V.K. The mitochondrial proteome and human disease. Annu. Rev. Genomics Hum. Genet. 2010, 11, 25-44.
73. Pessayre, D.; Mansouri, A.; Fromenty, B. Nonalcoholic steatosis and steatohepatitis. V. Mitochondrial dysfunction in steatohepatitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 282, G193-G199.
74. Boveris, A.; Chance, B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem. J. 1973, 134, 707-716.
75. Begriche, K.; Igoudjil, A.; Pessayre, D.; Fromenty, B. Mitochondrial dysfunction in NASH: Causes, consequences and possible means to prevent it. Mitochondrion 2006, 6, 1-28.
76. Mansouri, A.; Gaou, I.; de Kerguenec, C.; Amsellem, S.; Haouzi, D.; Berson, A.; Moreau, A.; Feldmann, G.; Letteron, P.; Pessayre, D.; et al. An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice. Gastroenterology 1999, 117, 181-190.
77. Caldwell, S.H.; Chang, C.Y.; Nakamoto, R.K.; Krugner-Higby, L. Mitochondria in nonalcoholic fatty liver disease. Clin. Liver Dis. 2004, 8, 595-617.
78. Sanyal, A.J.; Campbell-Sargent, C.; Mirshahi, F.; Rizzo, W.B.; Contos, M.J.; Sterling, R.K.; Luketic, V.A.; Shiffman, M.L.; Clore, J.N. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001, 120, 1183-1192.
79. Lammens, M.; Laak, H. Contribution of histopathological examination to the diagnosis of OXPHOS disorders. In Oxidative Phosphorylation in Health and Disease; Springer: New York, NY, USA, 2005; pp. 53-78.
80. Rolo, A.P.; Teodoro, J.S.; Palmeira, C.M. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radic. Biol. Med. 2012, 52, 59-69.
81. Ibdah, J.A.; Paul, H.; Zhao, Y.; Binford, S.; Salleng, K.; Cline, M.; Matern, D.; Bennett, M.J.; Rinaldo, P.; Strauss, A.W. Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death. J. Clin. Investig. 2001, 107, 1403-1409.
82. Wanders, R.J.; Ijist, L.; Poggi, F.; Bonnefont, J.P.; Munnich, A.; Brivet, M.; Rabier, D.; Saudubray, J.M. Human trifunctional protein deficiency: A new disorder of mitochondrial fatty acid beta-oxidation. Biochem. Biophys. Res. Commun. 1992, 188, 1139-1145.
83. Rector, R.S.; Payne, R.M.; Ibdah, J.A. Mitochondrial trifunctional protein defects: Clinical implications and therapeutic approaches. Adv. Drug Deliv. Rev. 2008, 60, 1488-1496.
84. Ibdah, J.A.; Perlegas, P.; Zhao, Y.; Angdisen, J.; Borgerink, H.; Shadoan, M.K.; Wagner, J.D.; Matern, D.; Rinaldo, P.; Cline, J.M. Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. Gastroenterology 2005, 128, 1381-1390.
85. Rector, R.S.; Morris, E.M.; Ridenhour, S.; Meers, G.M.; Hsu, F.F.; Turk, J.; Ibdah, J.A. Selective hepatic insulin resistance in a murine model heterozygous for a mitochondrial trifunctional protein defect. Hepatology 2013, 57, 2213-2223.
86. Zhou, M.; Xu, A.; Tam, P.K.; Lam, K.S.; Chan, L.; Hoo, R.L.; Liu, J.; Chow, K.H.; Wang, Y. Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury. Hepatology 2008, 48, 1087-1096.
87. Thyfault, J.P.; Rector, R.S.; Uptergrove, G.M.; Borengasser, S.J.; Morris, E.M.; Wei, Y.; Laye, M.J.; Burant, C.F.; Qi, N.R.; Ridenhour, S.E.; et al. Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury. J. Physiol. 2009, 587, 1805-1816.
88. Rector, R.S.; Thyfault, J.P.; Uptergrove, G.M.; Morris, E.M.; Naples, S.P.; Borengasser, S.J.; Mikus, C.R.; Laye, M.J.; Laughlin, M.H.; Booth F.W; et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J. Hepatol. 2010, 52, 727-736.
89. Kawano, K.; Hirashima, T.; Mori, S.; Saitoh, Y.; Kurosumi, M.; Natori, T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka long-evans tokushima fatty (OLETF) strain. Diabetes 1992, 41, 1422-1428.
90. Jeong, S.K.; Kim, Y.K.; Park, J.W.; Shin, Y.J.; Kim, D.S. Impact of visceral fat on the metabolic syndrome and nonalcoholic fatty liver disease. J. Korean Med. Sci. 2008, 23, 789-795.
91. Wang, Y.; Zhou, M.; Lam, K.S.; Xu, A. Protective roles of adiponectin in obesity-related fatty liver diseases: Mechanisms and therapeutic implications. Arq. Bras. Endocrinol. Metabol. 2009, 53, 201-212.
92. Bajaj, M.; Suraamornkul, S.; Piper, P.; Hardies, L.J.; Glass, L.; Cersosimo, E.; Pratipanawatr, T.; Miyazaki, Y.; DeFronzo, R.A. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J. Clin. Endocrinol. Metab. 2004, 89, 200-206.
93. Hui, J.M.; Hodge, A.; Farrell, G.C.; Kench, J.G.; Kriketos, A.; George, J. Beyond insulin resistance in NASH: TNF-α or adiponectin? Hepatology (Baltim., Md.) 2004, 40, 46-54.
94. Jung, U.J.; Choi, M.S. Obesity and its metabolic complications: The role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and nonalcoholic fatty liver disease. Int. J. Mol. Sci. 2014, 15, 6184-6223.
95. Negre-Salvayre, A.; Hirtz, C.; Carrera, G.; Cazenave, R.; Troly, M.; Salvayre, R.; Penicaud, L.; Casteilla, L. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 1997, 11, 809-815.
96. Chow, L.; From, A.; Seaquist, E. Skeletal muscle insulin resistance: The interplay of local lipid excess and mitochondrial dysfunction. Metab. Clin. Exp. 2010, 59, 70-85.
97. Morino, K.; Petersen, K.F.; Dufour, S.; Befroy, D.; Frattini, J.; Shatzkes, N.; Neschen, S.; White, M.F.; Bilz, S.; Sono, S.; et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J. Clin. Investig. 2005, 115, 3587-3593.
98. Petersen, K.F.; Dufour, S.; Befroy, D.; Garcia, R.; Shulman, G.I. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N. Engl. J. Med. 2004, 350, 664-671.
99. Morino, K.; Petersen, K.F.; Sono, S.; Choi, C.S.; Samuel, V.T.; Lin, A.; Gallo, A.; Zhao, H.; Kashiwagi, A.; Goldberg I.J; et al. Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin-resistant offspring of parents with type 2 diabetes. Diabetes 2012, 61, 877-887.
100. Petersen, K.F.; Dufour, S.; Morino, K.; Yoo, P.S.; Cline, G.W.; Shulman, G.I. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proc. Natl. Acad. Sci. USA 2012, 109, 8236-8240.
101. Andersson, U.; Scarpulla, R.C. Pgc-1-related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription in mammalian cells. Mol. Cell. Biol. 2001, 21, 3738-3749.
102. Vercauteren, K.; Gleyzer, N.; Scarpulla, R.C. Short hairpin RNA-mediated silencing of PRC (PGC-1-related coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria. J. Biol. Chem. 2009, 284, 2307-2319.
103. Handschin, C.; Spiegelman, B.M. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 2006, 27, 728-735.
104. Lin, J.; Puigserver, P.; Donovan, J.; Tarr, P.; Spiegelman, B.M. Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β), a novel PGC-1-related transcription coactivator associated with host cell factor. J. Biol. Chem. 2002, 277, 1645-1648.
105. Puigserver, P.; Wu, Z.; Park, C.W.; Graves, R.; Wright, M.; Spiegelman, B.M. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998, 92, 829-839.
106. Lai, L.; Leone, T.C.; Zechner, C.; Schaeffer, P.J.; Kelly, S.M.; Flanagan, D.P.; Medeiros, D.M.; Kovacs, A.; Kelly, D.P. Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart. Genes Dev. 2008, 22, 1948-1961.
107. Lelliott, C.J.; Medina-Gomez, G.; Petrovic, N.; Kis, A.; Feldmann, H.M.; Bjursell, M.; Parker, N.; Curtis, K.; Campbell, M.; Hu, P.; et al. Ablation of PGC-1β results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol. 2006, 4, e369.
108. Leone, T.C.; Lehman, J.J.; Finck, B.N.; Schaeffer, P.J.; Wende, A.R.; Boudina, S.; Courtois, M.; Wozniak, D.F.; Sambandam, N.; Bernal-Mizrachi, C.; et al. PGC-1α deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol. 2005, 3, e101.
109. Sonoda, J.; Mehl, I.R.; Chong, L.W.; Nofsinger, R.R.; Evans, R.M. PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. Proc. Natl. Acad. Sci. USA 2007, 104, 5223-5228.
110. Vianna, C.R.; Huntgeburth, M.; Coppari, R.; Choi, C.S.; Lin, J.; Krauss, S.; Barbatelli, G.; Tzameli, I.; Kim, Y.B.; Cinti, S.; et al. Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance. Cell Metab. 2006, 4, 453-464.
111. Horton, J.D.; Shah, N.A.; Warrington, J.A.; Anderson, N.N.; Park, S.W.; Brown, M.S.; Goldstein, J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA 2003, 100, 12027-12032.
112. Lin, J.; Yang, R.; Tarr, P.T.; Wu, P.-H.; Handschin, C.; Li, S.; Yang, W.; Pei, L.; Uldry, M.; Tontonoz, P.; et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1β coactivation of SREBP. Cell 2005, 120, 261-273.
113. Bellafante, E.; Murzilli, S.; Salvatore, L.; Latorre, D.; Villani, G.; Moschetta, A. Hepatic-specific activation of peroxisome proliferator-activated receptor γ coactivator-1β protects against steatohepatitis. Hepatology (Baltim., Md.) 2013, 57, 1343-1356.
114. Morris, E.M.; Meers, G.M.; Booth, F.W.; Fritsche, K.L.; Hardin, C.D.; Thyfault, J.P.; Ibdah, J.A. PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 303, G979-G992.
115. Laye, M.J.; Rector, R.S.; Borengasser, S.J.; Naples, S.P.; Uptergrove, G.M.; Ibdah, J.A.; Booth, F.W.; Thyfault, J.P. Cessation of daily wheel running differentially alters fat oxidation capacity in liver, muscle, and adipose tissue. J. Appl. Physiol. (Bethesda, Md.) 2009, 106, 161-168.
116. Hirschey, M.D.; Shimazu, T.; Jing, E.; Grueter, C.A.; Collins, A.M.; Aouizerat, B.; Stancakova, A.; Goetzman, E.; Lam, M.M.; Schwer, B.; et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell 2011, 44, 177-190.
117. Puigserver, P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-α. Int. J. Obes. Relat. Metab. Disord. 2005, 29, S5-S9.
118. Wu, Z.; Puigserver, P.; Andersson, U.; Zhang, C.; Adelmant, G.; Mootha, V.; Troy, A.; Cinti, S.; Lowell, B.; Scarpulla, R.C.; et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999, 98, 115-124.
119. Feige, J.N.; Auwerx, J. Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol. 2007, 17, 292-301.
120. Wright, D.C.; Geiger, P.C.; Han, D.H.; Jones, T.E.; Holloszy, J.O. Calcium induces increases in peroxisome proliferator-activated receptor γ coactivator-1α and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation. J. Biol. Chem. 2007, 282, 18793-9.
121. Canto, C.; Gerhart-Hines, Z.; Feige, J.N.; Lagouge, M.; Noriega, L.; Milne, J.C.; Elliott, P.J.; Puigserver, P.; Auwerx, J. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009, 458, 1056-1060.
122. Haigis, M.C.; Guarente, L.P. Mammalian sirtuins-Emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006, 20, 2913-1921.
123. Haigis, M.C.; Sinclair, D.A. Mammalian sirtuins: Biological insights and disease relevance. Annu. Rev. Pathol. 2010, 5, 253-295.
124. Nogueiras, R.; Habegger, K.M.; Chaudhary, N.; Finan, B.; Banks, A.S.; Dietrich, M.O.; Horvath, T.L.; Sinclair, D.A.; Pfluger, P.T.; Tschop, M.H. Sirtuin 1 and sirtuin 3, physiological modulators of metabolism. Physiol. Rev. 2012, 92, 1479-1514.
125. Guarente, L. Calorie restriction and sirtuins revisited. Genes Dev. 2013, 27, 2072-2085.
126. Banks, A.S.; Kon, N.; Knight, C.; Matsumoto, M.; Gutierrez-Juarez, R.; Rossetti, L.; Gu, W.; Accili, D. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008, 8, 333-341.
127. Kitada, M.; Kume, S.; Kanasaki, K.; Takeda-Watanabe, A.; Koya, D. Sirtuins as possible drug targets in type 2 diabetes. Curr. Drug Targets 2013, 14, 622-636.
128. Garcia-Rodriguez, J.L.; Barbier-Torres, L.; Fernandez-Alvarez, S.; Juan, V.G.; Monte, M.J.; Halilbasic, E.; Herranz, D.; Alvarez, L.; Aspichueta, P.; Marin, J.J.; et al. SIRT1 controls liver regeneration by regulating BA metabolism through FXR and mTOR signaling. Hepatology (Baltim., Md.) 2014, 59, 1972-1983.
129. Ruderman, N.B.; Xu, X.J.; Nelson, L.; Cacicedo, J.M.; Saha, A.K.; Lan, F.; Ido, Y. AMPK and SirT1, a long-standing partnership? Am. J. Physiol. Endocrinol. Metab. 2010, 298, E751-E760.
130. Chen, L.L.; Deng, X.Q.; Li, N.X. Effects of calorie restriction on SIRT1 expression in liver of nonalcoholic fatty liver disease: Experiment with rats. Zhonghua Yi Xue Za Zhi 2007, 87, 1434-1437.
131. Deng, X.Q.; Chen, L.L.; Li, N.X. The expression of SirT1 in nonalcoholic fatty liver disease induced by high-fat diet in rats. Liver Int. 2007, 27, 708-715.
132. Colak, Y.; Ozturk, O.; Senates, E.; Tuncer, I.; Yorulmaz, E.; Adali, G.; Doganay, L.; Enc, F.Y. SirT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med. Sci. Monit. 2011, 17, HY5-HY9.
133. Li, Y.; Xu, S.; Giles, A.; Nakamura, K.; Lee, J.W.; Hou, X.; Donmez, G.; Li, J.; Luo, Z.; Walsh, K.; et al. Hepatic overexpression of SirT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J. 2011, 25, 1664-1679.
134. Li, Y.; Wong, K.; Giles, A.; Jiang, J.; Lee, J.W.; Adams, A.C.; Kharitonenkov, A.; Yang, Q.; Gao, B.; Guarente, L.; et al. Hepatic SirT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 2014, 146, 539-549.
135. Purushotham, A.; Schug, T.T.; Xu, Q.; Surapureddi, S.; Guo, X.; Li, X. Hepatocyte-specific deletion of SirT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab. 2009, 9, 327-338.
136. Shin, S.Y.; Kim, T.H.; Wu, H.; Choi, Y.H.; Kim, S.G. SirT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis. Eur. J. Pharmacol. 2014, 727C, 115-124.
137. Lombard, D.B.; Alt, F.W.; Cheng, H.L.; Bunkenborg, J.; Streeper, R.S.; Mostoslavsky, R.; Kim, J.; Yancopoulos, G.; Valenzuela, D.; Murphy, A.; et al. Mammalian SirT2 homolog SirT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 2007, 27, 8807-8814.
138. Hebert, A.S.; Dittenhafer-Reed, K.E.; Yu, W.; Bailey, D.J.; Selen, E.S.; Boersma, M.D.; Carson, J.J.; Tonelli, M.; Balloon, A.J.; Higbee, A.J.; et al. Calorie restriction and SirT3 trigger global reprogramming of the mitochondrial protein acetylome. Mol. Cell 2013, 49, 186-199.
139. Hirschey, M.D.; Shimazu, T.; Goetzman, E.; Jing, E.; Schwer, B.; Lombard, D.B.; Grueter, C.A.; Harris, C.; Biddinger, S.; Ilkayeva, O.R.; et al. SirT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010, 464, 121-125.
140. Shimazu, T.; Hirschey, M.D.; Hua, L.; Dittenhafer-Reed, K.E.; Schwer, B.; Lombard, D.B.; Li, Y.; Bunkenborg, J.; Alt, F.W.; Denu, J.M.; et al. SirT3 deacetylates mitochondrial 3-hydroxy-3- methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010, 12, 654-661.
141. Fujino, T.; Kondo, J.; Ishikawa, M.; Morikawa, K.; Yamamoto, T.T. Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate. J. Biol. Chem. 2001, 276, 11420-11426.
142. Ahn, B.-H.; Kim, H.-S.; Song, S.; Lee, I.H.; Liu, J.; Vassilopoulos, A.; Deng, C.-X.; Finkel, T. A role for the mitochondrial deacetylase SirT3 in regulating energy homeostasis. Proc. Natl. Acad. Sci. USA 2008, 105, 14447-14452.
143. Cimen, H.; Han, M.-J.; Yang, Y.; Tong, Q.; Koc, H.; Koc, E.C. Regulation of succinate dehydrogenase activity by SirT3 in mammalian mitochondria. Biochemistry 2009, 49, 304-311.
144. Finley, L.W.; Haas, W.; Desquiret-Dumas, V.; Wallace, D.C.; Procaccio, V.; Gygi, S.P.; Haigis, M.C. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS One 2011, 6, e23295.
145. Zhang, D.; Liu, Z.X.; Choi, C.S.; Tian, L.; Kibbey, R.; Dong, J.; Cline, G.W.; Wood, P.A.; Shulman, G.I. Mitochondrial dysfunction due to long-chain acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc. Natl. Acad. Sci. USA 2007, 104, 17075-17080.
146. Kurtz, D.M.; Rinaldo, P.; Rhead, W.J.; Tian, L.; Millington, D.S.; Vockley, J.; Hamm, D.A.; Brix, A.E.; Lindsey, J.R.; Pinkert, C.A.; et al. Targeted disruption of mouse long-chain acyl-CoA dehydrogenase gene reveals crucial roles for fatty acid oxidation. Proc. Natl. Acad. Sci. USA 1998, 95, 15592-15597.
147. Qiu, X.; Brown, K.; Hirschey, M.D.; Verdin, E.; Chen, D. Calorie restriction reduces oxidative stress by SirT3-mediated SOD2 activation. Cell Metab. 2010, 12, 662-667.
148. Hirschey, M.D.; Shimazu, T.; Huang, J.Y.; Schwer, B.; Verdin, E. SirT3 regulates mitochondrial protein acetylation and intermediary metabolism. Cold Spring Harb. Symp. Quant. Biol. 2011, 76, 267-277.
149. Petro, A.E.; Cotter, J.; Cooper, D.A.; Peters, J.C.; Surwit, S.J.; Surwit, R.S. Fat, carbohydrate, and calories in the development of diabetes and obesity in the C57BL/6J mouse. Metab. Clin. Exp. 2004, 53, 454-457.
150. Rossmeisl, M.; Rim, J.S.; Koza, R.A.; Kozak, L.P. Variation in type 2 diabetes-Related traits in mouse strains susceptible to diet-induced obesity. Diabetes 2003, 52, 1958-1966.
151. Surwit, R.S.; Feinglos, M.N.; Rodin, J.; Sutherland, A.; Petro, A.E.; Opara, E.C.; Kuhn, C.M.; Rebuffe-Scrive, M. Differential effects of fat and sucrose on the development of obesity and diabetes in C57BL/6J and A/J mice. Metab. Clin. Exp. 1995, 44, 645-651.
152. Kendrick, A.A.; Choudhury, M.; Rahman, S.M.; McCurdy, C.E.; Friederich, M.; van Hove, J.L.; Watson, P.A.; Birdsey, N.; Bao, J.; Gius, D.; et al. Fatty liver is associated with reduced SirT3 activity and mitochondrial protein hyperacetylation. Biochem. J. 2011, 433, 505-514.
153. Crunkhorn, S.; Dearie, F.; Mantzoros, C.; Gami, H.; da Silva, W.S.; Espinoza, D.; Faucette, R.; Barry, K.; Bianco, A.C.; Patti, M.E. Peroxisome proliferator activator receptor gamma coactivator-1 expression is reduced in obesity: Potential pathogenic role of saturated fatty acids and p38 mitogen-activated protein kinase activation. J. Biol. Chem. 2007, 282, 15439-15450.
154. Ji, H.; Friedman, M.I. Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity. Metab. Clin. Exp. 2007, 56, 1124-1130.
155. Jing, E.; Emanuelli, B.; Hirschey, M.D.; Boucher, J.; Lee, K.Y.; Lombard, D.; Verdin, E.M.; Kahn, C.R. Sirtuin-3 (SirT3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc. Natl. Acad. Sci. USA 2011, 108, 14608-14613.
156. Bao, J.; Scott, I.; Lu, Z.; Pang, L.; Dimond, C.C.; Gius, D.; Sack, M.N. SirT3 is regulated by nutrient excess and modulates hepatic susceptibility to lipotoxicity. Free Radic. Biol. Med. 2010, 49, 1230-1237.
157. Mailloux, R.J.; Beriault, R.; Lemire, J.; Singh, R.; Chenier, D.R.; Hamel, R.D.; Appanna, V.D. The tricarboxylic acid cycle, an ancient metabolic network with a novel twist. PLoS One 2007, 2, e690.
158. Someya, S.; Yu, W.; Hallows, W.C.; Xu, J.; Vann, J.M.; Leeuwenburgh, C.; Tanokura, M.; Denu, J.M.; Prolla, T.A. SirT3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell 2010, 143, 802-812.
159. Yu, H.S.; Oyama, T.; Isse, T.; Kitagawa, K.; Pham, T.T.; Tanaka, M.; Kawamoto, T. Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chem. Biol. Interact. 2010, 188, 367-375.
160. Spitz, D.R.; Oberley, L.W. An assay for superoxide dismutase activity in mammalian tissue homogenates. Anal. Biochem. 1989, 179, 8-18.
161. Tao, R.; Coleman, M.C.; Pennington, J.D.; Ozden, O.; Park, S.-H.; Jiang, H.; Kim, H.-S.; Flynn, C.R.; Hill, S.; Hayes McDonald, W.; et al. SirT3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress. Mol. Cell 2010, 40, 893-904.
162. He, J.; Hu, B.; Shi, X.; Weidert, E.R.; Lu, P.; Xu, M.; Huang, M.; Kelley, E.E.; Xie, W. Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase SirT 3. Mol. Cell. Biol. 2013, 33, 2047-2055.
163. Amir, M.; Czaja, M.J. Autophagy in nonalcoholic steatohepatitis. Expert Rev. Gastroenterol. Hepatol. 2011, 5, 159-166.
164. Singh, R.; Kaushik, S.; Wang, Y.; Xiang, Y.; Novak, I.; Komatsu, M.; Tanaka, K.; Cuervo, A.M.; Czaja, M.J. Autophagy regulates lipid metabolism. Nature 2009, 458, 1131-1135.
165. 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. 2010, 11, 467-478.
166. Scarpulla, R.C.; Vega, R.B.; Kelly, D.P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 2012, 23, 459-466.
167. Aatsinki, S.M.; Buler, M.; Salomaki, H.; Koulu, M.; Pavek, P.; Hakkola, J. Metformin induces PGC-1α expression and selectively affects hepatic PGC-1α functions. Br. J. Pharmacol. 2014, 171, 2351-2363.
168. Srivastava, S.; Diaz, F.; Iommarini, L.; Aure, K.; Lombes, A.; Moraes, C.T. PGC-1α/β induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Hum. Mol. Genet. 2009, 18, 1805-1812.
169. Kong, X.; Wang, R.; Xue, Y.; Liu, X.; Zhang, H.; Chen, Y.; Fang, F.; Chang, Y. Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis. PLoS One 2010, 5, e11707.
170. St-Pierre, J.; Drori, S.; Uldry, M.; Silvaggi, J.M.; Rhee, J.; Jager, S.; Handschin, C.; Zheng, K.; Lin, J.; Yang, W.; et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 2006, 127, 397-408.
171. Giralt, A.; Hondares, E.; Villena, J.A.; Ribas, F.; Díaz-Delfín, J.; Giralt, M.; Iglesias, R.; Villarroya, F. Peroxisome proliferator-activated receptor-γ coactivator-1α controls transcription of the SirT3 Gene, an essential component of the thermogenic brown adipocyte phenotype. J. Biol. Chem. 2011, 286, 16958-16966.
172. Kubli, D.A.; Gustafsson, Å.B. Mitochondria and mitophagy: The yin and yang of cell death control. Circ. Res. 2012, 111, 1208-1221.
173. Babbar, M.; Sheikh, M.S. Metabolic stress and disorders related to alterations in mitochondrial fission or fusion. Mol. Cell. Pharmacol. 2013, 5, 109-133.
174. Palikaras, K.; Tavernarakis, N. Mitochondrial homeostasis: The interplay between mitophagy and mitochondrial biogenesis. Exp. Gerontol. 2014, doi.10.1016/j.exger.2014.01.021.
175. Van der Bliek, A.M.; Shen, Q.; Kawajiri, S. Mechanisms of mitochondrial fission and fusion. Cold Spring Harb. Perspect. Biol. 2013, doi:10.1101/cshperspect.a011072.
176. Geisler, S.; Holmstrom, K.M.; Treis, A.; Skujat, D.; Weber, S.S.; Fiesel, F.C.; Kahle, P.J.; Springer, W. The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations. Autophagy 2010, 6, 871-878.
177. Geisler, S.; Holmstrom, K.M.; Skujat, D.; Fiesel, F.C.; Rothfuss, O.C.; Kahle, P.J.; Springer, W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM 1. Nat. Cell Biol. 2010, 12, 119-131.
178. Jin, S.M.; Youle, R.J. PINK1- and Parkin-mediated mitophagy at a glance. J. Cell Sci. 2012, 125, 795-799.
179. Chan, N.C.; Salazar, A.M.; Pham, A.H.; Sweredoski, M.J.; Kolawa, N.J.; Graham, R.L.J.; Hess, S.; Chan, D.C. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 2011, 20, 1726-1737.
180. Poole, A.C.; Thomas, R.E.; Yu, S.; Vincow, E.S.; Pallanck, L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/Parkin pathway. PLoS One 2010, 5, e10054.
181. Gegg, M.E.; Cooper, J.M.; Chau, K.-Y.; Rojo, M.; Schapira, A.H.V.; Taanman, J.-W. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/Parkin-dependent manner upon induction of mitophagy. Hum. Mol. Genet. 2010, 19, 4861-4870.
182. Bhat, G.; Baba, C.S.; Pandey, A.; Kumari, N.; Choudhuri, G. Life style modification improves insulin resistance and liver histology in patients with non-alcoholic fatty liver disease. World J. Hepatol. 2012, 4, 209-217.
183. Browning, J.D.; Baker, J.A.; Rogers, T.; Davis, J.; Satapati, S.; Burgess, S.C. Short-term weight loss and hepatic triglyceride reduction: Evidence of a metabolic advantage with dietary carbohydrate restriction. Am. J. Clin. Nutr. 2011, 93, 1048-1052.
184. Elias, M.C.; Parise, E.R.; de Carvalho, L.; Szejnfeld, D.; Netto, J.P. Effect of 6-month nutritional intervention on non-alcoholic fatty liver disease. Nutrition 2010, 26, 1094-1099.
185. Goncalves, I.O.; Oliveira, P.J.; Ascensao, A.; Magalhaes, J. Exercise as a therapeutic tool to prevent mitochondrial degeneration in nonalcoholic steatohepatitis. Eur. J. Clin. Investig. 2013, 43, 1184-1194.
186. Goncalves, I.O.; Passos, E.; Rocha-Rodrigues, S.; Diogo, C.V.; Torrella, J.R.; Rizo, D.; Viscor, G.; Santos-Alves, E.; Marques-Aleixo, I.; Oliveira, P.J.; et al. Physical exercise prevents and mitigates non-alcoholic steatohepatitis-induced liver mitochondrial structural and bioenergetics impairments. Mitochondrion 2014, 15, 40-51.
187. Haus, J.M.; Solomon, T.P.; Kelly, K.R.; Fealy, C.E.; Kullman, E.L.; Scelsi, A.R.; Lu, L.; Pagadala, M.R.; McCullough, A.J.; Flask, C.A.; et al. Improved hepatic lipid composition following short-term exercise in nonalcoholic fatty liver disease. J. Clin. Endocrinol. Metab. 2013, 98, E1181-E1188.
188. He, Y.; Zhang, H.; Fu, F. The effects of swimming exercise on high-fat-diet-induced steatohepatitis. J. Sports Med. Phys. Fit. 2008, 48, 259-265.
189. Larson-Meyer, D.E.; Newcomer, B.R.; Heilbronn, L.K.; Volaufova, J.; Smith, S.R.; Alfonso, A.J.; Lefevre, M.; Rood, J.C.; Williamson, D.A.; Ravussin, E.; et al. Effect of 6-month calorie restriction and exercise on serum and liver lipids and markers of liver function. Obesity (Silver Spring, Md.) 2008, 16, 1355-1362.
190. Rector, R.S.; Thyfault, J.P.; Morris, R.T.; Laye, M.J.; Borengasser, S.J.; Booth, F.W.; Ibdah, J.A. Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in otsuka long-evans tokushima Fatty rats. Am. J. Physiol. Gastrointest. Liver Physiol. 2008, 294, G619-G626.
191. Pacana, T.; Sanyal, A.J. Vitamin E and nonalcoholic fatty liver disease. Curr. Opin. Clin. Nutr. Metab. Care 2012, 15, 641-648.
192. Linden, M.A.; Fletcher, J.A.; Morris, E.M.; Meers, G.M.; Kearney, M.L.; Crissey, J.M.; Laughlin, M.H.; Booth, F.W.; Sowers, J.R.; Ibdah, J.A.; et al. Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats. Am. J. Physiol. Endocrinol. Metab. 2014, 306, E300-E310.
193. Chachay, V.S.; Macdonald, G.A.; Martin, J.H.; Whitehead, J.P.; O'Moore-Sullivan, T.M.; Lee, P.; Franklin, M.; Klein, K.; Taylor, P.J.; Ferguson, M.; et al. Resveratrol does not benefit patients with non-alcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 2014, doi:10.1016/j.cgh. 2014.02.024.
194. Poulsen, M.M.; Larsen, J.O.; Hamilton-Dutoit, S.; Clasen, B.F.; Jessen, N.; Paulsen, S.K.; Kjaer, T.N.; Richelsen, B.; Pedersen, S.B. Resveratrol up-regulates hepatic uncoupling protein 2 and prevents development of nonalcoholic fatty liver disease in rats fed a high-fat diet. Nutr. Res. 2012, 32, 701-708.
195. Poulsen, M.M.; Vestergaard, P.F.; Clasen, B.F.; Radko, Y.; Christensen, L.P.; Stodkilde-Jorgensen, H.; Moller, N.; Jessen, N.; Pedersen, S.B.; Jorgensen, J.O. High-dose resveratrol supplementation in obese men: An investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes 2013, 62, 1186-1195.
196. Timmers, S.; Konings, E.; Bilet, L.; Houtkooper, R.H.; van de Weijer, T.; Goossens, G.H.; Hoeks, J.; van der Krieken, S.; Ryu, D.; Kersten, S.; et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab. 2011, 14, 612-622.
197. Teodoro, J.S.; Duarte, F.V.; Gomes, A.P.; Varela, A.T.; Peixoto, F.M.; Rolo, A.P.; Palmeira, C.M. Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: A possible role for SirT3 activation. Mitochondrion 2013, 13, 637-646.