References

1. Younossi, Z.M.; Koenig, A.B.; Abdelatif, D.; Fazel, Y.; Henry, L.; Wymer, M. Global Epidemiology of Nonalcoholic Fatty Liver Disease-Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes. Hepatology 2016, 64, 73–84.
2. Lindenmeyer, C.C.; McCullough, A.J. The Natural History of Nonalcoholic Fatty Liver Disease—An Evolving View. Clin. Liver. Dis. 2018, 22, 11–21.
3. Zhu, J.Z.; Hollis-Hansen, K.; Wan, X.Y.; Fei, S.J.; Pang, X.L.; Meng, F.D.; Yu, C.H.; Li, Y.M. Clinical Guidelines of Non-Alcoholic Fatty Liver Disease: A Systematic Review. World J. Gastroenterol. 2016, 22, 8226–8233.
4. Saverymuttu, S.H.; Joseph, A.E.; Maxwell, J.D. Ultrasound Scanning in the Detection of Hepatic Fibrosis and Steatosis. Br. Med. J. Clin. Res. 1986, 292, 13–15.
5. Thomas, E.L.; Hamilton, G.; Patel, N.; O’Dwyer, R.; Dore, C.J.; Goldin, R.D.; Bell, J.D.; Taylor-Robinson, S.D. Hepatic Triglyceride Content and Its Relation to Body Adiposity: A Magnetic Resonance Imaging and Proton Magnetic Resonance Spectroscopy Study. Gut 2005, 54, 122–127.
6. Tang, A.; Desai, A.; Hamilton, G.; Wolfson, T.; Gamst, A.; Lam, J.; Clark, L.; Hooker, J.; Chavez, T.; Ang, B.D.; et al. Accuracy of MR Imaging Estimated Proton Density Fat Fraction for Classification of Dichotomized Histologic Steatosis Grades in Nonalcoholic Fatty Liver Disease. Radiology 2015, 274, 416–425.
7. Yoshio, S.; Atsushi, N.; Yoshito, I. Limitations of Liver Biopsy and Non-Invasive Diagnostic Tests for the Diagnosis of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. World J. Gastroenterol. 2014, 20, 475–485.
8. Brunt, E.M.; Janney, C.G.; Di Bisceglie, A.M.; Neuschwander-Tetri, B.A.; Bacon, B.R. Nonalcoholic Steatohepatitis: A Proposal for Grading and Staging the Histological Lesions. Am. J. Gastroenterol. 1999, 94, 2467–2474.
9. Neuman, M.G.; Malnick, S.; Maor, Y.; Nanau, R.M.; Melzer, E.; Ferenci, P.; Seitz, H.K.; Mueller, S.; Mell, H.; Samuel, D.; et al. Alcoholic Liver Disease: Clinical and Translational Research. Exp. Mol. Pathol. 2015, 99, 596–610.
10. Park, S.H.; Jeon, W.K.; Kim, S.H.; Kim, H.J.; Park, D.I.; Cho, Y.K.; Sung, I.K.; Sohn, C.I.; Keum, D.K.; Kim, B.I. Prevalence and Risk Factors of Non-Alcoholic Fatty Liver Disease among Korean Adults. J. Gastroenterol. Hepatol. 2006, 21, 138–143.
11. Anstee, Q.M.; Targher, G.; Day, C.P. Nat Rev Progression of NAFLD to Diabetes Mellitus, Cardiovascular Disease or Cirrhosis. Gastroenterol. Hepatol. 2013, 10, 330–344.
12. Yan-Ci, Z.; Guo-Jun, Z.; Ze, C.; Zhi-Gang, S.; Jingjing, C.; Hongliang, L. Nonalcoholic Fatty Liver Disease An Emerging Driver of Hypertension. Hypertension 2020, 75, 275–284.
13. Catena, C.; Bernardi, S.; Sabato, N.; Grillo, A.; Ermani, M.; Sechi, L.A.; Fabris, B.; Carretta, R.; Fallo, F. Ambulatory Arterial Stiffness Indices and Nonalcoholic Fatty Liver Disease in Essential Hypertension. Nutr. Metab. Cardiovasc. Dis. 2012, 23, 389–393.
14. Lin, Y.C.; Lo, H.M.; Chen, J.D. Sonographic Fatty Liver, Overweight and Ischemic Heart Disease. World J. Gastroenterol. 2005, 11, 4838.
15. Schindhelm, R.K.; Dekker, J.M.; Nijpels, G.; Bouter, L.M.; Stehouwer, C.D.A.; Heine, R.J.; Diamant, M. Alanine Aminotransferase Predicts Coronary Heart Disease Events: A 10-Year Follow-up of the Hoorn Study. Atherosclerosis 2007, 191, 391–396.
16. Sinn, D.H.; Gwak, G.Y.; Park, H.N.; Kim, J.E.; Min, Y.W.; Kim, K.M.; Kim, Y.J.; Choi, M.S.; Lee, J.H.; Koh, K.C.; et al. Ultrasonographically Detected Non-Alcoholic Fatty Liver Disease Is an Independent Predictor for Identifying Patients with Insulin Resistance in Non-Obese, Non-Diabetic Middle-Aged Asian Adults. Am. J. Gastroenterol. 2012, 107, 561–567.
17. Musso, G.; Gambino, R.; Bo, S.; Uberti, S.; Biroli, G.; Pagano, G.; Cassader, M. Should Nonalcoholic Fatty Liver Disease Be Included in the Definition of Metabolic Syndrome? A Cross-Sectional Comparison with Adult Treatment Panel III Criteria in Nonobese Nondiabetic Subjects. Diabetes Care 2008, 31, 562–568.
18. Haukeland, J.W.; Damås, J.K.; Konopski, Z.; Løberg, E.M.; Haaland, T.; Goverud, I.; Torjesen, P.A.; Birkeland, K.; Bjøro, K.; Aukrust, P. Systemic Inflammation in Nonalcoholic Fatty Liver Disease Is Characterized by Elevated Levels of CCL2. J. Hepatol. 2006, 44, 1167–1174.
19. Stumpf, C.; Auer, C.; Yilmaz, A.; Lewczuk, P.; Klinghammer, L.; Schneider, M.; Daniel, W.G.; Schmieder, R.E.; Garlichs, C.D. Serum Levels of the Th1 Chemoattractant Interferon-γ-inducible Protein (IP) 10 Are Elevated in Patients with Essential Hypertension. Hypertens. Res. 2011, 34, 484–488.
20. Bai, L.; Li, H.I. Immune Regulatory Networks in Hepatic Lipid Metabolism. J. Mol. Med. Berl. 2019, 97, 593–604.
21. Meex, R.C.R.; Watt, M.J. Hepatokines: Linking Nonalcoholic Fatty Liver Disease and Insulin Resistance. Nat. Rev. Endocrinol. 2017, 13, 509.
22. Nunes, K.P.; de Oliveira, A.A.; Mowry, F.E.; Biancardi, V.C. Targeting Toll-like Receptor 4 Signalling Pathways: Can Therapeutics Pay the Toll for Hypertension? Br. J. Pharmacol. 2019, 176, 1864–1879.
23. Sinn, D.H.; Kang, D.; Jang, H.R.; Gu, S.; Cho, S.J.; Paik, S.W.; Ryu, S.; Chang, Y.; Lazo, M.; Guallar, E.; et al. Development of Chronic Kidney Disease in Patients with Non-Alcoholic Fatty Liver Disease: A Cohort Study. J. Hepatol. 2017, 67, 1274–1280.
24. Artunc, F.; Schleicher, E.; Weigert, C.; Fritsche, A.; Stefan, N.; Häring, H.U. The Impact of Insulin Resistance on the Kidney and Vasculature. Nat. Rev. Nephrol. 2016, 12, 721–737.
25. Watt, M.J.; Miotto, P.M.; De Nardo, W.; Montgomery, M.K. The Liver as an Endocrine Organ—Linking NAFLD and Insulin Resistance. Endocr. Rev. 2019, 40, 1367–1393.
26. Landsberg, L.; Young, J.B. Insulin Mediated Glucose Metabolism in the Relationship between Dietary Intake and Sympathetic Nervous System Activity. Int. J. Obes. 1985, 9, 63–68.
27. Jiao, N.; Baker, S.S.; Chapa-Rodriguez, A.; Liu, W.; Nugent, C.A.; Tsompana, M.; Mastrandrea, L.; Buck, M.J.; Baker, R.D.; Genco, R.J.; et al. Suppressed Hepatic Bile Acid Signalling despite Elevated Production of Primary and Secondary Bile Acids in NAFLD. Gut 2018, 67, 1881–1891.
28. Kasumov, T.; Edmison, J.M.; Dasarathy, S.; Bennett, C.; Lopez, R.; Kalhan, S.C. Plasma levels of asymmetric dimethylarginine (ADMA) in patients with biopsy-proven non-alcoholic fatty liver disease. Metabolism 2011, 60, 776–781.
29. Serg, M.; Kampus, P.; Kals, J.; Zagura, M.; Muda, P.; Tuomainen, T.P.; Zilmer, K.; Salum, E.; Zilmer, M.; Eha, J. Association between Asymmetric Dimethylarginine and Indices of Vascular Function in Patients with Essential Hypertension. Blood Press 2011, 20, 111–116.
30. Sydow, K.; Mondon, C.E.; Cooke, J.P. Insulin Resistance: Potential Role of the Endogenous Nitric Oxide Synthase Inhibitor ADMA. Vasc. Med. 2005, 10 (Suppl. 1), S35–S43.
31. Abbasi, F.; Asagmi, T.; Cooke, J.P.; Lamendola, C.; McLaughlin, T.; Reaven, G.M.; Stuehlinger, M.; Tsao, P.S. Plasma Concentrations of Asymmetric Dimethylarginine Are Increased in Patients with Type 2 Diabetes Mellitus. Am. J. Cardiol. 2001, 88, 1201–1203.
32. Villela-Nogueira, C.A.; Leite, N.C.; Cardoso, C.R.L.; Salles, G.F. NAFLD and Increased Aortic Stiffness: Parallel or Common Physiopathological Mechanisms? World J. Gastroenterol. 2014, 14, 8377–8392.
33. Johnson, C.P.; Baugh, R.; Wilson, C.A.; Burns, J. Age Related Changes in the Tunica Media of the Vertebral Artery: Implications for the Assessment of Vessels Injured by Trauma. J. Clin. Pathol. 2001, 54, 139–145.
34. Nickenig, G.; Roling, J.; Strehlow, K.; Schnabel, P.; Bohm, M. Insulin Induces Upregulation of Vascular AT1 Receptor Gene Expression by Posttranscriptional Mechanisms. Circulation 1998, 8, 2453–2460.
35. Jesmin, S.; Sakuma, I.; Salah-Eldin, A.; Nonomura, K.; Hattori, Y.; Kitabatake, A. Diminished Penile Expression of Vascular Endothelial Growth Factor and Its Receptors at the Insulin-Resistant Stage of a Type II Diabetic Rat Model: A Possible Cause for Erectile Dysfunction in Diabetes. J. Mol. Endocrinol. 2003, 31, 401–418.
36. Rizzoni, D.; Porteri, E.; Guelfi, D.; Muiesan, M.L.; Valentini, U.; Cimino, A.; Girelli, A.; Rodella, L.; Bianchi, R.; Sleiman, I.; et al. Structural Alterations in Subcutaneous Small Arteries of Normotensive and Hypertensive Patients with Non-Insulin-Dependent Diabetes Mellitus. Circulation 2001, 103, 1238–1244.
37. Vlachopoulos, C.; Manesis, E.; Baou, K.; Papatheodoridis, G.; Koskinas, J.; Tiniakos, D.; Aznaouridis, K.; Archimandritis, A.; Stefanadis, C. Increased Arterial Stiffness and Impaired Endothelial Function in Nonalcoholic Fatty Liver Disease: A Pilot Study. Am. J. Hypertens. 2010, 23, 1183–1189.
38. Kim, B.J.; Kim, N.H.; Kim, B.S.; Kang, J.H. The Association between Nonalcoholic Fatty Liver Disease, Metabolic Syndrome and Arterial Stiffness in Nondiabetic, Nonhypertensive Individuals. Cardiology 2012, 123, 54–61.
39. Huang, Y.; Bi, Y.; Xu, M.; Ma, Z.; Xu, Y.; Wang, T.; Li, M.; Liu, Y.; Lu, J.; Chen, Y.; et al. Nonalcoholic Fatty Liver Disease Is Associated with Atherosclerosis in Middle-Aged and Elderly Chinese. Arter. Thromb. Vasc. Biol. 2012, 32, 2321–2326.
40. Lee, Y.J.; Shim, J.Y.; Moon, B.S.; Shin, Y.H.; Jung, D.H.; Lee, J.H.; Lee, H.R. The Relationship between Arterial Stiffness and Nonalcoholic Fatty Liver Disease. Dig. Sci. 2012, 57, 196–203.
41. Ozturk, A.K.; Uygun, A.A.; Guler, B.A.K.; Demirci, A.H.; Ozdemir, C.C.; Cakir, B.M.; Sakin, A.Y.S.; Turker, D.T.; Sari, E.S.; Demirbas, B.S.; et al. Nonalcoholic Fatty Liver Disease Is an Independent Risk Factor for Atherosclerosis in Young Adult Men. Atherosclerosis 2015, 240, 380–386.
42. Jain, S.; Khera, R.; Corrales-Medina, V.F.; Townsend, R.R.; Chirinos, J.A. Inflammation and Arterial Stiffness in Humans. Atherosclerosis 2014, 237, 381–390.
43. Farzanegi, P.; Amir, D.; Ebrahimpoor, Z.; Mahdieh, A.; Azarbayjani, M.A. Mechanisms of Beneficial Effects of Exercise Training on Non-Alcoholic Fatty Liver Disease (NAFLD): Roles of Oxidative Stress and Inflammation. Eur. J. Sport Sci. 2019, 19, 994–1003.
44. Colagar, A.H.; Marzony, E.T. Ascorbic Acid in Human Seminal Plasma: Determination and Its Relationship to Sperm Quality. J. Clin. Biochem. Nutr. 2009, 45, 144–149.
45. Yu, Y.; Cai, J.; She, Z.; Li, H. Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases. Adv. Sci. Weinh. 2019, 6, 1801585.
46. Distrutti, E.; Mencarelli, A.; Santucci, L.; Renga, B.; Orlandi, S.; Donini, A.; Shah, V.; Fiorucci, S. The Methionine Connection: Homocysteine and Hydrogen Sulfide Exert Opposite Effects on Hepatic Microcirculation in Rats. Hepatology 2008, 47, 659–667.
47. Polimeni, L.; Del Ben, M.; Baratta, F.; Perri, L.; Albanese, F.; Pastori, D.; Violi, F.; Angelico, F. Oxidative Stress: New Insights on the Association of Non-Alcoholic Fatty Liver Disease and Atherosclerosis. World J. Hepatol. 2015, 7, 1325–1336.
48. Wang, Y.; Chen, S.; Yao, T.; Li, D.; Wang, Y.; Li, Y.; Wu, S.; Cai, J. Homocysteine; as a Risk Factor for Hypertension: A 2-Year Follow-up Study. PLoS ONE 2014, 9, e108223.
49. Björkholm, B.; Bok, C.M.; Lundin, A.; Rafter, J.; Hibberd, M.L.; Pettersson, S. Intestinal Microbiota Regulate Xenobiotic Metabolism in the Liver. PLoS ONE 2009, 4, e6958.
50. Safari, Z.; Gérard, P. The Links between the Gut Microbiome and Non Alcoholic Fatty Liver Disease (NAFLD). Cell. Mol. Life Sci. 2019, 76, 1541–1558.
51. Marques, F.Z.; Mackay, C.R.; Kaye, D.M. Beyond Gut Feelings; How the Gut Microbiota Regulates Blood Pressure. Nat. Rev. Cardiol. 2018, 15, 20–32.
52. Del Campo, J.A.; Gallego-Durán, R.; Gallego, P.; Grande, L. Genetic and Epigenetic Regulation in Nonalcoholic Fatty Liver Disease (NAFLD). Int. J. Mol. Sci. 2018, 19, 911.
53. Fan, W.; Qu, X.; Li, J.; Wang, X.; Bai, Y.; Cao, Q.; Ma, L.; Zhou, X.; Zhu, A.W.; Liu, B.W.; et al. Associations between Polymorphisms of the ADIPOQ Gene and Hypertension Risk: A Systematic and Meta-Analysis. Sci. Rep. 2017, 7, 41683.
54. Zhu, W.; Cheng, K.K.; Vanhoutte, P.M.; Lam, K.S.; Xu, A. Vascular Effects of Adiponectin: Molecular Mechanisms and Potential Therapeutic Intervention. Clin. Sci. 2008, 114, 361–374.
55. Musso, G.; Saba, F.; Cassader, M.; Paschetta, E.; De Michieli, F.; Pinach, S.; Framarin, L.; Berrutti, M.; Leone, N.; Parente, R.; et al. Angiotensin II Type 1 Receptor Rs5186 Gene Variant Predicts Incident NAFLD and Associated Hypertension: Role of Dietary Fat-Induced pro-Inflammatory Cell Activation. Am. J. Gastroenterol. 2019, 114, 607–619.
56. Srivastava, R.A.K. Life-Style-Induced Metabolic Derangement and Epigenetic Changes Promote Diabetes and Oxidative Stress Leading to NASH and Atherosclerosis Severity. J. Diabetes Metab. Disord. 2018, 17, 381–391.
57. Costantino, S.; Mohammed, S.A.; Ambrosini, S.; Paneni, F. Epigenetic Processing in Cardiometabolic Disease. Atherosclerosis 2019, 281, 150–158.
58. Bungau, S.; Behl, T.; Tit, D.M.; Banica, F.; Bratu, O.G.; Diaconu, C.C.; Nistor-Cseppento, C.D.; Bustea, C.; Aron, R.A.C.; Vesa, C.M. Interactions between Leptin and Insulin Resistance in Patients with Prediabetes, with and without NAFLD. Exp. Ther. Med. 2020, 20, 197.
59. Gheorghe, G.; Bungau, S.; Ceobanu, G.; Ilie, M.; Bacalbasa, N.; Bratu, O.G.; Vesa, C.M.; Gaman, M.A.; Diaconu, C.C. The Non-Invasive Assessment of Hepatic Fibrosis. J. Formos. Med. Assoc. 2021, 120, 794–803.
60. Ampuero, J.; Gallego-Durán, R.; Romero-Gómez, M. Association of NAFLD with Subclinical Atherosclerosis and Coronary-Artery Disease: Meta-Analysis. J. Rev. Esp. Enferm. Dig. 2015, 107, 10–16.
61. Yoosoo, C.; Seungho, R.; Ki-Chul, S.; Yong, K.C.; Eunju, S.; Han-Na, K.; Hyun-Suk, J.; Kyung, E.Y.; Jiin, A.; Hocheol, S.; et al. Alcoholic and Non-Alcoholic Fatty Liver Disease and Associations with Coronary Artery Calcification (CAC): Evidence from the Kangbuk Samsung Health Study. Gut 2019, 68, 1667–1675.
62. Treeprasertsuk, S.; Lopez-Jimenez, F.; Lindor, K.D. Nonalcoholic Fatty Liver Disease and the Coronary Artery Disease. Dig. Sci. 2011, 56, 35–45.
63. Kotronen, A.; Juurinen, L.; Tiikkainen, M.; Vehkavaara, S.; Järvinen Hannele, Y. Increased Liver Fat, Impaired Insulin Clearance, and Hepatic and Adipose Tissue Insulin Resistance in Type 2 Diabetes. Gastroenterology 2008, 135, 122–130.
64. Tarantino, G.; Caputi, A. JNKs, Insulin Resistance and Inflammation: A Possible Link between NAFLD and Coronary Artery Disease. World J. Gastroenterol. 2011, 17, 3785–3794.
65. Ebato, C.; Uchida, T.; Arakawa, M.; Komatsu, M.; Ueno, T.; Komiya, K.; Azuma, K.; Hirose, T.; Tanaka, K.; Kominami, E.; et al. Autophagy Is Important in Islet Homeostasis and Compensatory Increase of b Cell Mass in Response to High-Fat Diet. Cell. Metab. 2008, 8, 325–332.
66. Weickert, M.O. Signalling Mechanisms Linking Hepatic Glucose and Lipid Metabolism. Pfeiffer. AF Diabetol. 2006, 49, 1732–1741.
67. Nguyen, M.T.; Satoh, H.; Favelyukis, S.; Babendure, J.L.; Imamura, T.; Sbodio, J.I.; Zalevsky, J.; Dahiyat, B.I.; Chi, N.W.; Olefsky, J.M. JNK and Tumor Necrosis Factor-Alpha Mediate Free Fatty Acid-Induced Insulin Resistance in 3T3-L1 Adipocytes. J. Biol. Chem. 2005, 280, 35361–35371.
68. Yilmaz, Y.; Kurt, R.; Gurdal, A.; Alahdaba, Y.O.; Yonal, O.; Senates, E.; Polat, N.; Erend, F.; Imeryuz, N.; Oflaz, H. Circulating Vaspin Levels and Epicardial Adipose Tissue Thickness Are Associated with Impaired Coronary Flow Reserve in Patients with Nonalcoholic Fatty Liver Disease. Atherosclerosis 2011, 217, 125–129.
69. Crespo, J.; Cayon, A.; Fernandez-Gil, P.; Hernandez-Guerra, M.; Mayorga, M.; Dominguez-Diez, A.; Fernandez -Escalante, J.C.; Pons-Romero, F. Gene Expression of Tumor Necrosis Factor and TNF-Receptors, P55 and P75, in Nonalcoholic Steatohepatitis Patients. Hepatology 2001, 34, 1158–1163.
70. Maeda, N.; Shimomura, I.; Kishida, K.; Nishizawa, H.; Matsuda, M.; Nagaretani, H.; Furuyama, N.; Kondo, H.; Takahashi, M.; Arita, Y.; et al. Diet-Induced Insulin Resistance in Mice Lacking Adiponectin/ACRP30. Nat. Med. 2002, 8, 731–737.
71. Xu, A.; Wang, Y.; Keshaw, H.; Xu, L.Y.; Lam, K.S.L.; Cooper, G.J.S. The Fat-Derived Hormone Adiponectin Alleviates Alcoholic and Nonalcoholic Fatty Liver Diseases in Mice. J. Clin. Investig. 2003, 112, 91–100.
72. McKimmie, R.L.; Daniel, K.R.; Carr, J.J.; Bowden, D.W.; Freedman, B.I.; Register, T.C.; Hsu, F.C.; Lohman, K.K.; Weinberg, R.B.; Wagenknecht, L.E. Hepatic Steatosis and Subclinical Cardiovascular Disease in a Cohort Enriched for Type 2 Diabetes: The Diabetes Heart Study. Am. J. Gastroenterol. 2008, 103, 3029–3035.
73. Otsuka, F.; Sugiyama, S.; Kojima, S.; Maruyoshi, H.; Funahashi, T.; Sakamoto, T.; Yoshimura, K.; Kimura, K.; Umemura, S.; Ogawa, H. Hypoadiponectinemia Is Associated with Impaired Glucose Tolerance and Coronary Artery Disease in Non-Diabetic Men. Circ. J. 2007, 71, 1703–1709.
74. Edmison, J.; McCullough, A.J. Pathogenesis of Non-Alcoholic Steatohepatitis: Human Data. Clin. Liver Dis. 2007, 11, 75–104.
75. Solga, S.F.; Diehl, A.M. Nonalcoholic Fatty Liver Disease: Lumen-Liver Interactions and Possible Role for Probiotics. J. Hepatol. 2003, 38, 681–687.
76. Wanless, I.R.; Bargman, J.M.; Oreopoullos, D.G.; Vas, S.I. Subcapsular Steatonecrosis in Response to Peritoneal Insulin Deliver: A Clue to the Pathogenesis of Steatonecrosis in Obesity. Mod. Pathol. 1989, 2, 69–74.
77. Khalili, K.; Lan, F.P.; Hanbidge, A.E.; Muradali, D.; Oreopoulos, D.G.; Wanless, I.R. Hepatic Subcapsular Steatosis in Response to Intraperitoneal Insulin Delivery: CT Findings and Prevalence. AJR Am. J. Roentgenol. 2003, 180, 1601–1604.
78. Goldstein, B.J.; Kalyankar, M.; Wu, X. Insulin Action Is Facilitated by Insulin-Stimulated Reactive Oxygen Species with Multiple Potential Signaling Targets. Diabetes 2005, 54, 311–321.
79. Li, X.L.; Man, K.; Ng, K.T.; Lee, T.K.; Lo, C.M.; Fan, S.T. Insulin in UW Solution Exacerbates Hepatic Ischemia/Reperfusion Injury by Energy Depletion through the IRS-2/SREBP-1c Pathway. Liver Transpl. 2004, 10, 1172–1182.
80. Ozcan, U.; Cao, Q.; Yilmaz, E.; Lee, A.H.; Iwakoshi, N.N.; Ozdelen, E.; Tuncman, G.; Gorgun, C.; Glimcher, L.H.; Hotamisligil, G.S. Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes. Science 2004, 306, 457–461.
81. Fargion, S.; Mattioli, M.; Fracanzani, A.L.; Sampietro, M.; Tavazzi, D.; Fociani, P.; Taioli, E.; Valenti, L.; Fiorelli, G. Hyperferritinemia, Iron Overload, and Multiple Metabolic Alterations Identify Patients at Risk for Nonalcoholic Steatohepatitis. Am. J. Gastroenterol. 2001, 96, 2448–2455.
82. Fernandez Real, J.M.; Casamitjana-Abella, R.; Ricart-Engel, W.; Arroyo, E.; Balanca, R.; Casamitjana-Abella, R.; Cabrero, D.; Fernandez-Castaner, M.; Soler, J. Serum Ferritin as a Component of the Insulin Resistance Syndrome. Diabetes Care 1998, 21, 62–68.
83. Mendler, M.-H.; Turlin, B.; Moirand, R.; Jouanolle, A.-M.; Sapey, T.; Guyader, D.; le Gall, J.-Y.; Brissot, P.; David, V.; Deugnier, Y. Insulin Resistance-Associated Hepatic Iron Overload. Gastroenterology 1999, 117, 1155–1163.
84. Riquelme, A.; Soza, A.; Nazal, L.; Martinez, G.; Kolbach, M.; Patillo, A.; Arellano, M.; Duarte, I.; Martinez, J.; Molgo, M.; et al. Histological Resolution of Steatohepatitis after Iron Depletion. Dig. Sci. 2004, 49, 1012–1015.
85. Clarke, S.D. Nonalcoholic Steatosis and Steatohepatitis. I. Molecular Mechanism for Polyunsaturated Fatty Acid Regulation of Gene Transcription. Am. J. Physiol. Gastrointest. Liver Physiol. 2001, 281, G865–G869.
86. Tafani, M.; Schneider, T.G.; Pastorino, J.G.; Farber, J.L. Cytochrome Dependent Activation of Caspase 3 by Tumor Necrosis Factor Requires Induction of the Mitochondrial Permeability Transition. Am. J. Pathol. 2000, 156, 2111–2121.
87. Pastorini, J.G.; Simbula, G.; Yamamoto, K.; Glascott, P.A., Jr.; Rothman, R.J.; Farber, J.L. Cytotoxicity of TNF Depends on Induction of the Mitochondrial Permeability Transition. J. Biochem. 1996, 271, 29792–29798.
88. Paradis, V.; Perle, G.; Bonvoust, F.; Dargere, D.; Parfait, B.; Vidaud, M.; Conti, M.; Huet, S.; Ba, N.; Buffet, C.; et al. High Glucose and Hyperinsulinemia Stimulate Connective Tissue Growth Factor Expression: A Potential Mechanism Involved in Progression to Fibrosis in Nonalcoholic Steatohepatitis. Hepatology 2001, 74, 738–744.
89. Poli, G. Pathogenesis of Liver Fibrosis: The Role of Oxidative Stress. Mol Asp. Med. 2000, 21, 49–98.
90. Canbay, A.; Taimr, P.; Torok, N.; Higuchi, H.; Friedman, S.; Gores, G.J. Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic. Lab. Investig. 2003, 83, 655–663.
91. Feldstein, A.E.; Canbay, A.; Angulo, P.; Taniai, M.; Burgart, L.J.; Lindor, K.D.; Gores, G.J. Hepatocyte Apoptosis and FAS Expression Are Prominent Features of Human Nonalcoholic Steatohepatitis. Gastroenterology 2003, 125, 437–443.
92. Li, Z.; Oben, J.A.; Yang, S.; Lin, H.; Stafford, E.A.; Soloski, M.J.; Thomas, S.A.; Diehl, A.M. Norepinephrine Regulates Hepatic Innate Immune System in Leptin Deficient Mice with Nonalcoholic Steatohepatitis. Hepatology 2004, 40, 434–441.
93. Käräjämäki, A.J.; Olli-Pekka, P.; Markku, S.; Kesäniemi, Y.A.; Heikki, H.; Ukkola, O. Non-Alcoholic Fatty Liver Disease as a Predictor of Atrial Fibrillation in Middle-Aged Population (OPERA Study). PLoS ONE 2015, 10, e0142937.
94. Targher, G.; Valbuso, F.; Bonapace, S.; Bertolini, L.; Zenari, L.; Rodella, S.; Zoppini, G.; Mantovani, W.; Barbieri, E.; Byrne, C.D. Non-Alcoholic Fatty Liver Disease Is Associated with an Increased Incidence of Atrial Fibrillation in Patients with Type 2 Diabetes. Clin. Sci. 2013, 125, 301–309.
95. Hung, C.S.; Tseng, P.H.; Tu, C.H.; Chen, C.C.; Liao, W.C.; Lee, Y.C.; Chiu, H.M.; Lin, H.J.; Ho, Y.L.; Yang, W.S.; et al. Nonalcoholic Fatty Liver Disease Is Associated with QT Prolongation in the General Population. J. Am. Heart Assoc. 2015, 4, e001820.
96. Mantovani, A.; Rigamonti, A.; Bonapace, S.; Bolzan, B.; Pernigo, M.; Morani, F.; Giovanni, L.; Bergamini, C.; Bertolini, L.; Valbusa, F.; et al. Nonalcoholic Fatty Liver Disease Is Associated with Ventricular Arrhythmias in Patients with Type 2 Diabetes Referred for Clinically Indicated 24-h Holter Monitoring. Diabetes Care 2016, 39, 1416–1423.
97. Mantovani, A.; Rigolon, R.; Bonapace, S.; Morani, G.; Zoppini, G.; Bonora, E.; Targher, G. Nonalcoholic Fatty Liver Disease Is Associated with an Increased Risk of Heart Block in Hospitalized Patients with Type 2 Diabetes Mellitus. PLoS ONE 2017, 12, e0185459.
98. Tsang, T.S.; Barnes, M.E.; Miyasaka, Y.; Cha, S.S.; Bailey, K.R.; Verzosa, G.C.; Seward, J.B.; Gersh, B.J. Obesity as a Risk Factor for the Progression of Paroxysmal to Permanent Atrial Fibrillation: A Longitudinal Cohort Study of 21 Years. Eur. Heart J. 2008, 29, 2227–2233.
99. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the Management of Non-Alcoholic Fatty Liver Disease. Diabetologia 2016, 59, 1141–1144.
100. Graner, M.; Nyman, K.; Siren, R.; Pentikainen, M.O.; Lundbom, J.; Hakkarainen, A.; Lauerma, K.; Lundbom, N.; Nieminen, M.S.; Taskinen, M.R. Ectopic Fat Depots and Left Ventricular Function in Nondiabetic Men with Nonalcoholic Fatty Liver Disease. Circ. Cardiovasc. Imaging 2014, 8, e001979.
101. Käräjämäki, A.J.; Hukkanen, J.; Ukkola, O. The Association of Non-Alcoholic Fatty Liver Disease and Atrial Fibrillation: A Review. Ann. Med. 2018, 50, 371–380.
102. Liu, Y.C.; Hung, C.S.; Wu, Y.W.; Lee, Y.C.; Lin, Y.H.; Lin, C.; Lo, M.T.; Chan, C.C.; Ma, H.P.; Ho, Y.L.; et al. Influence of Non-Alcoholic Fatty Liver Disease on Autonomic Changes Evaluated by the Time Domain, Frequency Domain, and Symbolic Dynamics of Heart Rate Variability. PLoS ONE 2013, 8, e61803.
103. Park, H.W.; Shen, M.J.; Lin, S.F.; Fishbein, M.C.; Chen, L.S.; Chen, P.S. Neural Mechanisms of Atrial Fibrillation. Curr. Opin. Cardiol. 2012, 27, 24–28.
104. Guo, Y.; Lip, G.Y.; Apostolakis, S. Inflammation in Atrial Fibrillation. J. Am. Coll. Cardiol. 2012, 60, 2263–2270.
105. Ding, Y.H.; Ma, Y.; Qian, L.Y.; Xu, Q.; Wang, L.H.; Huang, D.S.; Zou, H. Linking Atrial Fibrillation with Non-Alcoholic Fatty Liver Disease: Potential Common Therapeutic Targets. Oncotarget 2017, 8, 60673–60683.
106. Lin, Y.K.; Chen, Y.C.; Chen, J.H.; Chen, S.A.; Chen, Y.J. Adipocytes Modulate the Electrophysiology of Atrial Myocytes: Implications in Obesity-Induced Atrial Fibrillation. Basic Res. Cardiol. 2012, 107, 293.
107. Chung, M.K.; Martin, D.O.; Sprecher, D.; Wazni, O.; Kanderian, A.; Carnes, C.A.; Bauer, J.A.; Tchou, P.J.; Niebauer, M.J.; Natale, A.; et al. C-Reactive Protein Elevation in Patients with Atrial Arrhythmias: Inflammatory Mechanisms and Persistence of Atrial Fibrillation. Circulation 2001, 104, 2886–2891.
108. Mantovani, A.; Pernigo, M.; Bergamini, C.; Bonapace, S.; Lipari, P.; Valbusa, F.; Bertolini, L.; Zenari, L.; Pichiri, I.; Dauriz, M.; et al. Heart Valve Calcification in Patients with Type 2 Diabetes and Nonalcoholic Fatty Liver Disease. Metabolism 2015, 64, 879–887.
109. Mantovani, A. Nonalcoholic Fatty Liver Disease (NAFLD) and Risk of Cardiac Arrhythmias: A New Aspect of the Liver-Heart Axis. J. Clin. Transl. Hepatol. 2017, 5, 134–141.
110. Ballestri, S.; Lonardo, A.; Bonapace, S.; Byrne, C.D.; Loria, P.; Targher, G. Risk of Cardiovascular, Cardiac and Arrhythmic Complications in Patients with Non-Alcoholic Fatty Liver Disease. World J. Gastroenterol. 2014, 20, 1724–1745.
111. Perseghin, G.; Lattuada, G.; De Cobelli, F.; Esposito, A.; Belloni, E.; Ntali, G.; Ragogna, F.; Canu, T.; Scifo, P.; Del Maschio, A.; et al. Increased Mediastinal Fat and Impaired Left Ventricular Energy Metabolism in Young Men with Newly Found Fatty Liver. Hepatology 2008, 47, 51–58.
112. Camici, P.; Ferrannini, E.; Opie, L.H. Myocardial Metabolism in Ischemic Heart Disease: Basic Principles and Application to Imaging by Positron Emission Tomography. Prog. Cardiovasc. Dis. 1989, 32, 217–238.
113. Taegtmeyer, H.; McNulty, P.; Young, M.E. Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts. Circulation 2002, 105, 1727–1733.
114. Alp, H.; Karaarslan, S.; Eklioğlu, B.S.; Atabek, M.E.; Altın, H.; Baysal, T. Association between Nonalcoholic Fatty Liver Disease and Cardiovascular Risk in Obese Children and Adolescents. Can. J. Cardiol. 2013, 29, 1118–1125.
115. De Simone, G.; Richard, B.D.; Marcello, C.; Mary, J.R.; Elisa, T.L.; Helaine, E.R.; Barbara, V.H. Metabolic Syndrome and Left Ventricular Hypertrophy in the Prediction of Cardiovascular Events-The Strong Heart Study. Nutr. Metab. Cardiovasc. Dis. 2009, 19, 98–104.
116. Peterson, L.R.; Herrero, P.; Schechtman, K.B.; Racette, S.B.; Waggoner, A.D.; Kisrieva-Ware, Z.; Dence, C.; Klein, S.B.; Marsala, J.; Meyer, T.; et al. Effect of Obesity and Insulin Resistance on Myocardial Substrate Metabolism and Efficiency in Young Women. Circulation 2004, 109, 2191–2196.
117. Borges-Canha, M.; Neves, J.S.; Libâni, D.; Von-Hafe, M.; Vale, C.; Araújo-Martins, M.; Leite, A.R.; Pimentel-Nunes, P.; Davide, C.; Adelino, L.M. Association between Nonalcoholic Fatty Liver Disease and Cardiac Function and Structure—A Meta-Analysis. Endocrine 2019, 66, 467–476.
118. Kocabay, G.; Karabay, C.Y.; Colak, Y.; Oduncu, V.; Kalayci, A.; Akgun, T.; Guler, A.; Kirma, C. Left Atrial Deformation Parameters in Patients with Non-Alcoholic Fatty Liver Disease: A 2D Speckle Tracking Imaging Study. Clin. Sci. 2014, 126, 297–304.
119. Mondillo, S.; Cameli, M.; Caputo, M.L.; Lisi, M.; Palmerini, E.; Padeletti, M.; Ballo, P. Early Detection of Left Atrial Strain Abnormalities by Speckle-Tracking in Hypertensive and Diabetic Patients with Normal Left Atrial Size. J. Am. Soc. Echocardiogr. 2011, 24, 898–908.
120. Bekler, A.; Gazi, E.; Erbag, G.; Binnetoglu, E.; Barutcu, A.; Sen, H.; Temiz, A.; Altun, B. Right Ventricular Function and Its Relationship with Grade of Hepatosteatosis in Non-Alcoholic Fatty Liver Disease. Cardiovasc. J. Afr. 2015, 26, 109–113.
121. Anstee, Q.M.; Mantovani, A.; Tilg, H.; Targher, G. Risk of Cardiomyopathy and Cardiac Arrhythmias in Patients with Nonalcoholic Fatty Liver Disease. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 425–439.
122. Volzke, H.; Haring, R.; Lorbeer, R.; Wallaschofski, H.; Reffelmann, T.; Empen, K.; Rettig, R.; John, U.; Felix, S.B.; Dorr, M. Heart Valve Sclerosis Predicts All-Cause and Cardiovascular Mortality. Atherosclerosis 2010, 209, 606–610.
123. Targher, G.; Day, C.P.; Bonora, E. Risk of Cardiovascular Disease in Patients with Nonalcoholic Fatty Liver Disease. N. Engl. J. Med. 2010, 363, 1341–1350.
124. Otto, C.M.; Kuusisto, J.; Reichenbach, D.D.; Gown, A.M.; O’Brien, K.D. Characterization of the Early Lesion of ‘Degenerative’ Valvular Aortic Stenosis. Histological and Immunohistochemical Studies. Circulation 1994, 90, 844–853.
125. Goto, T.; Onuma, T.; Takebe, K.; Kral, J.G. The Influence of Fatty Liver on Insulin Clearance and Insulin Resistance in Non-Diabetic Japanese Subjects. Int. J. Obes. Relat. Metab. Disord. 1995, 19, 841–845.
126. Paulista, M.; Marcello, R.; Baumeister, S.E.; Dörr, J.M.; Wallaschofski, H.; Völzke, H.; Lieb, W. Hepatic Steatosis Is Associated With Aortic Valve Sclerosis in the General Population The Study of Health in Pomerania (SHIP). Arterioscler. Thromb. Vasc. Biol. 2013, 33, 1690–1695.
127. Paulus, W.J.; Tschope, C. A Novel Paradigm for Heart Failure with Preserved Ejection Fraction: Comorbidities Drive Myocardial Dysfunction and Remodeling through Coronary Microvascular Endothelial Inflammation. J. Am. Coll. Cardiol. 2013, 62, 263–271.
128. Belke, D.D.; Betuing, S.; Tuttle, M.J.; Graveleau, C.; Young, M.E.; Pham, M.; Zhang, D.; Cooksey, R.C.; McClain, D.A.; Litwin, S.E.; et al. Insulin Signaling Coordinately Regulates Cardiac Size, Metabolism, and Contractile Protein Isoform Expression. J. Clin. Investig. 2002, 109, 629–639.
129. Dhingra, R.; Gona, P.; Wang, T.J.; Fox, C.S.; D’Agostino, R.B.; Vasan, R.S. Serum Gamma-Glutamyl Transferase and Risk of Heart Failure in the Community. Arter. Thromb. Vasc. Biol. 2010, 30, 1855–1860.
130. Wannamethee, S.G.; Whincup, P.H.; Shaper, A.G.; Lennon, L.; Sattar, N. Γ-Glutamyltransferase, Hepatic Enzymes, and Risk of Incident Heart Failure in Older Men. Arter. Thromb. Vasc. Biol. 2012, 32, 830–835.
131. Emdin, M.; Pompella, A.; Paolicchi, A. γ-Glutamyltransferase, Atherosclerosis, and Cardiovascular Disease: Triggering Oxidative Stress within the Plaque. Circulation 2005, 112, 2078–2208.
132. Hamaguchi, M.; Kojima, T.; Takeda, N.; Nagata, C.; Takeda, J.; Sarui, H.; Kawahito, Y.; Yoshida, N.; Suetsugu, A.; Kato, T.; et al. Nonalcoholic Fatty Liver Disease Is a Novel Predictor of Cardiovascular Disease. World J. Gastroenterol. 2007, 13, 1579–1584.
133. Abdeldyem, S.M.; Goda, T.; Khodeir, S.A.; Abou, S.S.; Abd-Elsalam, S. Nonalcoholic Fatty Liver Disease in Patients with Acute Ischemic Stroke Is Associated with More Severe Stroke and Worse Outcome. J. Clin. Lipidol. 2017, 11, 915–919.
134. El Hadi, H.; Di Vincenzo, A.; Vettor, R.; Rossato, M. Cardio-Metabolic Disorders in Non-Alcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2019, 20, 2215.
135. Bots, M.L.; Salonen, J.; Elwood, P.; Nikitin, Y.; Freire, D.; Inzitari, D.; Sivenius, J.; Trichopoulou, A.; Tuomilehto, J.; Koudstaal, P.; et al. Gamma-Glutamyltransferase and Risk of Stroke: The EUROSTROKE Project. J. Epidemiol. Community Health 2002, 56, i25–i29.
136. Paolicchi, A.; Emdin, M.; Ghliozeni, E.; Ciancia, E.; Passino, C.; Popoff, G.; Pompella, A. Images in Cardiovascular Medicine, Human Atherosclerotic Plaques Contain Gamma-Glutamyl Transpeptidase Enzyme Activity. Circulation 2004, 109, 1440.
137. Emdin, M.; Passino, C.; Franzini, M.; Paolicchi, A.; Pompella, A. γ-Glutamyltransferase and Pathogenesis of Cardiovascular Diseases. Future Cardiol. 2007, 263–270.
138. Khalaf, M.R.; Hayhoe, F.G. Cytochemistry of Gamma-Glutamyltransferase in Haemic Cells and Malignancies. Histochem. J. 1987, 19, 385–395.
139. Stark, A.A.; Zeiger, E.; Pagano, D.A. Glutathione Metabolism by Gamma-Glutamyltranspeptidase Leads to Lipid Peroxidation: Characterization of the System and Relevance to Hepatocarcinogenesis. Carcinogenesis 1993, 14, 183–189.
140. Stocker, R.; Keaney, J.; John, F. Role of Oxidative Modifications in Atherosclerosis. Physiol. Rev. 2004, 84, 1381–1478.
141. Ciavarella, A.; Gnocchi, D.; Custodero, C.; Lenato, G.M.; Fiore, G.; Sabbà, C.; Mazzocca, A. Translational Insight into Prothrombotic State and Hypercoagulation in Nonalcoholic Fatty Liver Disease. Thromb. Res. 2021, 198, 139–150.
142. Di Minno, M.N.D.; Tufano, A.; Rusolillo, A.; Di Minno, G.; Tarantino, G. High Prevalence of Nonalcoholic Fatty Liver in Patients with Idiopathic Venous Thromboembolism. World J. Gastroenterol. 2010, 28, 6119–6122.
143. Stine, J.; Jonathan, G.; Shah, N.L.; Argo, C.K.; Pelletier, S.J.; Caldwell, S.H.; Northup, P.G. Northup Increased Risk of Portal Vein Thrombosis in Patients With Cirrhosis Due to Nonalcoholic Steatohepatitis. Liver Transpl. 2015, 21, 1016–1021.
144. Nieuwdorp, M.; Stroes, E.S.; Meijers, J.C.; Buller, H. Hypercoagulability in the Metabolic Syndrome. Curr. Opin. Pharmacol. 2005, 5, 155–159.
145. Kim, J.A.; Kim, J.E.; Song, S.H.; Kim, H.K. Influence of Blood Lipids on Global Coagulation Test Results. Ann. Lab. Med. 2015, 35, 15–21.
146. Yun, J.W.; Cho, Y.K.; Park, J.H.; Kim, H.J.; Park, D.I.; Sohn, C.I.; Jeon, W.K.; Kim, B.I. Abnormal Glucose Tolerance in Young Male Patients with Nonalcoholic Fatty Liver Disease. Liver Int. 2009, 29, 525–529.
147. Undas, A.; Wiek, I.; Stepien, E.; Zmudka, K.; Tracz, W. Hyperglycemia Is Associated with Enhanced Thrombin Formation, Platelet Activation, and Fibrin Clot Resistance to Lysis in Patients with Acute Coronary Syndrome. Diabetes Care 2008, 31, 1590–1595.
148. Vinik, A.I.; Erbas, T.; Park, T.S.; Nolan, R.; Pittenger, G.L. Platelet Dysfunction in Type 2 Diabetes. Diabetes Care 2001, 24, 1476–1485.
149. Ceriello, A. Coagulation Activation in Diabetes Mellitus: The Role of Hyperglycaemia and Therapeutic Prospects. Diabetologia 1993, 36, 1119–1125.
150. Mitropoulos, K.A.; Miller, G.J.; Watts, G.F.; Durrington, P.N. Lipolysis of Triglyceride-Rich Lipoproteins Activates Coagulant Factor XII: A Study in Familial Lipoprotein-Lipase Deficiency. Atherosclerosis 1992, 95, 119–125.
151. Alderton, W.K.; Cooper, C.E.; Knowles, R.G. Nitric Oxide Synthases: Structure, Function and Inhibition. Biochem. J. 2001, 357, 593–615.
152. Dumas, M.E.; Barton, R.H.; Toye, A.; Cloarec, O.; Blancher, C.; Rothwell, A.; Fearnside, J.; Tatoud, R.; Blanc, V.; Lindon, J.C.; et al. Metabolic Profiling Reveals a Contribution of Gut Microbiota to Fatty Liver Phenotype in Insulin-Resistant Mice. Proc. Natl. Acad. Sci. USA 2006, 103, 12511–12516.
153. Chen, Y.M.; Liu, Y.; Zhou, R.F.; Chen, X.L.; Wang, C.; Tan, X.Y.; Wang, L.J.; Zheng, R.D.; Zhang, H.W.; Ling, W.H.; et al. Associations of Gut-Flora-Dependent Metabolite Trimethylamine-Noxide, Betaine and Choline with Non-Alcoholic Fatty Liver Disease in Adults. Sci. Rep. 2016, 6, 19076.
154. Zhu, W.; Gregory, J.C.; Org, E.; Buffa, J.A.; Gupta, N.; Wang, Z.; Li, L.; Fu, X.; Wu, Y.; Mehrabian, M.; et al. Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell 2016, 165, 111–124.
155. Sookoian, S.; Castano, G.O.; Burgueno, A.L.; Rosselli, M.S.; Gianotti, T.F.; Mallardi, P.; Martino, J.S.; Pirola, C.J. Circulating Levels and Hepatic Expression of Molecular Mediators of Atherosclerosis in Nonalcoholic Fatty Liver Disease. Atherosclerosis 2010, 209, 585–591.
156. Esmon, C.T. The Interactions between Inflammation and Coagulation. Br. J. Haematol. 2005, 131, 417–430.
157. Dole, V.S.; Bergmeier, W.; Patten, I.S.; Hirahashi, J.; Mayadas, T.N.; Wagner, D.D. PSGL-1 Regulates Platelet P-Selectin-Mediated Endothelial Activation and Shedding of P-Selectin from Activated Platelets. Thromb. Haemost. 2007, 98, 806–812.