The renin-angiotensin system in fructose-induced metabolic syndrome

The widespread use of fructose in processed foods is accepted to cause an increase in metabolic syndrome characterized by insulin resistance, abdominal obesity, hypertriglyceridemia, and hypertension. Fructose-induced metabolic syndrome is also associated with various diseases such as type 2 diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). The renin-angiotensin system (RAS) has essential roles in blood pressure regulation, fluid-electrolyte homeostasis, cell growth, and glucose homeostasis. Angiotensin I (Agt I) and angiotensin II (Agt II), which are derived from angiotensinogen by renin and angiotensin-converting enzyme (ACE), respectively, are essential players of RAS. Experimental and clinical studies showed that excessive fructose consumption causes activation in RAS. Increased Agt II in fructose-induced metabolic syndrome initiates insulin resistance by disrupting the insulin signaling pathway and thus predisposes to type 2 diabetes, hypertension and NAFLD. Angiotensin 1-7 (Agt 1-7), which is formed from Agt II by angiotensin-converting enzyme 2 (ACE2) has contra-balancing effects to Agt II as well as regulatory effects on insulin resistance and hepatic fat accumulation.

Anahtar Kelimeler:

fructose, metabolic syndrome, insulin resistance, renin-angiotensin system

Fruktozla oluşturulan metabolik sendromda renin-anjiyotensin sistemi

Fruktozun işlenmiş gıdalarda yaygın olarak kullanılması insülin direnci, abdominal obezite, hipertrigliseridemi ve hipertansiyon ile karakterize olan metabolik sendromun artmasına neden olmaktadır. Fruktozla oluşturulan metabolik sendrom tip 2 diyabet, kardiyovasküler hastalıklar ve alkole bağlı olmayan yağlı karaciğer hastalığı (NAFLD) gibi çeşitli hastalıklara zemin hazırlamaktadır. Renin-anjiyotensin sistemi (RAS), kan basıncının düzenlenmesi, sıvı-elektrolit homeostazı, hücre büyümesi ve glikoz homeostazı üzerinde önemli rollere sahiptir. Renin ve anjiyotensin dönüştürücü enzim (ACE) tarafından anjiyotensinojenden türetilen anjiyotensin I (Agt I) ve anjiyotensin II (Agt II), RAS'ın temel bileşenleridir. Deneysel ve klinik çalışmalar, aşırı fruktoz tüketiminin RAS aktivasyonunu artırdığını göstermiştir. Fruktozla oluşturulan metabolik sendromda artan Agt II, insülin sinyal yolunu bozarak insülin direncini başlatmakta ve böylece tip 2 diyabet, hipertansiyon ve NAFLD'e zemin hazırlamaktadır. Anjiyotensin dönüştürücü enzim 2 (ACE2) tarafından Agt II'den oluşturulan anjiyotensin 1-7 (Agt 1-7), insülin direnci ve hepatik yağ birikimi üzerinde düzenleyici etkilerin yanı sıra Agt II'ye karşı dengeleyici etkilere sahiptir.

Keywords:

fructose; metabolic syndrome; insulin resistance; renin-angiotensin system, fructose; metabolic syndrome; insulin resistance; renin-angiotensin system, fructose,

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1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365(9468): 1415-28.
2. Xu H, Li X, Adams H, Kubena K, Guo S. Etiology of Metabolic Syndrome and Dietary Intervention. Int J Mol Sci 2018; 20(1):128.
3. Saklayen MG. The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep 2018; 20(2):12.
4. Ortiz-Rodríguez MA, Bautista-Ortiz LF, Villa AR, et al. Prevalence of Metabolic Syndrome Among Mexican Adults. Metab Syndr Relat Disord 2022; 20(5): 264-272.
5. de Siqueira Valadares LT, de Souza LSB, Salgado Júnior VA, de Freitas Bonomo L, de Macedo LR, Silva M. Prevalence of metabolic syndrome in Brazilian adults in the last 10 years: a systematic review and meta-analysis. BMC Public Health 2022; 22(1): 327.
6. Mahmoud I, Sulaiman N. Prevalence of Metabolic Syndrome and Associated Risk Factors in the United Arab Emirates: A Cross-Sectional Population-Based Study. Front Public Health 2022; 9:811006.
7. Bovolini A, Garcia J, Andrade MA, Duarte JA. Metabolic Syndrome Pathophysiology and Predisposing Factors. Int J Sports Med 2021; 42(3): 199-214.
8. Kanwar P, Kowdley KV. The Metabolic Syndrome and Its Influence on Nonalcoholic Steatohepatitis. Clin Liver Dis 2016; 20(2): 225-43. 9. International Diabetes Federation (2006) The IDF consensus worldwide definition of the metabolic syndrome. https://www.idf.org/e-library/consensus-statements/60-idfconsensus-worldwide-definitionof-the-metabolic-syndrome.html 10. Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 2018; 98(4): 2133-2223. 11. Pirola L, Johnston AM, Van Obberghen E. Modulation of insulin action. Diabetologia 2004; 47(2): 170-84.
12. Lavin DP, White MF, Brazil DP. IRS proteins and diabetic complications. Diabetologia 2016; 59(11): 2280-2291.
13. Gaston SA, Tulve NS, Ferguson TF. Abdominal obesity, metabolic dysfunction, and metabolic syndrome in U.S. adolescents: National Health and Nutrition Examination Survey 2011-2016. Ann Epidemiol 2019; 30: 30-36.
14. Jayawardena R, Sooriyaarachchi P, Misra A. Abdominal obesity and metabolic syndrome in South Asians: prevention and management. Expert Rev Endocrinol Metab 2021; 16(6): 339-349.
15. Neeland IJ, Ayers CR, Rohatgi AK, et al. Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity (Silver Spring) 2013; 21(9): E439-47.
16. Hu L, Huang X, You C, et al. Prevalence of overweight, obesity, abdominal obesity and obesity-related risk factors in southern China. PLoS One 2017; 12(9): e0183934.
17. Wang Y, Rimm EB, Stampfer MJ, Willett WC, Hu FB. Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr 2005; 81(3): 555-63.
18. O’Neill, S.; O’Driscoll, L. Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies. Obes Re. 2015; 16: 1–12.
19. Febbraio MA, Karin M. "Sweet death": Fructose as a metabolic toxin that targets the gut-liver axis. Cell Metab 2021; 33(12): 2316-2328.
20. Babacanoglu C, Yildirim N, Sadi G, Pektas MB, Akar F. Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats. Food Chem Toxicol 2013; 60:160-7.
21. Pektas MB, Koca HB, Sadi G, Akar F. Dietary Fructose Activates Insulin Signaling and Inflammation in Adipose Tissue: Modulatory Role of Resveratrol. Biomed Res Int 2016; 8014252.
22. Korkmaz OA, Sumlu E, Koca HB, et al. Effects of Lactobacillus Plantarum and Lactobacillus Helveticus on Renal Insulin Signaling, Inflammatory Markers, and Glucose Transporters in High-Fructose-Fed Rats. Medicina (Kaunas) 2019; 55(5): 207.
23. Akar F, Sumlu E, Alçığır ME, Bostancı A, Sadi G. Potential mechanistic pathways underlying intestinal and hepatic effects of kefir in high-fructose-fed rats. Food Res Int 2021; 143: 110287.
24. Sumlu E, Bostancı A, Sadi G, Alçığır ME, Akar F. Lactobacillus plantarum improves lipogenesis and IRS-1/AKT/eNOS signalling pathway in the liver of high-fructose-fed rats. Arch Physiol Biochem 2022; 128(3): 786-794.
25. Taskinen MR, Packard CJ, Borén J. Dietary Fructose and the Metabolic Syndrome. Nutrients 2019; 11(9): 1987.
26. Malik VS, Hu FB. Fructose and Cardiometabolic Health: What the Evidence From Sugar-Sweetened Beverages Tells Us. J Am Coll Cardiol 2015; 66(14): 1615-1624.
27. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 2009; 119(5): 1322-34.
28. Crescenzo R, Bianco F, Coppola P, et al. Adipose tissue remodeling in rats exhibiting fructose-induced obesity. Eur J Nutr 2014; 53(2): 413-9.
29. Sangüesa G, Roglans N, Montañés JC, et al. Chronic Liquid Fructose, but not Glucose, Supplementation Selectively Induces Visceral Adipose Tissue Leptin Resistance and Hypertrophy in Female Sprague-Dawley Rats. Mol Nutr Food Res 2018; 62(22): e1800777.
30. Tran LT, Yuen VG, McNeill JH. The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem 2009; 332(1-2): 145-59.
31. Kalupahana NS, Moustaid-Moussa N. The adipose tissue renin-angiotensin system and metabolic disorders: a review of molecular mechanisms. Crit Rev Biochem Mol Biol 2012; 47(4): 379-90.
32. Verdecchia P, Angeli F, Mazzotta G, Gentile G, Reboldi G. The renin angiotensin system in the development of cardiovascular disease: role of aliskiren in risk reduction. Vasc Health Risk Manag 2008; 4(5): 971-81.
33. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet 2007; 369(9568): 1208-19.
34. Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev 2012; 13(2): 136-149.
35. Jones BH, Standridge MK, Taylor JW, Moustaïd N. Angiotensinogen gene expression in adipose tissue: analysis of obese models and hormonal and nutritional control. Am J Physiol 1997; 273(1 Pt 2): R236-42. 36. Frigolet ME, Torres N, Tovar AR. The renin-angiotensin system in adipose tissue and its metabolic consequences during obesity. J Nutr Biochem 2013; 24(12): 2003-15.
37. Tran LT, MacLeod KM, McNeill JH. Endothelin-1 modulates angiotensin II in the development of hypertension in fructose-fed rats. Mol Cell Biochem 2009; 325(1-2): 89-97.
38. Alshuniaber MA, Alshammari GM, Eleawa SM, et al. Camel milk protein hydrosylate alleviates hepatic steatosis and hypertension in high fructose-fed rats. Pharm Biol 2022; 60(1): 1137-1147.
39. White MF, Kahn CR. Insulin action at a molecular level - 100 years of progress. Mol Metab 2021; 52: 101304.
40. Yaribeygi H, Farrokhi FR, Butler AE, Sahebkar A. Insulin resistance: Review of the underlying molecular mechanisms. J Cell Physiol 2019; 234(6) :8152-8161.
41. Haeusler RA, McGraw TE, Accili D. Biochemical and cellular properties of insulin receptor signalling. Nat Rev Mol Cell Biol 2018; 19(1): 31-44.
42. Lebovitz HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes 2001;109 Suppl 2:S135-48.
43. Kim M, Do GY, Kim I. Activation of the renin-angiotensin system in high fructose-induced metabolic syndrome. Korean J Physiol Pharmacol 2020; 24(4): 319-328.
44. Zhang JX, Lin X, Xu J, Tang F. Hyperuricemia Inhibition Protects SD Rats Against Fructose-Induced Obesity Hypertension Via Modulation of Inflammation and Renin-Angiotensin System in Adipose Tissue. Exp Clin Endocrinol Diabetes 2021; 129: 314–321.
45. Kalupahana NS, Moustaid-Moussa N. The renin-angiotensin system: a link between obesity, inflammation and insulin resistance. Obes Rev 2012; 13(2): 136-49.
46. Rabie EM, Heeba GH, Abouzied MM, Khalifa MM. Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats. Eur J Pharmacol 2015; 760:145-53.
47. Chou CL, Lai YH, Lin TY, Lee TJ, Fang TC. Aliskiren prevents and ameliorates metabolic syndrome in fructose-fed rats. Arch Med Sci 2011; 7(5): 882-8.
48. Iyer SN, Katovich MJ. Effect of acute and chronic losartan treatment on glucose tolerance and insulin sensitivity in fructose-fed rats. Am J Hypertens 1996; 9(7): 662-8.
49. Iimura O, Shimamoto K, Matsuda K, et al. Effects of angiotensin receptor antagonist and angiotensin converting enzyme inhibitor on insulin sensitivity in fructose-fed hypertensive rats and essential hypertensives. Am J Hypertens 1995; 8(4 Pt 1): 353-7.
50. Giani JF, Mayer MA, Muñoz MC, et al. Chronic infusion of angiotensin-(1-7) improves insulin resistance and hypertension induced by a high-fructose diet in rats. Am J Physiol Endocrinol Metab 2009; 296(2): E262-71.
51. Marcus Y, Shefer G, Sasson K, et al. Angiotensin 1-7 as means to prevent the metabolic syndrome: lessons from the fructose-fed rat model. Diabetes 2013; 62(4): 1121-30.
52. Muñoz MC, Giani JF, Burghi V,et al. The Mas receptor mediates modulation of insulin signaling by angiotensin-(1-7). Regul Pept 2012; 177(1-3): 1-11.
53. Calegari VC, Alves M, Picardi PK,et al. Suppressor of cytokine signaling-3 Provides a novel interface in the cross-talk between angiotensin II and insulin signaling systems. Endocrinology 2005;146(2): 579-88.
54. Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamura T. Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 2004; 43(2): 255-62.
55. Engin A. The Definition and Prevalence of Obesity and Metabolic Syndrome. Adv Exp Med Biol 2017; 960: 1-17.
56. Neeland IJ, Ayers CR, Rohatgi AK, et al. Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. Obesity (Silver Spring) 2013; 21(9): E439-47.
57. Seidell JC, Hautvast JG, Deurenberg P. Overweight: fat distribution and health risks. Epidemiological observations. A review. Infusionstherapie 1989; 16(6): 276-81.
58. Bocarsly ME, Powell ES, Avena NM, Hoebel BG. High-fructose corn syrup causes characteristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacol Biochem Behav 2010; 97(1): 101-6.
59. Mamikutty N, Thent ZC, Sapri SR, Sahruddin NN, Mohd Yusof MR, Haji Suhaimi F. The establishment of metabolic syndrome model by induction of fructose drinking water in male Wistar rats. Biomed Res Int 2014; 2014: 263897.
60. Crescenzo R, Bianco F, Coppola P, et al. Adipose tissue remodeling in rats exhibiting fructose-induced obesity. Eur J Nutr 2014; 53(2): 413-9.
61. Giacchetti G, Sechi LA, Griffin CA, Don BR, Mantero F, Schambelan M. The tissue renin-angiotensin system in rats with fructose-induced hypertension: overexpression of type 1 angiotensin II receptor in adipose tissue. J Hypertens 2000; 18(6): 695-702.
62. Bundalo M, Djordjevic A, Bursac B, Zivkovic M, Koricanac G, Stanković A. Fructose-rich diet differently affects angiotensin II receptor content in the nucleus and a plasma membrane fraction of visceral adipose tissue. Appl Physiol Nutr Metab 2017; 42(12): 1254-1263.
63. Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension 2002; 40(5): 609-11.
64. Furuhashi M, Ura N, Takizawa H, et al. Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens 2004; 22(10): 1977-82.
65. Chou CL, Lin H, Chen JS, Fang TC. Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats. PLoS One 2017; 12(7): e0180712.
66. Roncal CA, Reungjui S, Sánchez-Lozada LG, et al. Combination of captopril and allopurinol retards fructose-induced metabolic syndrome. Am J Nephrol 2009; 30(5): 399-404.
67. Giussani M, Lieti G, Orlando A, Parati G, Genovesi S. Fructose Intake, Hypertension and Cardiometabolic Risk Factors in Children and Adolescents: From Pathophysiology to Clinical Aspects. A Narrative Review. Front Med (Lausanne) 2022; 9: 792949.
68. Xu C, Yu J. Pathophysiological mechanisms of hypertension development induced by fructose consumption. Food Funct 2022; 13(4): 1702-1717.
69. Iyer SN, Katovich MJ. Vascular reactivity to phenylephrine and angiotensin II in hypertensive rats associated with insulin resistance. Clin Exp Hypertens 1996; 18(2): 227-42.
70. Hsieh PS, Tai YH, Loh CH, Shih KC, Cheng WT, Chu CH. Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats. Metabolism 2005; 54(2): 157-64.
71. Iyer SN, Katovich MJ. Effect of chronic losartan potassium treatment on fructose-induced hypertension. Life Sci 1994; 55(7): PL139-44.
72. Juan CC, Fang VS, Hsu YP, et al. Overexpression of vascular endothelin-1 and endothelin-A receptors in a fructose-induced hypertensive rat model. J Hypertens 1998; 16(12 Pt 1): 1775-82.
73. Akar F, Uludağ O, Aydın A, et al. High-fructose corn syrup causes vascular dysfunction associated with metabolic disturbance in rats: protective effect of resveratrol. Food Chem Toxicol 2012; 50(6): 2135-41.
74. Jalal DI, Smits G, Johnson RJ, Chonchol M. Increased fructose associates with elevated blood pressure. J Am Soc Nephrol 2010; 21(9): 1543-9.
75. Nguyen S, Choi HK, Lustig RH, Hsu CY. Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents. J Pediatr 2009; 154(6): 807-13.
76. Brown CM, Dulloo AG, Yepuri G, Montani JP. Fructose ingestion acutely elevates blood pressure in healthy young humans. Am J Physiol Regul Integr Comp Physiol 2008; 294(3): R730-7.
77. Perez-Pozo SE, Schold J, Nakagawa T, Sánchez-Lozada LG, Johnson RJ, Lillo JL. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond) 2010; 34(3): 454-61.
78. Chou CL, Pang CY, Lee TJ, Fang TC. Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats. PLoS One 2015; 10(3): e0119843.
79. Hsieh PS, Tai YH, Loh CH, Shih KC, Cheng WT, Chu CH. Functional interaction of AT1 and AT2 receptors in fructose-induced insulin resistance and hypertension in rats. Metabolism 2005; 54(2): 157-64.
80. Rubio-Ruíz ME, Del Valle-Mondragón L, Castrejón-Tellez V, Carreón-Torres E, Díaz-Díaz E, Guarner-Lans V. Angiotensin II and 1-7 during aging in Metabolic Syndrome rats. Expression of AT1, AT2 and Mas receptors in abdominal white adipose tissue. Peptides 2014; 57: 101-8.
81. Nyby MD, Abedi K, Smutko V, Eslami P, Tuck ML. Vascular Angiotensin type 1 receptor expression is associated with vascular dysfunction, oxidative stress and inflammation in fructose-fed rats. Hypertens Res 2007; 30(5): 451-7.
82. Froogh G, Kandhi S, Duvvi R, et al. The contribution of chymase-dependent formation of ANG II to cardiac dysfunction in metabolic syndrome of young rats: roles of fructose and EETs. Am J Physiol Heart Circ Physiol 2020; 318(4): H985-H993.
83. Bundalo MM, Zivkovic MD, Romic SDj, et al. Fructose-rich diet induces gender-specific changes in expression of the renin-angiotensin system in rat heart and up-regulates the ACE/AT1R axis in the male rat aorta. J Renin Angiotensin Aldosterone Syst 2016; 17(2): 1470320316642915.
84. Kobayashi R, Nagano M, Nakamura F, et al. Role of angiotensin II in high fructose-induced left ventricular hypertrophy in rats. Hypertension 1993; 21(6 Pt 2): 1051-5.
85. 85. Bouchard-Thomassin AA, Lachance D, Drolet MC, Couet J, Arsenault M. A high-fructose diet worsens eccentric left ventricular hypertrophy in experimental volume overload. Am J Physiol Heart Circ Physiol 2011; 300(1): H125-34.
86. Cabral PD, Hong NJ, Hye Khan MA, et al. Fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Hypertension 2014; 63(3): e68-73.
87. Diehl AM, Day C. Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 2017; 377(21): 2063-2072.
88. Riazi K, Azhari H, Charette JH, et al. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2022; 7(9): 851-861.
89. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332(6037): 1519-23.
90. Fabbrini E, Sullivan S, Klein S. Obesity and non-alcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010; 51(2): 679-89.
91. Birkenfeld AL, Shulman GI. Non-alcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 2014; 59(2): 713-23.
92. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol 2008; 48(6): 993-9.
93. Collison KS, Maqbool ZM, Inglis AL, et al. Effect of dietary monosodium glutamate on HFCS-induced hepatic steatosis: expression profiles in the liver and visceral fat. Obesity (Silver Spring) 2010; 18(6): 1122-34.
94. Ackerman Z, Oron-Herman M, Grozovski M, et al. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension 2005; 45(5): 1012-8.
95. Matthew Morris E, Fletcher JA, Thyfault JP, Rector RS. The role of angiotensin II in non-alcoholic steatohepatitis. Mol Cell Endocrinol 2013; 378(1-2): 29-40.
96. Attia H, Albekairi N, Albdeirat L, et al. Chrysin Attenuates Fructose-Induced Nonalcoholic Fatty Liver in Rats via Antioxidant and Anti-Inflammatory Effects: The Role of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis. Oxid Med Cell Longev 2022; 2022: 9479456.
97. Orlic L, Mikolasevic I, Lukenda V, Anic K, Jelic I, Racki S. Nonalcoholic fatty liver disease and the renin-angiotensin system blockers in the patients with chronic kidney disease. Wien Klin Wochenschr 2015; 127(9-10): 355-62.
98. Pelusi S, Petta S, Rosso C, et al. Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disease. PLoS One 2016; 11(9): e0163069.
99. Alqarni I, Bassiouni YA, Badr AM, Ali RA. Telmisartan and/or chlorogenic acid attenuates fructose-induced non-alcoholic fatty liver disease in rats: Implications of cross-talk between angiotensin, the sphingosine kinase/sphingoine-1-phosphate pathway, and TLR4 receptors. Biochem Pharmacol 2019; 164: 252-262.
100. Ackerman Z, Oron-Herman M, Grozovski M, et al. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension 2005; 45(5): 1012-8. 193