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Angiotensin receptor blockers in the treatment of NASH/NAFLD: Could they be a first-class option?

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a condition pathogenically linked to metabolic syndrome (MS) by insulin resistance (IR), and characterized by hepatic steatosis in the absence of significant alcohol use, hepatotoxicity, and/or other known liver diseases.

The principles of NAFLD therapy target IR: the key point of MS. As the renin-angiotensin system (RAS) plays a central role in IR, and subsequently in NAFLD and nonalcoholic steatohepatitis (NASH), an attempt to block the deleterious effects of RAS overexpression seems a logical target. While many potential therapies tested in NASH target only the consequences of this condition, or try to “get rid” of excessive fat, angiotensin receptor blockers (ARBs) could act as an elegant tool for adequate correction of the various imbalances that act in harmony in NASH/NAFLD. Indeed, by inhibiting RAS we can improve the intracellular insulin signaling pathway, better control adipose tissue proliferation and adipokine production, and produce more balanced local and systemic levels of various cytokines. At the same time, by controlling the local RAS in the liver we might be able to prevent at least fibrosis and also slow down the vicious cycle that links steatosis to necroinflammation. By targeting the pancreatic effects of angiotensin we should be able to preserve an adequate insulin secretion and acquire a better metabolic balance.

In our opinion there are two major advantages of ARBs that make them a possible therapeutic option for treating NASH and MS: their specific antihypertensive effect, and their impact on liver fibrosis. In light of this, and based on the current evidence (including existent human studies), we can speculate that some ARBs like telmisartan, candesartan, and losartan can be beneficial in treating NASH/NAFLD and its consequences, and further larger controlled clinical trials will bring consistent data into this field.

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References

  1. Angulo P. GI epidemiology: nonalcoholic fatty liver disease. Aliment Pharmacol Ther. 2007;25:883–889.

    PubMed  CAS  Google Scholar 

  2. Powell EE, Jonsson JR, Clouston AD. Steatosis: co-factor in other liver diseases. Hepatology. 2006;42:5–13.

    Google Scholar 

  3. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology. 1999;29:664–669.

    PubMed  CAS  Google Scholar 

  4. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123:134–140.

    PubMed  Google Scholar 

  5. Kleiner DE, Brunt EM, Van Natta M, et al. for the Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;4:1313–1321.

    Google Scholar 

  6. Chitturi S, Farrell GC. Etiopathogenesis of nonalcoholic steatohepatitis. Semin Liver Dis. 2001;21:27–41.

    PubMed  CAS  Google Scholar 

  7. Diehl AM. Fatty liver, hypertension, and the metabolic syndrome. Gut. 2004;53:923–924.

    PubMed  CAS  Google Scholar 

  8. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37:917–923.

    PubMed  Google Scholar 

  9. Falck-Ytter Y, Younossi ZM, Marchesini G, McCullough AJ. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21:17–26.

    PubMed  CAS  Google Scholar 

  10. Mulhall BP, Ong JP, Younossi ZM. Nonalcoholic fatty liver disease: an overview. J Gastroenterol Hepatol. 2002;17:1136–1143.

    PubMed  CAS  Google Scholar 

  11. Hilden M, Christoffersen P, Juhl E, Dalgaard JB. Liver histology in a “normal” population-examinations of 503 consecutive fatal traffic casualties. Scand J Gastroenterol. 1977;12:593–597.

    PubMed  CAS  Google Scholar 

  12. Charlton M, Kasparova P, Weston S, et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001;7:608–614.

    PubMed  CAS  Google Scholar 

  13. Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology. 1990;12:1106–1110.

    PubMed  CAS  Google Scholar 

  14. Grattagliano I, Portincasa P, Palmieri V, Palasciano G. Managing nonalcoholic fatty liver disease. Recommendations for family physicians. Can Fam Physician. 2007;53:857–863.

    PubMed  Google Scholar 

  15. Harrison SA, Torgerson S, Hayashi PH. The natural history of nonalcoholic fatty liver disease: a clinical histopathological study. Comment in: Am J Gastroenterol. 2003;98:1915–1917.

    Google Scholar 

  16. Fassio E, Alvarez E, Domínguez N, et al. Natural history of nonalcoholic steatohepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40:820–826.

    PubMed  Google Scholar 

  17. Björnsson E. The clinical aspects of nonalcoholic fatty liver disease. Minerva Gastroenterol Dietol. 2008;54:7–18.

    PubMed  Google Scholar 

  18. Neuschwander-Tetri BA. Fatty liver and the metabolic syndrome. Curr Opin Gastroenterol. 2007;3:193–198.

    Google Scholar 

  19. Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol. 2007;22:293–303.

    PubMed  CAS  Google Scholar 

  20. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37:1595–1607.

    PubMed  CAS  Google Scholar 

  21. Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, metabolic syndrome: further evidence for an etiologic association. Hepatology. 2002;35:365–372.

    Google Scholar 

  22. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–845.

    PubMed  CAS  Google Scholar 

  23. Lima FB, Thies RS, Garvey WT. Glucose and insulin regulate insulin sensitivity in primary cultured adipocytes without affecting insulin receptor kinase activity. Endocrinology. 1991;128:2415–2426.

    PubMed  CAS  Google Scholar 

  24. Zamora-Valdes D, Chavez-Tapia NC, Mendez-Sanchez N. Molecular mechanisms of insulin resistance. Med Sur. 2004;11:149–159.

    Google Scholar 

  25. White MF. Insulin signaling in health and disease. Science. 2003;302:1710–1711.

    PubMed  CAS  Google Scholar 

  26. Shulman GI. Cellular mechanisms of insulin resistance in humans. Am J Cardiol. 1999;84:3–10.

    Google Scholar 

  27. Dupont J, Derouet M, Simon J, Taouis M. Effect of nutritional state on the formation of a complex involving insulin receptor IRS-1, the 52 kDa Src homology/collagen protein (Shc) isoform and phosphatidylinositol 3′-kinase activity. Biochem J. 1998;335:293–300.

    PubMed  CAS  Google Scholar 

  28. Sattar AA, Berhanu C, Gebreselassie S, Berhanu P. Human insulin receptor juxtamembrane domain independent insulin signaling. Cell Biol Int. 2007;31:815–824.

    PubMed  CAS  Google Scholar 

  29. Pearson G, Robinson F, Beers Gibson T, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–183.

    PubMed  CAS  Google Scholar 

  30. Choi BM, Yoo KH, Bae IS, et al. Angiotensin-converting enzyme inhibition modulates mitogen-activated protein kinase family expressions in the neonatal rat kidney. Pediatr Res. 2005; 57:115–123.

    PubMed  CAS  Google Scholar 

  31. Wang X, Martindale JL, Liu Y, Holbrook NJ. The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. Biochem J. 1998;333:291–300.

    PubMed  CAS  Google Scholar 

  32. Duvnjak M, Lerotic I, Barsic N, et al. Pathogenesis and management issues for non-alcoholic fatty liver disease. World J Gastroenterol. 2007;13:4539–4550.

    PubMed  CAS  Google Scholar 

  33. Capeau J, Bastard JP, Vigouroux C. Syndrome metabolique et insulinoresistance: physiopathologie. Mt Cardio. 2006;2:155–164.

    CAS  Google Scholar 

  34. Méndez-Sánchez N, Arrese M, Zamora-Valdés D, Uribe M. Current concepts in the pathogenesis of nonalcoholic fatty liver disease. Liver Int. 2007;27:423–433.

    PubMed  Google Scholar 

  35. McAvoy NC, Ferguson JW, Campbell IW, Hayes PC. Non-alcoholic fatty liver disease: natural history, pathogenesis and treatment. Br J Diabetes Vasc Dis. 2006;6:251–260.

    CAS  Google Scholar 

  36. Cusi K, Maezono K, Osman A, et al. Insulin resistance differentially affects the PI 3-kinase-and MAP kinase-mediated signaling in human muscle. J Clin Invest. 2000;105:311–320.

    PubMed  CAS  Google Scholar 

  37. Low Wang CC, Goalstone ML, Draznin B. Molecular mechanisms of insulin resistance that impact cardiovascular biology. Diabetes. 2004;53:2735–2740.

    Google Scholar 

  38. Miles JM, Park YS, Walewicz D, et al. Systemic and forearm triglyceride metabolism: fate of lipoprotein lipase-generated glycerol and free fatty acids. Diabetes. 2004;53:521–527.

    PubMed  CAS  Google Scholar 

  39. Havel RJ, Hamilton RL. Hepatic catabolism of remnant lipoproteins: where the action is. Arterioscler Thromb Vasc Biol. 2004;24:213–215.

    PubMed  CAS  Google Scholar 

  40. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1343–1351.

    PubMed  CAS  Google Scholar 

  41. Tamura S, Shimomura I. Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease. J Clin Invest. 2005;115:1139–1142.

    PubMed  CAS  Google Scholar 

  42. Timlin MT, Parks EJ. Temporal pattern of de novo lipogenesis in the postprandial state in healthy men. Am J Clin Nutr. 2005;81:35–42.

    PubMed  CAS  Google Scholar 

  43. Schwarz J-M, Linfoot P, Dare D, et al. Hepatic de novo lipogenesis in normoinsulinemic and hyperinsulinemic subjects consuming high-fat, low-carbohydrate and low-fat, high-carbohydrate isoenergetic diets. Am J Clin Nutr. 2003;77:43–50.

    PubMed  CAS  Google Scholar 

  44. Coleman RA, Lee DP. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res. 2004;43:134–176.

    PubMed  CAS  Google Scholar 

  45. Postic C, Girard J. Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest. 2008;118:829–838

    PubMed  CAS  Google Scholar 

  46. Yamaguchi K, Yang L, McCall S, et al. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology. 2007;45:1366–1374.

    PubMed  CAS  Google Scholar 

  47. Kohli R, Pan X, Malladi P, et al. Mitochondrial reactive oxygen species signal hepatocyte steatosis by regulating the phosphatidylinositol 3-kinase cell survival pathway. J Biol Chem. 2007;282:21327–21336.

    PubMed  CAS  Google Scholar 

  48. Samuel VT, Liu ZX, Qu X, et al. Mechanism of hepatic insulin resistance in nonalcoholic fatty liver disease. J Biol Chem. 2004;279:32345–32353.

    PubMed  CAS  Google Scholar 

  49. Samuel VT, Liu ZX, Wang A, et al. Inhibition of protein kinase C epsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest. 2007;117:739–745.

    PubMed  CAS  Google Scholar 

  50. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest. 2004;114:147–152.

    PubMed  CAS  Google Scholar 

  51. Bergamini CM, Gambetti S, Dondi A, Cervellati C. Oxygen, reactive oxygen species and tissue damage. Curr Pharm Des. 2004;10:1611–1626.

    PubMed  CAS  Google Scholar 

  52. Perez-Carreras M, Del Hoyo P, Martín MA, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38:999–1007.

    PubMed  CAS  Google Scholar 

  53. Pan M, Cederbaum AI, Zhang YL, et al. Lipid peroxidation and oxidant stress regulate hepatic apolipoprotein B degradation and VLDL production. J Clin Invest. 2004;113:1277–1287.

    PubMed  CAS  Google Scholar 

  54. Sugimoto R, Enjoji M, Kohjima M, et al. High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase. Liver Int. 2005;25:1018–1026.

    PubMed  CAS  Google Scholar 

  55. Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093–12101.

    PubMed  CAS  Google Scholar 

  56. Van Ginderachter JA, Movahedi K, Van den Bossche J, De Baetselier P. Macrophages, PPARs, and cancer. PPAR Res. 2008;2008:169414.

    PubMed  Google Scholar 

  57. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–964.

    PubMed  CAS  Google Scholar 

  58. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–184.

    PubMed  CAS  Google Scholar 

  59. Lacasa D, Taleb S, Keophiphath M, et al. Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. Endocrinology. 2007;148:868–877.

    PubMed  CAS  Google Scholar 

  60. Sharma AM, Staels B. Review: peroxisome proliferator-activated receptor gamma and adipose tissue-understanding obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab. 2007;92:386–395.

    PubMed  CAS  Google Scholar 

  61. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–1801.

    PubMed  CAS  Google Scholar 

  62. Lalor PF, Faint J, Aarbodem Y, et al. The role of cytokines and chemokines in the development of steatohepatitis. Semin Liver Dis. 2007;27:173–193.

    PubMed  CAS  Google Scholar 

  63. Zeyda M, Stulnig TM. Adipose tissue macrophages. Immunol Lett. 2007;112:61–67.

    PubMed  CAS  Google Scholar 

  64. Wigg AJ, Roberts-Thomson IC, Dymock RB, et al. The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis. Gut. 2001;48:206–211.

    PubMed  CAS  Google Scholar 

  65. Feldstein AE, Werneburg NW, Li Z, et al. Bax inhibition protects against free fatty acid-induced lysosomal permeabilization. Am J Physiol Gastrointest Liver Physiol. 2006;290:1339–1346.

    Google Scholar 

  66. Schwabe RF, Brenner DA. Mechanisms of liver injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol. 2006;290:583–589.

    Google Scholar 

  67. Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332–339.

    PubMed  CAS  Google Scholar 

  68. Wu X, Motoshima H, Mahadev K, et al. Involvement of AMP-activated protein kinase in glucose uptake stimulated by the globular domain of adiponectin in primary rat adipocytes. Diabetes. 2003;52:1355–1363.

    PubMed  CAS  Google Scholar 

  69. Minokoshi Y, Kim YB, Peroni OD, et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature. 2002;415:339–343.

    PubMed  CAS  Google Scholar 

  70. Saxena NK, Ikeda K, Rockey DC, et al. Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. J Hepatol. 2002;35:761–771.

    Google Scholar 

  71. Leclercq IA, Farrell GC, Schriemer R, Robertson GR. Leptin is essential for the hepatic fibrogenic response to chronic liver injury. J Hepatol. 2002;37:206–213.

    PubMed  CAS  Google Scholar 

  72. Muse ED, Lam TK, Scherer PE, Rossetti L. Hypothalamic resistin induces hepatic insulin resistance. J Clin Invest. 2007;117:1670–1678.

    PubMed  CAS  Google Scholar 

  73. Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14:222–231.

    PubMed  CAS  Google Scholar 

  74. Jager J, Gremeaux T, Cormont M, et al. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology. 2007;148:241–251.

    PubMed  CAS  Google Scholar 

  75. Jin X, Zimmers TA, Perez EA, et al. Paradoxical effects of short-and long-term interleukin-6 exposure on liver injury and repair. Hepatology. 2006;43:474–484.

    PubMed  CAS  Google Scholar 

  76. Ardaillou R. Active fragments of angiotensin II: enzymatic pathways of synthesis and biological effects. Curr Opin Nephrol Hypertens. 1997;6:28–34.

    PubMed  CAS  Google Scholar 

  77. Carey RM, Siragy HM. Newly recognized components of the renin-angiotensin system: potential roles in cardiovascular and renal regulation. Endocr Rev. 2003;24:261–271.

    PubMed  CAS  Google Scholar 

  78. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res. 2000;87:1–9.

    Google Scholar 

  79. Schindler C, Bramlage P, Kirch W, Ferrario CM. Role of the vasodilator peptide angiotensin-(1–7) in cardiovascular drug therapy. Vasc Health Risk Manag. 2007;3:125–137.

    PubMed  CAS  Google Scholar 

  80. Guo DF, Sun YL, Hamet P, Inagami T. The angiotensin II type 1 receptor and receptorassociated proteins. Cell Res. 2001;11:165–180.

    PubMed  CAS  Google Scholar 

  81. Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: regulation, signalling and function. Blood Press. 2003;12:70–88.

    PubMed  CAS  Google Scholar 

  82. Santos RAS, Simoes e Silva AC, Maric C, et al. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A. 2003;100:8258–8263.

    PubMed  CAS  Google Scholar 

  83. Velloso LA, Folli F. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996;93:12490–12495.

    PubMed  CAS  Google Scholar 

  84. Zhai, P, Yamamoto M, Galeotti J, et al. Cardiac-specific overexpression of AT1 receptor mutant lacking Gαq/Gαi coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest. 2005;115:3045–3056.

    PubMed  CAS  Google Scholar 

  85. Rajagopal K, Lefkowitz RJ, Rockman HA. When 7 transmembrane receptors are not G protein-coupled receptors. J Clin Invest. 2005;115:2971–2974.

    PubMed  CAS  Google Scholar 

  86. Kohout T, Lefkowitz R. Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol. 2003;63:9–18.

    PubMed  CAS  Google Scholar 

  87. Kenakin, T. Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci. 2003;24:346–354.

    PubMed  CAS  Google Scholar 

  88. Nickenig G, Roling J, Bohm M, et al. Insulin induces upregulation of vascular AT-1 receptor gene expression by post-transcriptional mechanisms. Circulation. 1998;98:2453–2460.

    PubMed  CAS  Google Scholar 

  89. Wei Y, Sowers JR, Nistala R, et al. Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells. J Biol Chem. 2006;281:35137–35146.

    PubMed  CAS  Google Scholar 

  90. Wei Y, Sowers JR, Clark SE, et al. Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. Am J Physiol Endocrinol Metab. 2008;294:345–351.

    Google Scholar 

  91. Motley ED, Eguchi K, Gardner C, et al. Insulin-induced Akt activation is inhibited by Angiotensin II in the vasculature through Protein Kinase C-α. Hypertension. 2003;41:775–780.

    PubMed  CAS  Google Scholar 

  92. Izawa Y, Yoshizumi M, Fujita Y, et al. ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells. Exp Cell Res. 2005;308:291–299.

    PubMed  CAS  Google Scholar 

  93. Engeli S, Negrel R, Sharma AM. Physiology and physiopathology of the adipose tissue renin-angiotensin system. Hypertension. 2000;35:1270–1277.

    PubMed  CAS  Google Scholar 

  94. Matsushita K, Wu Y, Okamoto Y, et al. Local renin angiotensin expression regulates human mesenchymal stem cell differentiation to adipocytes. Hypertension. 2006;48:1095–1102.

    PubMed  CAS  Google Scholar 

  95. Saint-Marc P, Kozak LP, Ailhaud G, et al. Angiotensin II as a trophic factor of white adipose tissue: stimulation of adipose cell formation. Endocrinology. 2001;142:487–492.

    PubMed  CAS  Google Scholar 

  96. Janke J, Engeli S, Gorzelniak K, et al. Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes. 2002;51:1699–1707.

    PubMed  CAS  Google Scholar 

  97. Mogi M, Iwai M, Horiuchi M. Emerging concept of adipogenesis aregulation by the rennin-angiotensin system. Hypertension. 2006;48:1020–1022.

    PubMed  CAS  Google Scholar 

  98. 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;22:1977–1982.

    PubMed  CAS  Google Scholar 

  99. Santos SH, Fernandes LR, Mario EG, et al. Mas deficiency in FVB/N mice produces marked changes in lipid and glycemic metabolism. Diabetes. 2008;57:340–347.

    PubMed  CAS  Google Scholar 

  100. Borglum JD, Richelsen B, Darimont C, et al. Expression of the two isoforms of prostaglandin endoperoxide synthase (PGHS-1 and PGHS-2) during adipose cell differentiation. Mol Cell Endocrinol. 1997;131:67–77.

    PubMed  CAS  Google Scholar 

  101. Fain JN, Ballou LR, Bahouth SW. Obesity is induced in mice heterozygous for cyclooxygenase-2. Prostaglandins Other Lipid Mediat. 2001;65:199–209.

    PubMed  CAS  Google Scholar 

  102. Jones BH, Standridge MK, Moustaid N. Angiotensin II increases lipogenesis in 3T3-L1 and human adipose cells. Endocrinology. 1997;138:1512–1519.

    PubMed  CAS  Google Scholar 

  103. Kim S, Whelan J, Claycombe K, et al. Angiotensin II increases leptin secretion by 3T3-L1 and human adipocytes via a prostaglandin-independent mechanism. J Nutr. 2002;132:1135–1140.

    PubMed  CAS  Google Scholar 

  104. Skurk T, van Harmelen V, Blum WF, Hauner H. Angiotensin II promotes leptin production in cultured human fat cells by an ERK1/2-dependent pathway. Obes Res. 2005;13:969–973.

    PubMed  CAS  Google Scholar 

  105. Kim S, Soltani-Bejnood M, Quignard-Boulange A, et al. The adipose reninangiotensin system modulates systemic markers of insulin sensitivity and activates the intrarenal renin-angiotensin system. J Biomed Biotechnol. 2006;2006:27012.

    PubMed  Google Scholar 

  106. Fasshauer M, Klein J, Neumann S, et al. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2002;290:1084–1089.

    PubMed  CAS  Google Scholar 

  107. Furuhashi M, Ura N, Higashiura K, et al. Blockade of the renin-angiotensin system increases adiponectin concentrations in patients with essential hypertension. Hypertension. 2003;42:76–81.

    PubMed  CAS  Google Scholar 

  108. Xu SQ, Mahadev K, Wu X, et al. Adiponectin protects against angiotensin II or tumor necrosis factor alpha-induced endothelial cell monolayer hyperpermeability: role of cAMP/PKA signaling. Arterioscler Thromb Vasc Biol. 2008;28:899–905.

    PubMed  CAS  Google Scholar 

  109. Nakamura A, Johns EJ, Imaizumi A, et al. Role of angiotensin II-induced cAMP in mesangial TNF-alpha production. Cytokine. 2002;19:47–51.

    PubMed  CAS  Google Scholar 

  110. Bucher M, Ittner KP, Hobbhalm J, et al. Downregulation of angiotensin II-type 1 receptors during sepsis. Hypertension. 2001;38:177–182.

    PubMed  CAS  Google Scholar 

  111. Cowling RT, Gurantz D, Peng J, et al. Transcription factor NF-kappa B is necessary for up-regulation of type 1 angiotensin II receptor mRNA in rat cardiac fibroblasts treated with tumor necrosis factoralpha or interleukin-1 beta. J Biol Chem. 2003;277:5719–57124.

    Google Scholar 

  112. Skurk T, van Harmelen V, Hauner H. Angiotensin II stimulates the release of interleukin-6 and interleukin-8 from cultured human adipocytes by activation of NF-kappaB. Arterioscler Thromb Vasc Biol. 2004;24:1199–1203.

    PubMed  CAS  Google Scholar 

  113. Schoonbroodt S, Piette J. Oxidative stress interference with the nuclear factor-kappa B activation pathways. Biochem Pharmacol. 2000;60:1075–1083.

    PubMed  CAS  Google Scholar 

  114. Choudhary S, Lu M, Cui R, Brasier AR. Involvement of a novel Rac/RhoA guanosine triphosphatase-nuclear factorkB inducing kinase signaling pathway mediating Angiotensin II-induced RelA transactivation. Mol Endocrinol. 2007;21:2203–2217.

    PubMed  CAS  Google Scholar 

  115. Sironi L, Gelosa P, Guerrini U, et al. Anti-inflammatory effects of AT1 receptor blockade provide end-organ protection in stroke-prone rats independently from blood pressure fall. J Pharmacol Exp Ther. 2004;311:989–995.

    PubMed  CAS  Google Scholar 

  116. Janssen SW, Hermus AR, Lange WP, et al. Progressive histopathological changes in pancreatic islets of Zucker diabetic fatty rats. Exp Clin Endocrinol Diabetes. 2001;109:273–282.

    PubMed  CAS  Google Scholar 

  117. Lau T, Carlsson PO, Leung PS. Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucosestimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia. 2004;47:240–248.

    PubMed  CAS  Google Scholar 

  118. Huang Z, Jansson L, Sjöholm A. Vasoactive drugs enhance pancreatic islet blood flow, augment insulin secretion and improve glucose tolerance in female rats. Clin Sci (Lond). 2007;112:69–76.

    CAS  Google Scholar 

  119. Carlsson PO, Berne C, Jansson L. Angiotensin II and the endocrine pancreas: effects on islet blood flow and insulin secretion in rats. Diabetologia. 1998;41:127–133.

    PubMed  CAS  Google Scholar 

  120. Dal Ponte DB, Fogt DL, Jacob S, Henriksen EJ. Interactions of captopril and verapamil on glucose tolerance and insulin action in an animal model of insulin resistance. Metabolism. 1998;47:982–987.

    Google Scholar 

  121. Tikellis C, Wookey PJ, Candido R, et al. Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat. Diabetes. 2004;53:989–997.

    PubMed  CAS  Google Scholar 

  122. Chu KY, Lau T, Carlsson PO, Leung PS. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes. 2006;55:367–374.

    PubMed  CAS  Google Scholar 

  123. Ramracheya RD, Muller DS, Wu Y, et al. Direct regulation of insulin secretion by angiotensin II in human islets of Langerhans. Diabetologia. 2006;49:321–331.

    PubMed  CAS  Google Scholar 

  124. Leung PS. The physiology of a local reninangiotensin system in the pancreas. J Physiol. 2007;580:31–37.

    PubMed  CAS  Google Scholar 

  125. Oliveira HR, Verlengia R, Carvalho CR, et al. Pancreatic β-cells express phagocyte-like NAD(P)H oxidase. Diabetes. 2003;52:1457–1463.

    PubMed  CAS  Google Scholar 

  126. Lupi R, Del Guerra S, Bugliani M, et al. The direct effects of the angiotensin-converting enzyme inhibitors, zofenoprilat and enalaprilat, on isolated human pancreatic islets. Eur J Endocrinol. 2006;154:355–361.

    PubMed  CAS  Google Scholar 

  127. Habibi J, Whaley-Connell A, Hayden MR, et al. Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat. Endocrinology. 2008; Jul 24. [Epub ahead of print.]

  128. Sun Y, Zhang J, Zhang JQ, Ramires FJ. Local angiotensin II and transforming growth factor-beta1 in renal fibrosis of rats. Hypertension. 2000;35:1078–1084.

    PubMed  CAS  Google Scholar 

  129. Chipitsyna G, Gong Q, Gray CF, et al. Induction of monocyte chemoattractant protein-1 expression by angiotensin II in the pancreatic islets and beta-cells. Endocrinology. 2007;148:2198–2208.

    PubMed  CAS  Google Scholar 

  130. Hirose A, Ono M, Saibara T, et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology. 2007;45:1375–1381.

    PubMed  CAS  Google Scholar 

  131. Warner FJ, Lubel JS, McCaughan GW, et al. Liver fibrosis: a balance of ACEs? Clin Sci (Lond). 2007;113:109–118.

    CAS  Google Scholar 

  132. Nabeshima Y, Tazuma S, Kanno K, et al. Anti-fibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis. Biochem Biophys Res Commun. 2006;346:658–664.

    PubMed  CAS  Google Scholar 

  133. Bataller R, Gabele E, Schoonhoven R, et al. Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol Gastrointest Liver Physiol. 2003;285:642–651.

    Google Scholar 

  134. Toblli JE, Munoz MC, Cao G, et al. ACE inhibition and AT1 receptor blockade prevent fatty liver and fibrosis in obese Zucker rats. Obesity (Silver Spring). 2008;16:770–776.

    CAS  Google Scholar 

  135. Takeshita Y, Takamura T, Takazakura A, et al. Cross talk of tumor necrosis factor-alpha and the renin-angiotensin system in tumor necrosis factor-alpha-induced plasminogen activator inhibitor-1 production from hepatocytes. Eur J Pharmacol. 2008;579:426–432.

    PubMed  CAS  Google Scholar 

  136. Ruiz-Ortega M, Lorenzo O, Suzuki Y, et al. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens. 2001;10:321–329.

    PubMed  CAS  Google Scholar 

  137. Jamaluddin M, Meng T, Sun J, et al. Angiotensin II induces nuclear factor (NF)-kappaB1 isoforms to bind the angiotensinogen gene acute-phase response element: a stimulus-specific pathway for NF-kappaB activation. Mol Endocrinol. 2000;14:99–113.

    PubMed  CAS  Google Scholar 

  138. Ramadori G, Saile B. Portal tract fibrogenesis in the liver. Lab Invest. 2004;84:153–159.

    PubMed  Google Scholar 

  139. Gabele E, Brenner DA, Rippe RA. Liver fibrosis: signals leading to the amplification of the fibrogenic hepatic stellate cell. Front Biosci. 2003;8:69–77.

    Google Scholar 

  140. Bataller R, Sancho-Bru P, Gines P, et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology. 2003;125:117–125.

    PubMed  CAS  Google Scholar 

  141. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–218.

    PubMed  CAS  Google Scholar 

  142. Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.

    PubMed  CAS  Google Scholar 

  143. Gorelik L, Flavell RA. Transforming growth factor in T-cell biology. Nat Rev Immunol. 2002;2:46–53.

    PubMed  CAS  Google Scholar 

  144. Roberts AB, Russo A, Felici A, Flanders KC. Smad3: a key player in pathogenetic mechanisms dependent on TGF. Ann NY Acad Sci. 2003;995:1–10.

    PubMed  CAS  Google Scholar 

  145. Schnabl B, Kweon YO, Frederick JP, et al. The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology. 2001;34:89–100.

    PubMed  CAS  Google Scholar 

  146. Baik SK, Jo HS, Suk KT, et al. Inhibitory effect of angiotensin 2 receptor antagonist on the contraction and growth of hepatic stellate cells. Korean J Gastroenterol. 2003;42:134–141.

    PubMed  Google Scholar 

  147. Liu J, Gong H, Zhang Z, Wang Y. Effect of angiotensin II and angiotensin II type 1 receptor antagonist on the proliferation, contraction and collagen synthesis in rat hepatic stellate cells. Chinese Med J. 2008;121:161–165.

    CAS  Google Scholar 

  148. Yoshiji H, Kuriyama S, Fukui H. Blockade of renin-angiotensin system in antifibrotic therapy. J Gastroenterol Hepatol. 2007;22(suppl. 1):93–95.

    Google Scholar 

  149. Gillespie EL, White CM, Kardas M, et al. The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes. Diabetes Care. 2005;28:2261–2266.

    PubMed  CAS  Google Scholar 

  150. Abuissa H, Jones PG, Marso SP, O’Keefe JHJr. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes. A meta-analysis of randomized clinical trials. J Am Coll Cardiol. 2005;46:821–826.

    PubMed  CAS  Google Scholar 

  151. Israili ZH. Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens. 2000;14(suppl. 1):73–86.

    Google Scholar 

  152. Oparil S. Newly emerging pharmacologic differences in angiotensin II receptor blockers. Am J Hypertens. 2000;13:18–24.

    Google Scholar 

  153. Unger T. Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different? Am J Cardiol. 1999;84:9–15.

    Google Scholar 

  154. Clemenz M, Frost N, Schupp MN, et al. Liver-specific peroxisome proliferatoractivated receptor alpha target gene regulation by the angiotensin type 1 receptor blocker telmisartan. Diabetes. 2008;57:1405–1413.

    PubMed  CAS  Google Scholar 

  155. Grange RL, Ziogas J, North AJ, et al. Selenosartans: novel selenophene analogues of milfasartan and eprosartan. Bioorg Med Chem Lett. 2008;18:1241–1244.

    PubMed  CAS  Google Scholar 

  156. Georgescu EF, Georgescu M. Therapeutic options in non-alcoholic steatohepatitis (NASH). Are all agents alike? Results of a preliminary study. J Gastrointestin Liver Dis. 2007;16:39–46.

    PubMed  Google Scholar 

  157. Yokohama S, Tokusashi Y, Nakamura K, et al. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J Gastroenterol. 2006;12:322–326.

    PubMed  CAS  Google Scholar 

  158. Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology. 2004;40:1222–1225.

    PubMed  CAS  Google Scholar 

  159. Zhang YJ, Yang XS, Wu PS, et al. Effects of angiotensin II and losartan on the growth and proliferation of hepatic stellate cells. Di Yi Jun Yi Da Xue Xue Bao. 2003;23:219–221.

    PubMed  CAS  Google Scholar 

  160. Wei YH, Jun L, Qiang CJ. Effect of losartan, an angiotensin II antagonist, on hepatic fibrosis induced by CCl4 in rats. Dig Dis Sci. 2004;49:1589–1594.

    PubMed  CAS  Google Scholar 

  161. Wei HS, Lu HM, Li DG, et al. The regulatory role of AT 1 receptor on activated HSCs in hepatic fibrogenesis:effects of RAS inhibitors on hepatic fibrosis induced by CCl(4). World J Gastroenterol. 2000;6:824–828.

    PubMed  CAS  Google Scholar 

  162. Wei HS, Li DG, Lu HM, et al. Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4). World J Gastroenterol. 2000;6:540–545.

    PubMed  CAS  Google Scholar 

  163. Ibañez P, Solis N, Pizarro M, et al. Effect of losartan on early liver fibrosis development in a rat model of nonalcoholic steatohepatitis. J Gastroenterol Hepatol. 2007;22:846–851.

    PubMed  Google Scholar 

  164. Kobayashi N, Ohno T, Yoshida K, et al. Cardioprotective mechanism of telmisartan via PPAR-gamma-eNOS pathway in dahl salt-sensitive hypertensive rats. Am J Hypertens. 2008;21:576–581.

    PubMed  CAS  Google Scholar 

  165. Georgescu EF, Ionescu R, Georgescu M, et al. Are angiotensin-receptor blockers candidates for first choice treatment in non-alcoholic steatohepatitis associated to mild-to moderate hypertension? J Hepatol. 2008;48(suppl. 2):346–347.

    Google Scholar 

  166. Fujita K, Yoneda M, Wada K, et al. Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. Dig Dis Sci. 2007;52:3455–3464.

    PubMed  CAS  Google Scholar 

  167. Jin H, Yamamoto N, Uchida K, et al. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet. Biochem Biophys Res Commun. 2007;364:801–807.

    PubMed  CAS  Google Scholar 

  168. Sugimoto K, Qi NR, Kazdová L, et al. Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension. 2006;47:822–823.

    Google Scholar 

  169. Yoshida T, Yamagishi S, Matsui T, et al. Telmisartan, an angiotensin II type 1 receptor blocker, inhibits advanced glycation end-product (AGE)-elicited hepatic insulin resistance via peroxisome proliferatoractivated receptor-gamma activation. J Int Med Res. 2008;36:237–243.

    PubMed  CAS  Google Scholar 

  170. Yamada S, Ano N, Toda K. Telmisartan but not candesartan affects adiponectin expression in vivo and in vitro. Hypertens Res. 2008;31:601–606.

    PubMed  CAS  Google Scholar 

  171. Derosa G, Ragonesi PD, Mugellini A, et al. Effects of telmisartan compared with eprosartan on blood pressure control, glucose metabolism and lipid profile in hypertensive, type 2 diabetic patients: a randomized, double-blind, placebo-controlled 12-month study. Hypertens Res. 2004;27:457–464.

    PubMed  CAS  Google Scholar 

  172. Shimabukuro M, Tanaka H, Shimabukuro T. Effects of telmisartan on fat distribution in individuals with the metabolic syndrome. J Hypertens. 2007;25:841–848.

    PubMed  CAS  Google Scholar 

  173. Benndorf RA, Rudolph T, Appel D, et al. Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Metabolism. 2006;55:1159–1164.

    PubMed  CAS  Google Scholar 

  174. Araki K, Masaki T, Katsuragi I, et al. Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice. Hypertension. 2006;48:51–57.

    PubMed  CAS  Google Scholar 

  175. Cianchetti S, Del Fiorentino A, Colognato R, et al. Anti-inflammatory and anti-oxidant properties of telmisartan in cultured human umbilical vein endothelial cells. Atherosclerosis. 2008;198:22–28.

    PubMed  CAS  Google Scholar 

  176. Yoshida T, Yamagishi S, Nakamura K, et al. Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation. Diabetologia. 2006;49:3094–3099.

    PubMed  CAS  Google Scholar 

  177. Walcher D, Hess K, Heinz P, et al. Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma. Hypertension. 2008;51:259–266.

    PubMed  CAS  Google Scholar 

  178. Ran J, Hirano T, Adachi M. Angiotensin II infusion increases hepatic triglyceride production via its type 2 receptor in rats. J Hypertens. 2005;23:1525–1530.

    PubMed  CAS  Google Scholar 

  179. Ran J, Hirano T, Adachi M. Angiotensin II type 1 receptor blocker ameliorates overproduction and accumulation of triglyceride in the liver of Zucker fatty rats. Am J Physiol Endocrinol Metab. 2004;287:227–232.

    Google Scholar 

  180. Kurikawa N, Suga M, Kuroda S, et al. An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol. 2003;139:1085–1094.

    PubMed  CAS  Google Scholar 

  181. Debernardi-Venon W, Martini S, Biasi F, et al. AT1 receptor antagonist candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol. 2007;46:1026–1033.

    PubMed  CAS  Google Scholar 

  182. Yu F, Takahashi T, Moriya J, et al. Angiotensin-II receptor antagonist alleviates non-alcoholic fatty liver in KKAy obese mice with type 2 diabetes. J Int Med Res. 2006;34:297–302.

    PubMed  CAS  Google Scholar 

  183. Yoshiji H, Kuriyama S, Yoshii J. Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology. 2001;34:745–750.

    PubMed  CAS  Google Scholar 

  184. Ueki M, Koda M, Yamamoto S, et al. Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats. J Gastroenterol. 2006;41:996–1004.

    PubMed  CAS  Google Scholar 

  185. Töx U, Scheller I, Kociok N, et al. Expression of angiotensin II receptor type 1 is reduced in advanced rat liver fibrosis. Dig Dis Sci. 2007;52:1995–2005.

    PubMed  Google Scholar 

  186. Tuncer I, Ozbek H, Ugras S, et al. Anti-fibrogenic effects of captopril and candesartan cilexetil on the hepatic fibrosis development in rat. The effect of AT1-R blocker on the hepatic fibrosis. Exp Toxicol Pathol. 2003;55:159–166.

    PubMed  CAS  Google Scholar 

  187. Clasen R, Schupp M, Foryst-Ludwig A, et al. PPAR gamma activating angiotensin type 1 receptor blockers induce adiponectin. Hypertension. 2005;46:137–143.

    PubMed  CAS  Google Scholar 

  188. Erbe DV, Gartrell K, Zhang YL, et al. Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists. Vascul Pharmacol. 2006;45:154–162.

    PubMed  CAS  Google Scholar 

  189. Nie L, Imamura M, Itoh H, Ueno H. Pitavastatin enhances the anti-fibrogenesis effects of candesartan, an angiotensin II receptor blocker, on CCl4-induced liver fibrosis in rats. J UOEH. 2004;26:165–177.

    PubMed  CAS  Google Scholar 

  190. Wei Y, Clark SE, Morris EM, et al. Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats. J Hepatol. 2008;49:417–428.

    PubMed  CAS  Google Scholar 

  191. Ilanne-Parikka P, Eriksson JG, Lindström J, et al. Prevalence of the metabolic syndrome and its components: findings from a Finnish general population sample and the Diabetes Prevention Study cohort. Diabetes Care. 2004;27:2135–2140.

    Google Scholar 

  192. Mancia G, Bombelli M, Corrao G, et al. Metabolic syndrome in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study: daily life blood pressure, cardiac damage, and prognosis. Hypertension. 2007;49:40–47.

    PubMed  CAS  Google Scholar 

  193. Govindarajan G, Whaley-Connell A, Mugo M, et al. The cardiometabolic syndrome as a cardiovascular risk factor. Am J Med Sci. 2005;330:311–318.

    PubMed  Google Scholar 

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Correspondence to Eugen Florin Georgescu.

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Georgescu, E.F. Angiotensin receptor blockers in the treatment of NASH/NAFLD: Could they be a first-class option?. Adv Therapy 25, 1141–1174 (2008). https://doi.org/10.1007/s12325-008-0110-2

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