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Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

Abstract

The prevalence of hypertension in individuals with obesity or type II diabetes is substantially elevated. Increased levels of non-esterified fatty acids (NEFAs) in abdominally obese subjects were reported to contribute in the development of various disturbances related to the metabolic syndrome, such as hepatic and peripheral insulin resistance (IR), dyslipidaemia, β-cell apoptosis, endothelial dysfunction and others. However, the involvement of NEFAs in the development of hypertension has been much less studied in comparison to other mechanisms linking IR and central obesity with blood pressure (BP) elevation. This article reviews the existing evidence on the relation between NEFA and hypertension in an attempt to shed a light on it. In vivo data from both animal and human studies support that acute plasma NEFA elevation leads to increase in BP levels, whereas epidemiological evidence suggests a link between increased NEFA levels and hypertension. Further, accumulating data indicate the existence of several pathways through which NEFAs could promote BP elevation, that is α1-adrenergic stimulation, endothelial dysfunction, increase in oxidant stress, stimulation of vascular cell's growth and others. The above data support a possible important role of NEFA in hypertension development in patients with obesity and the metabolic syndrome and raise hypotheses for future research.

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References

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

    Article  CAS  Google Scholar 

  2. Sarafidis PA, Nilsson PM . The metabolic syndrome: a glance in its history. J Hypertens 2006; 24: 621–626.

    Article  CAS  Google Scholar 

  3. Kaplan NM . The deadly quartet. Upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension. Arch Intern Med 1989; 149: 1514–1520.

    Article  CAS  Google Scholar 

  4. Wajchenberg BL . Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev 2000; 21: 697–738.

    Article  CAS  Google Scholar 

  5. Jensen MD, Haymond MW, Rizza RA, Cryer PE, Miles JM . Influence of body fat distribution on free fatty acid metabolism in obesity. J Clin Invest 1989; 83: 1168–1173.

    Article  CAS  Google Scholar 

  6. Martin ML, Jensen MD . Effects of body fat distribution on regional lipolysis in obesity. J Clin Invest 1991; 88: 609–613.

    Article  CAS  Google Scholar 

  7. Bevilacqua S, Bonadonna R, Buzzigoli G, Boni C, Ciociaro D, Maccari F et al. Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. Metabolism 1987; 36: 502–506.

    Article  CAS  Google Scholar 

  8. Boden G, Chen X, Ruiz J, White JV, Rosseti L . Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994; 93: 2438–2446.

    Article  CAS  Google Scholar 

  9. Shimabukuro M, Zhou YT, Levi M, Unger R . Fatty acid-induced β cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci USA 1998; 95: 2498–2502.

    Article  CAS  Google Scholar 

  10. Steinberg HO, Baron AD . Vascular function, insulin resistance and fatty acids. Diabetologia 2002; 45: 623–634.

    Article  CAS  Google Scholar 

  11. Nilsson L, Banfi C, Diczfalusy U, Tremoli E, Hamsten A, Eriksson P . Unsaturated fatty acids increase plasminogen activator inhibitor-1 in endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 1679–1685.

    Article  CAS  Google Scholar 

  12. Abate N . Obesity and Cardiovascular disease. Pathogenic role of the metabolic syndrome and therapeutic implications. J Diabetes Complications 2000; 14: 154–174.

    Article  CAS  Google Scholar 

  13. Sarafidis PA, Lasaridis AN . Actions of PPARγ agonists explaining a possible blood pressure lowering effect. Am J Hypertens 2006; 19: 646–653.

    Article  CAS  Google Scholar 

  14. Rocchini AP . Obesity hypertension. Am J Hypertens 2002; 15: 50S–52S.

    Article  Google Scholar 

  15. Sharma AM, Engeli S, Pischon T . New developments in mechanisms of obesity-induced hypertension: role of adipose tissue. Curr Hypertens Rep 2001; 3: 152–156.

    Article  CAS  Google Scholar 

  16. Egan BM, Greene EL, Goodfriend TL . Nonesterified fatty acids in blood pressure control and cardiovascular complications. Curr Hypertens Rep 2001; 3: 107–116.

    Article  CAS  Google Scholar 

  17. Bulow J, Madsen J, Hojgaard L . Reversibility of the effects on local circulation of high lipid concentrations in blood. Scand J Clin Lab Invest 1990; 50: 291–296.

    Article  CAS  Google Scholar 

  18. Meng HC, Edgren B . Source of plasma free fatty acids in dogs receiving fat emulsion and heparin. Am J Physiol 1963; 204: 691–695.

    Article  CAS  Google Scholar 

  19. Grekin RJ, Vollmer AP, Sider RS . Pressor effects of portal venous oleate infusion. A proposed mechanism for obesity hypertension. Hypertension 1995; 26: 193–198.

    Article  CAS  Google Scholar 

  20. Grekin RJ, Dumont CJ, Vollmer AP, Watts SW, Webb RC . Mechanisms in the pressor effects of hepatic portal venous fatty acid infusion. Am J Physiol 1997; 273: R324–R330.

    CAS  PubMed  Google Scholar 

  21. Egan BM, Hennes MMI, Stepniakowski KT, O'Shaughnessy IM, Kissebach AH, Goodfriend TL . Obesity hypertension is related more to insulin's fatty acid than glucose action. Hypertension 1996; 27: 723–728.

    Article  CAS  Google Scholar 

  22. Fagot-Campagna A, Balkau B, Simon D, Warnet JM, Claude JR, Ducimetiere P et al. High free fatty acid concentration: an independent risk factor for hypertension in the Paris Prospective Study. Int J Epidemiol 1998; 27: 808–813.

    Article  CAS  Google Scholar 

  23. Steinberg HO, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest 1997; 100: 1230–1239.

    Article  CAS  Google Scholar 

  24. Steinberg HO, Paradisi G, Hook G, Crowder K, Cronin J, Baron AD . Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. Diabetes 2000; 49: 1231–1238.

    Article  CAS  Google Scholar 

  25. Stojiljkovic MP, Zhang D, Lopes HF, Lee CG, Goodfriend TL, Egan BM . Hemodynamic effects of lipids in humans. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1674–R1679.

    Article  CAS  Google Scholar 

  26. Lopes HF, Stojiljkovic MP, Zhang D, Goodfriend TL, Egan BM . The pressor response to acute hyperlipidemia is enhanced in lean normotensive offspring of hypertensive parents. Am J Hypertens 2001; 14: 1032–1037.

    Article  CAS  Google Scholar 

  27. Lopes HF, Martin KL, Nashar K, Morrow JD, Goodfriend TL, Egan BM . DASH diet lowers blood pressure and lipid-induced oxidative stress in obesity. Hypertension 2003; 41: 422–430.

    Article  CAS  Google Scholar 

  28. Egan BM, Panis R, Hinderliter A, Shork N, Julius S . Mechanism of increased alpha-adrenergic vasoconstriction in human essential hypertension. J Clin Invest 1987; 80: 812–817.

    Article  CAS  Google Scholar 

  29. Egan BM, Shork NJ, Weder AB . Regional hemodynamic abnormalities in overweight men: focus on α-adrenergic vascular responses. Am J Hypertens 1989; 2: 428–434.

    Article  CAS  Google Scholar 

  30. Stepniakowski KT, Egan BM . Additive effects of hypertension and obesity to limit venous distensibility. Am J Physiol 1995; 268: R562–R568.

    CAS  PubMed  Google Scholar 

  31. Neahring JM, Stepniakowski K, Greene AS, Egan BM . Insulin does not reduce forearm alpha-vasoreactivity in obese hypertensive or lean normotensive men. Hypertension 1993; 22: 584–590.

    Article  CAS  Google Scholar 

  32. Stepniakowski KT, Goodfriend TL, Egan BM . Fatty acids enhance vascular α-adrenergic sensitivity. Hypertension 1995; 25: II774–II778.

    Article  Google Scholar 

  33. Stepniakowski KT, Sallee FR, Goodfriend TL, Zhang Z, Egan BM . Fatty acids enhance neurovascular reflex responses by effects on alpha 1-adrenoceptors. Am J Physiol 1996; 270: R1340–R1346.

    CAS  PubMed  Google Scholar 

  34. Haastrup AT, Stepniakowski KT, Goodfriend TL, Egan BM . Intralipid enhances alpha1-adrenergic receptor mediated pressor sensitivity. Hypertension 1998; 32: 693–698.

    Article  CAS  Google Scholar 

  35. Lundman P, Eriksson M, Schenck-Gustafsson K, Karpe F, Tornvall P . Transient triglyceridemia decreases vascular reactivity in young, healthy men without risk factors for coronary heart disease. Circulation 1997; 96: 3266–3268.

    Article  CAS  Google Scholar 

  36. Davda RK, Stepniakowski KT, Lu G, Ullian ME, Goodfriend TL, Egan BM . Oleic acid inhibits endothelial cell nitric oxide synthase by a PKC-independent mechanism. Hypertension 1995; 26: 764–770.

    Article  CAS  Google Scholar 

  37. Gupta MP, Steinberg H, Baron A, Hart CM . Fatty acids impair nitric oxide production in cultured endothelial cells [Abstract]. J Investig Med 1998; 46: 288A.

    Google Scholar 

  38. de Kreutzenberg SV, Crepaldi C, Marchetto S, Calo L, Tiengo A, Del Prato S et al. Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition. J Clin Endocrinol Metab 2000; 85: 793–798.

    Article  CAS  Google Scholar 

  39. Scherrer U, Randin D, Vollenweider P, Vollenweider L, Nicod P . Nitric oxide release accounts for insulin's vascular effects in humans. J Clin Invest 1994; 94: 2511–2515.

    Article  CAS  Google Scholar 

  40. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD . Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest 1994; 94: 1172–1179.

    Article  CAS  Google Scholar 

  41. Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron AD . Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest 1996; 97: 2601–2610.

    Article  CAS  Google Scholar 

  42. Laine H, Knuuti MJ, Ruotsalainen U, Raitakari M, Iida H, Kapanen J et al. Insulin resistance in essential hypertension is characterized by impaired insulin stimulation of blood flow in skeletal muscle. J Hypertens 1998; 16: 211–219.

    Article  CAS  Google Scholar 

  43. Sartori C, Scherrer U . Insulin, nitric oxide and the sympathetic nervous system: at the crossroads of metabolic and cardiovascular regulation. J Hypertens 1999; 17: 1517–1525.

    Article  CAS  Google Scholar 

  44. Shepherd PR, Wither DJ, Siddle K . Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 1998; 333: 471–490.

    Article  CAS  Google Scholar 

  45. Zeng G, Quon MJ . Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest 1996; 98: 894–898.

    Article  CAS  Google Scholar 

  46. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 1996; 97: 2859–2865.

    Article  CAS  Google Scholar 

  47. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999; 103: 253–259.

    Article  CAS  Google Scholar 

  48. Lu G, Greene EL, Nagai T, Egan BM . Reactive oxygen species are critical in the oleic acid-mediated mitogenic signaling pathway in vascular smooth muscle cells. Hypertension 1998; 32: 1003–1010.

    Article  CAS  Google Scholar 

  49. Stojiljkovic MP, Lopes HF, Zhang D, Morrow JD, Goodfriend TL, Egan BM . Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster. J Hypertens 2002; 20: 1215–1221.

    Article  CAS  Google Scholar 

  50. Lopes HF, Morrow JD, Stojiljkovic MP, Goodfriend TL, Egan BM . Acute hyperlipidemia increases oxidative stress more in African Americans than in white Americans. Am J Hypertens 2003; 16: 331–336.

    Article  CAS  Google Scholar 

  51. Nosratola D, Vaziri D, Wang XQ, Oveisi F, Rad B . Induction of oxidative stress by glutathione depletion causes severe hypertension in normal rats. Hypertension 2000; 36: 142–146.

    Article  Google Scholar 

  52. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997; 336: 1117–1124.

    Article  CAS  Google Scholar 

  53. Kaplan NM . Primary hypertension: pathogenesis. In: Kaplan NM (ed). Clinical Hypertension, 8th edn. Lippincott Williams & Wilkins: Philadelphia, PA, 2002, pp 56–135.

    Google Scholar 

  54. Lever AF, Harrap SB . Essential hypertension: a disorder of growth with origins in childhood? J Hypertens 1992; 10: 101–120.

    Article  CAS  Google Scholar 

  55. Lu G, Morinelli TA, Meier KE, Rosenzweig SA, Egan BM . Oleic acid-induced mitogenic signaling in vascular smooth muscle cells. A role for protein kinase C. Circ Res 1996; 79: 611–618.

    Article  CAS  Google Scholar 

  56. Lu G, Meier KE, Jaffa AA, Rosenzweig SA, Egan BM . Oleic acid and angiotensin induce a synergistic mitogenic response. Hypertension 1998; 31: 978–985.

    Article  CAS  Google Scholar 

  57. Greene EL, Lu G, Zhang D, Egan BM . Signaling events mediating the additive effects of oleic acid and angiotensin II on vascular smooth muscle cell migration. Hypertension 2001; 37: 308–312.

    Article  CAS  Google Scholar 

  58. Khan WA, Blobe G, Halpern A, Wetsel WC, Burns D, Loomis C et al. Selective regulation of protein kinase C isoezymes by oleic acid in human platelets. J Biol Chem 1993; 268: 5063–5068.

    CAS  PubMed  Google Scholar 

  59. Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, Lozano J et al. Protein kinase C-z is critical for mitogenic signal transduction. Cell 1993; 74: 555–563.

    Article  CAS  Google Scholar 

  60. Liao D-F, Monia B, Dean N, Berk BC . Protein kinase C-z mediates angiotensin II activation of ERK-1 and -2 in vascular smooth muscle cells. J Biol Chem 1997; 272: 6146–6150.

    Article  CAS  Google Scholar 

  61. Askari B, Carroll MA, Capparelli M, Kramer F, Gerrity RG, Bornfeldt KE . Oleate and linoleate enhance the growth-promoting effects of insulin-like growth factor-I through a phospholipase D-dependent pathway in arterial smooth muscle cells. J Biol Chem 2002; 277: 36338–36344.

    Article  CAS  Google Scholar 

  62. Sowers JR . Insulin and insulin-like growth factor in normal and pathological cardiovascular physiology. Hypertension 1997; 29: 691–699.

    Article  CAS  Google Scholar 

  63. Safonova I, Aubert J, Negrel R, Ailhaud G . Regulation by fatty acids of angiotensinogen gene expression in preadipose cells. Biochem J 1997; 322: 235–239.

    Article  CAS  Google Scholar 

  64. Goodfriend TL, Ball DL, Egan BM, Campbell WB, Nithipatikom K . Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion. Hypertension 1004; 43: 358–363.

    Article  Google Scholar 

  65. Tamura M, Kuwano H, Kinoshita T, Inagami T . Identification of linoleic and oleic acids as endogenous Na+,K+-ATPase inhibitors from acute volume-expanded hog plasma. J Biol Chem 1985; 260: 9672–9677.

    CAS  PubMed  Google Scholar 

  66. Ng LL, Hockaday TD . Non-esterified fatty acids may regulate human leucocyte sodium pump activity. Clin Sci (London) 1986; 71: 737–742.

    Article  CAS  Google Scholar 

  67. Lijnen P . Alterations in sodium metabolism as an etiological model for hypertension. Cardiovasc Drugs Ther 1995; 9: 377–399.

    Article  CAS  Google Scholar 

  68. Sowers JR, Whitfield L, Beck FW, Catania RA, Tuck ML, Dornfeld L et al. Role of enhanced sympathetic nervous system activity and reduced Na+,K+-dependent adenosine triphosphatase activity in the maintenance of elevated blood pressure in obesity: effects of weight loss. Clin Sci 1982; 63: 121S–124S.

    Article  Google Scholar 

  69. Weder AB . Sodium metabolism, hypertension and diabetes. Am J Med Sci 1994; 307: S53–S59.

    PubMed  Google Scholar 

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Correspondence to P A Sarafidis.

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Sarafidis, P., Bakris, G. Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?. J Hum Hypertens 21, 12–19 (2007). https://doi.org/10.1038/sj.jhh.1002103

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  • DOI: https://doi.org/10.1038/sj.jhh.1002103

Keywords

  • non-esterified fatty acids
  • hypertension
  • obesity
  • insulin resistance
  • type II diabetes

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