Skip to main content
Log in

Mechanisms Linking Nonalcoholic Fatty Liver Disease with Coronary Artery Disease

  • Review
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is coronary artery disease (CAD), not chronic liver disease. Fatty liver increases cardiovascular risk by classical (dyslipidemia, hypertension, diabetes) and by less conventional mechanisms. Common pathways involved in the pathogenesis of fatty liver and CAD includes hepatic insulin resistance and sub clinical inflammation. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased FFA, which causes lipotoxicity and impairs endothelium-dependent vasodilatation, increases oxidative stress, and has a cardio toxic effect. Additional metabolic risk factors include leptin, adiponectin, pro inflammatory cytokines [such as IL-6, C-reactive protein and plasminogen activator inhibitor-1 (PAI-1)], which together lead to increased oxidative stress and endothelial dysfunction, finally promoting coronary artery disease (CAD). When classical risk factors are superimposed on fatty liver accumulation, they may further increase the new metabolic risk factors, exacerbating CAD. The clinical implication is that patients with NAFLD are at higher risk (steatohepatitis, diabetes, obesity, atherogenic dyslipidemia) and should undergo periodic cardiovascular risk assessment including the Framingham score, cardiac effort test, and measurement of intimae-media thickening of the carotids arteries. This may improve risk stratification for CAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346:1221–1231.

    Article  PubMed  CAS  Google Scholar 

  2. Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis. 2007;191:235–240.

    Article  PubMed  CAS  Google Scholar 

  3. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;4:917–923.

    Article  Google Scholar 

  4. Younossi Z, Diehl AM, Ong JP. Nonalcoholic fatty liver disease: an agenda for clinical research. Hepatology. 2002;35:746–752.

    Article  PubMed  Google Scholar 

  5. Caldwell S, Argo C. The natural history of non-alcoholic fatty liver disease. Dig Dis. 2010;28:162–168.

    Article  PubMed  Google Scholar 

  6. Petersen KF, Dufour S, Hariri A, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med. 2010;362:1082–1089.

    Article  PubMed  CAS  Google Scholar 

  7. Gami AS, Witt BJ, Howard DE, et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systemic review and meta-analysis of longitudinal studies. J Am Coll Cardiol. 2007;30:403–414.

    Article  CAS  Google Scholar 

  8. Ford ES, Schulze MB, Pischon T, Bergmann MM, Joost HG, Boeing H. Metabolic syndrome and risk of incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. Cardiovasc Diabetol. 2008;7:35.

    Article  PubMed  Google Scholar 

  9. Ford ES, Li C, Sattar N. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care. 2008;9:1898–1904.

    Article  Google Scholar 

  10. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;21:2709–2716.

    Article  Google Scholar 

  11. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683–689.

    Article  PubMed  CAS  Google Scholar 

  12. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation. 2004;10:1245–1250.

    Article  Google Scholar 

  13. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–1395.

    Article  PubMed  Google Scholar 

  14. Sagi R, Reif S, Neuman G, Webb M, Phillip M, Shalitin S. Nonalcoholic fatty liver disease in overweight children and adolescents. Acta Paediatr. 2007;96:1209–1213.

    Article  PubMed  CAS  Google Scholar 

  15. Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol. 2007;13:1579–1584.

    PubMed  CAS  Google Scholar 

  16. Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol. 2009;51:918–924.

    Article  PubMed  CAS  Google Scholar 

  17. Targher G, Bertolini L, Padovani R, Zenari L, Zoppini G, Falezza G. Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care. 2004;10:2498–2500.

    Article  Google Scholar 

  18. Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol. 2005;5:1040–1050.

    Google Scholar 

  19. Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol. 2005;11:4838–4842.

    PubMed  Google Scholar 

  20. Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;2:473–480.

    Article  Google Scholar 

  21. Schindhelm RK, Diamant M, Bakker SJ, et al. Liver alanine aminotransferase, insulin resistance and endothelial dysfunction in normotriglyceridaemic subjects with type 2 diabetes mellitus. Eur J Clin Invest. 2005;6:369–374.

    Article  Google Scholar 

  22. Targher G, Bertolini L, Padovani R, et al. Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease. Diabet Med. 2006;23:403–409.

    Article  PubMed  CAS  Google Scholar 

  23. Targher G, Bertolini L, Padovani R, et al. Relation between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care. 2006;29:1325–1330.

    Article  PubMed  Google Scholar 

  24. Akabame S, Hamaguchi M, Tomiyasu K, et al. Evaluation of vulnerable coronary plaques and non-alcoholic fatty liver disease (NAFLD) by 64-detector multislice computed tomography (MSCT). Circ J. 2008;72:618–625.

    Article  PubMed  Google Scholar 

  25. Assy N, Djibre A, Farah R, Grosovski M, Marmor A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology. 2010;254:393–400.

    Article  PubMed  Google Scholar 

  26. Pacifico L, Cantisani V, Ricci P, et al. Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Paediatr Res. 2008;63:423–427.

    Article  CAS  Google Scholar 

  27. Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;1:113–121.

    Article  Google Scholar 

  28. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;6:1413–1419.

    Article  Google Scholar 

  29. Targher G, Bertolini L, Poli F, et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes. 2005;54:3541–3546.

    Article  PubMed  CAS  Google Scholar 

  30. Targher G, Bertolini L, Rodella S, et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care. 2007;8:2119–2121.

    Article  CAS  Google Scholar 

  31. Dunn W, Xu R, Wingard DL, et al. Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol. 2008;9:2263–2271.

    Article  Google Scholar 

  32. Ruttmann E, Brant LJ, Concin H, Diem G, Rapp K, Ulmer H. Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation. 2005;14:2130–2137.

    Article  CAS  Google Scholar 

  33. Lee DS, Evans JC, Robins SJ, et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol. 2007;1:127–133.

    Article  CAS  Google Scholar 

  34. Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology. 2006;40:865–873.

    Article  CAS  Google Scholar 

  35. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49:608–612.

    Article  PubMed  Google Scholar 

  36. Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology. 2010;2:595–602.

    Article  Google Scholar 

  37. Park SH, Kim BI, Yun JW, et al. Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men. J Gastroenterol Hepatol. 2004;6:694–698.

    Article  Google Scholar 

  38. Lee S, Jin Kim Y, Yong Jeon T, et al. Obesity is the only independent factor associated with ultrasound-diagnosed non-alcoholic fatty disease: a cross-sectional case-control study. Scand J Gastroenterol. 2006;51:566–572.

    Article  Google Scholar 

  39. Hirsch S, Poniachick J, Avendano M, et al. Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition. 2005;2:137–141.

    Article  CAS  Google Scholar 

  40. Assy N, Bekirov I, Mejritsky Y, Solomon L, Szvalb S, Hussein O. Association between thrombotic risk factors and extent of fibrosis in patients with non-alcoholic fatty liver diseases. World J Gastroenterol. 2005;37:5834–5839.

    Google Scholar 

  41. Sookoian S, Castano GO, Burgueno AL, et al. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis. 2010;2:585–591.

    Article  CAS  Google Scholar 

  42. Ruhl CE, Everhart JE. Epidemiology of nonalcoholic fatty liver. Clin Liver Dis. 2004;3:501–519.

    Article  Google Scholar 

  43. Carulli L, Lonardo A, Lombardini S, Marchesini G, Loria P. Gender, fatty liver and GGT. Hepatology. 2006;44:278–279.

    Article  PubMed  Google Scholar 

  44. Powell KE, Thompson PD, Caspersen CJ, Kendrick JS. Physical activity and the incidence of coronary heart disease. Annu Rev Public Health. 1987;8:253–287.

    Article  PubMed  CAS  Google Scholar 

  45. Hsieh SD, Yoshinaga H, Muto T, Sakurai Y. Regular physical activity and coronary risk factors in Japanese men. Circulation. 1998;97:661–665.

    PubMed  CAS  Google Scholar 

  46. Church TS, Kuk JL, Ross R, Priest EL, Biltoft E, Blair SN. Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology. 2006;7:2023–2030.

    Article  CAS  Google Scholar 

  47. Zelber-Sagi S, Nitzan-Kaliski D, Goldsmith R, et al. Role of leisure-time physical activity in alcoholic fatty liver disease: a population-based study. Hepatology. 2008;48:1791–1798.

    Article  PubMed  Google Scholar 

  48. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434–444.

    Article  PubMed  CAS  Google Scholar 

  49. Adlerberth AM, Rosengren A, Wilhelmsen L. Diabetes and long-term risk of mortality from coronary and other causes in middle-aged Swedish men. A general population study. Diabetes Care. 1998;21:539–545.

    Article  PubMed  CAS  Google Scholar 

  50. De Marco R, Locatelli F, Zoppini G, Verlato G, Bonora E, Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care. 1999;22:756–761.

    Article  PubMed  Google Scholar 

  51. Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and metabolic syndrome. Curr Opin Lipidol. 2005;16:421–427.

    Article  PubMed  CAS  Google Scholar 

  52. Hanley AJ, Williams K, Festa A, et al. Insulin resistance atherosclerosis study. Diabetes. 2004;53:2623–2632.

    Article  PubMed  CAS  Google Scholar 

  53. Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart continues and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986;256:2823–2828.

    Article  PubMed  CAS  Google Scholar 

  54. Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci. 2000;45:1929–1934.

    Article  PubMed  CAS  Google Scholar 

  55. Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA. 2003;289:3000–3004.

    Article  PubMed  Google Scholar 

  56. Radu C, Grigoriscu M, Crisan D, Lupsor M, Constantin D, Dina L. Prevalence and associated risk factors of non-alcoholic fatty liver disease in hospitalized patients. J Gastrointestin Liver Dis. 2008;17:255–260.

    PubMed  Google Scholar 

  57. Rabkin SW, Mathewson FA, Hsu PH. Relation of body weight to development of ischemic heart disease in a cohort of young North American men after a 26 year of observation period: the Manitoba study. Am J Cardiol. 1977;39:452–458.

    Article  PubMed  CAS  Google Scholar 

  58. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1983;67:968–977.

    Article  PubMed  CAS  Google Scholar 

  59. Ruhl CE, Everhart JE. Determination of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71–79.

    Article  PubMed  CAS  Google Scholar 

  60. Marcos A, Fisher RA, Ham JM, et al. Selection and outcome of living donors for adult-to-adult right lobe transplantation. Transplantation. 2000;69:2410–2415.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  62. Lee RG. Nonalcoholic steatohepatitis a study of 49 patients. Hum Pathol. 1989;20:594–598.

    Article  PubMed  CAS  Google Scholar 

  63. Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidity obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg. 2000;12:49–51.

    Article  Google Scholar 

  64. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs. Lancet. 2000;356:1955–1964.

    Article  PubMed  CAS  Google Scholar 

  65. Donati G, Stagni B, Piscaglia F, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut. 2004;53:1020–1023.

    Article  PubMed  CAS  Google Scholar 

  66. 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.

    Article  PubMed  CAS  Google Scholar 

  67. Day CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut. 2002;50:585–588.

    Article  PubMed  CAS  Google Scholar 

  68. Yang S, Zhu H, Gabrielson K, Trush MA, Diehl AM. Mitochondrial adaptation to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378:259–268.

    Article  PubMed  CAS  Google Scholar 

  69. Leclercq IA, Farrel GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest. 2000;105:1067–1075.

    Article  PubMed  CAS  Google Scholar 

  70. Seki S, Kitada T, Yamada T, Sakaguchi H, Nakatani K, Wakasa K. In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver disease. J Hepatol. 2002;37:56–62.

    Article  PubMed  CAS  Google Scholar 

  71. Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2004;99:1497–1502.

    Article  PubMed  CAS  Google Scholar 

  72. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic mechanism. Oxidation, inflammation, and genetics. Circulation. 1995;91:2488–2496.

    PubMed  CAS  Google Scholar 

  73. Schulz E, Anter E, Keaney JF. Oxidative stress, antioxidants, and endothelial function. Curr Med Chem. 2004;11:1093–1104.

    PubMed  CAS  Google Scholar 

  74. Ahmed MH, Byrne CD. Obstructive sleep apnea syndrome and fatty liver: association or causal link? World J Gastroenterol. 2010;16:4243–4252.

    Article  PubMed  CAS  Google Scholar 

  75. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42:987–1000.

    Article  PubMed  CAS  Google Scholar 

  76. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87:3023–3028.

    Article  PubMed  CAS  Google Scholar 

  77. Bonora E, Formentini G, Calcaterra F, et al. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care. 2002;25:1135–1141.

    Article  PubMed  Google Scholar 

  78. Pilz S, Scharnagl H, Tiran B, et al. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J Clin Endocrinol Metab. 2006;91:2542–2547.

    Article  PubMed  CAS  Google Scholar 

  79. Stefan N, Kantartzis K, Ulrich Häring H. Causes and metabolic consequences of fatty liver. Endocrine Reviews. 2008;29:939–960.

    Article  PubMed  CAS  Google Scholar 

  80. Targher G, Bertolini L, Scala L, Zoppini G, Zenari L, Falezza G. Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue. Diabet Med. 2005;22:1354–1358.

    Article  PubMed  CAS  Google Scholar 

  81. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol. 2008;103:1372–1379.

    Article  PubMed  CAS  Google Scholar 

  82. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation. 2000;101:2149–2153.

    PubMed  CAS  Google Scholar 

  83. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000;101:1767–1772.

    PubMed  CAS  Google Scholar 

  84. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Eng J Med. 2000;342:836–843.

    Article  CAS  Google Scholar 

  85. Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during instability in coronary artery disease. Circulation. 1997;96:4204–4210.

    PubMed  CAS  Google Scholar 

  86. Rebuzzi AG, Quaranta G, Liuzzo G, et al. Incremental prognosis value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol. 1998;82:715–719.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  88. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875–880.

    Article  PubMed  CAS  Google Scholar 

  89. Day CP. From fat to inflammation. Gastroenterology. 2006;130:207–210.

    Article  PubMed  CAS  Google Scholar 

  90. Marra F, Svegliati Gastaldelli A, Baroni G, Tell C, Tiribelli C. Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med. 2008;14:72–81.

    Article  PubMed  CAS  Google Scholar 

  91. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–874.

    Article  PubMed  CAS  Google Scholar 

  92. Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.

    Article  PubMed  CAS  Google Scholar 

  93. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology. 2004;40:46–54.

    Article  PubMed  CAS  Google Scholar 

  94. Kumada M, Kihara S, Ouchi N, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109:2046–2049.

    Article  PubMed  CAS  Google Scholar 

  95. Kobayashi H, Ouchi N, Kihara S, et al. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res. 2004;94:e27–e31.

    Article  PubMed  CAS  Google Scholar 

  96. Schram K, Sweeney G. Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure. Trends Cardiovasc Med. 2008;18:199–205.

    Article  PubMed  CAS  Google Scholar 

  97. Perseghin G, Lattuada G, De Cobelli F, et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology. 2008;47:51–58.

    Article  PubMed  CAS  Google Scholar 

  98. Taskinen MR. Lipoprotein lipase in diabetes. Diabetes Metab Rev. 1987;3:551–570.

    Article  PubMed  CAS  Google Scholar 

  99. Verges B. New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. Diabetes Metab. 2005;31:429–439.

    Article  PubMed  CAS  Google Scholar 

  100. Frenais R, Nazih H, Ouguerram K, et al. In vivo evidence for the role of lipoprotein lipase activity in the regulation of Apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus. J Clin Endocrinol Metab. 2001;86:1962–1967.

    Article  PubMed  CAS  Google Scholar 

  101. Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49:755–765.

    Article  PubMed  CAS  Google Scholar 

  102. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. J Am Med Assoc. 1996;276:875–881.

    Article  CAS  Google Scholar 

  103. Kwiterovich PO. Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. Am J Cardiol. 2002;90:30i–47i.

    Article  PubMed  CAS  Google Scholar 

  104. Adiels M, Olofsson SO, Taskinen MR, Boren J. Diabetic dyslipidemia. Curr Opin Lipidol. 2006;17:238–246.

    Article  PubMed  CAS  Google Scholar 

  105. Cassader M, Gambino R, Musso G, et al. Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids. 2001;36:1117–1124.

    Article  PubMed  CAS  Google Scholar 

  106. Roche HM, Gibney MJ. The impact of postprandial lipemia in accelerating atherothrombosis. J Cardiovasc Risk. 2000;7:317–324.

    PubMed  CAS  Google Scholar 

  107. Tanaka A. Postprandial hyperlipidemia and atherosclerosis. J Atheroscler Thromb. 2004;11:322–329.

    Article  PubMed  CAS  Google Scholar 

  108. Brown ML, Ramprassad MP, Umeda PK, et al. A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis. Proc Natl Acad Sci USA. 2000;97:7488–7493.

    Article  PubMed  CAS  Google Scholar 

  109. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose- sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensivity in overweight/obese humans. J Clin Invest. 2009;119:1322–1334.

    Article  PubMed  CAS  Google Scholar 

  110. Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005;42:1175–1183.

    Article  PubMed  CAS  Google Scholar 

  111. Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology. 2003;37:909–916.

    Article  PubMed  CAS  Google Scholar 

  112. Musso G, Gambino R, De Michieli F, Durazzo M, Pagano G, Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin responses to dietary fat: possible pathogenetic role in NASH. Hepatology. 2008;47:1167–1177.

    Article  PubMed  CAS  Google Scholar 

  113. Bastelica D, Morange P, Berthet B, et al. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat: evidence of differences between visceral and subcutaneous deposits. Arterioscler Thromb Vasc Biol. 2002;22:173–178.

    Article  PubMed  CAS  Google Scholar 

  114. Fan JG, Chen LH, Xu ZJ, Zeng MD. Overexpression of hepatic plasminogen activator inhibitor type 1 mRNA in rabbits with fatty liver. World J Gastroenterol. 2001;7:710–712.

    PubMed  CAS  Google Scholar 

  115. Esmon CT. The interactions between inflammation and coagulation. Br J Haematol. 2005;131:417–430.

    Article  PubMed  CAS  Google Scholar 

  116. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implication for the metabolic syndrome and atherothrombosis. Circulation. 2003;107:398–404.

    Article  PubMed  CAS  Google Scholar 

  117. Targher G. Non-alcoholic fatty liver disease and cardiovascular disease. Curr Cardio Risk Rep. 2010;4:32–39.

    Article  Google Scholar 

  118. Kantartzis K, Thamer C, Peter A, et al. High cardiorespiratory fitness is a an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut. 2009;58:1281–1288.

    Article  PubMed  CAS  Google Scholar 

  119. Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51:121–129.

    Article  PubMed  CAS  Google Scholar 

  120. Assy N, Nassar F, Nasser G, Grosovski M. Olive oil consumption and non-alcoholic fatty liver disease. World J Gastroenterol. 2009;15:1809–1815.

    Article  PubMed  CAS  Google Scholar 

  121. Estruch R, Martinez-Gonzalez MA, Corella D, et al. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med. 2008;22:2449–2458.

    Google Scholar 

  122. Nseir W, Nassar F, Assy N. Soft drinks consumption and nonalcoholic fatty liver disease. World J Gastroenterol. 2010;16:2579–2588.

    Article  PubMed  CAS  Google Scholar 

  123. Dunn W, Xu R, Schwimmer JB. Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology. 2008;47:1947–1954.

    Article  PubMed  Google Scholar 

  124. Yilmaz Y. Systematic review: caspase-cleaved fragments of cytokeratin 18—the promises and challenges of a biomarker for chronic liver disease. Aliment Pharmacol Ther. 2009;30:1103–1109.

    Article  PubMed  CAS  Google Scholar 

  125. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:846–854.

    Article  PubMed  CAS  Google Scholar 

  126. Hwang ST, Cho YK, Yun JW, Park JH, Kim HJ, Park DI, et al. Impact of NAFLD on microalbuminuria in patients with prediabetes and diabetes. Intern Med J. 2010;40:437–442.

    Google Scholar 

  127. Wong VW, Wong GL, Tsang SW, Fan T, Chu WC, Woo J, Chan AW, Choi PC, Chim AM, Lau JY, Chan FK, Sung JJ, Chan HL. High prevalence of colorectal neoplasm in patients with non-alcoholic steatohepatitis. Gut. 2011;60:829–836

    Google Scholar 

  128. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet. 2001;9285:893–894.

    Article  Google Scholar 

  129. Promrat K, Lutchman G, Uwaifo GI, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;1:188–196.

    Article  CAS  Google Scholar 

  130. Paradis V, Perlemuter G, Bonvoust F, 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;34:738–744.

    Article  PubMed  CAS  Google Scholar 

  131. Klonoff DC, Buse JB, Nielsen LL, et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;1:275–286.

    Google Scholar 

  132. Balaban YH, Korkusuz P, Simsek H, et al. Dipeptidyl peptidase IV (DDP IV) in NASH patients. Ann Hepatol. 2007;4:242–250.

    Google Scholar 

  133. Antonopoulos S, Mikros S, Mylonopoulou M, Kokkoris S, Giannoulis G. Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis. 2006;1:233–234.

    Article  CAS  Google Scholar 

  134. Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, García-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther. 2006;11:1643–1647.

    Article  CAS  Google Scholar 

  135. Browning JD. Stains and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology. 2006;44:466–471.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  137. Georgescu EF, Ionescu R, Niculescu M, Mogoanta L, Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol. 2009;8:942–954.

    Article  CAS  Google Scholar 

  138. Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–1685.

    Article  PubMed  CAS  Google Scholar 

  139. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids—a promising novel therapy for non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2010;7:679–692.

    Article  Google Scholar 

  140. Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142:37–46.

    PubMed  CAS  Google Scholar 

  141. Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010;52:472–479.

    Article  PubMed  CAS  Google Scholar 

  142. Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010;363:1341–1350.

    Article  PubMed  CAS  Google Scholar 

Download references

Financial disclosure

The authors state they have no financial disclosure to declare.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to N. Assy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nseir, W., Shalata, A., Marmor, A. et al. Mechanisms Linking Nonalcoholic Fatty Liver Disease with Coronary Artery Disease. Dig Dis Sci 56, 3439–3449 (2011). https://doi.org/10.1007/s10620-011-1767-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-011-1767-y

Keywords

Navigation