Skip to main content

Advertisement

Log in

Nonalcoholic fatty liver disease and atherosclerosis

  • SYMPOSIUM SIMI–SIAI – FATTY LIVER DISEASE
  • Published:
Internal and Emergency Medicine Aims and scope Submit manuscript

Abstract

Atherosclerosis is a complex inflammatory disease comprising multiple plaque phenotypes. The development of advanced atheromatous plaques with necrotic core represents the result of the invasion of lipid pools by macrophages. The release of activated proteolytic enzymes degrades the surrounding tissue and contributes to the formation of vulnerable plaque. Thinning of the fibrous cap and necrotic core expansion are considered to be critical for the progression toward plaque rupture and acute thrombosis. The pathogenic mechanisms leading the progression of atherosclerotic lesions are various and involve endothelial cells, inflammatory cells, and platelets. Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases ranging from simple fatty liver to nonalcoholic steatohepatitis (NASH) and may progress to cirrhosis and hepatocellular carcinoma. The prevalence of this pathology is quite high in the general population and is one of the most important causes of liver-related morbidity and mortality in children. NAFLD is considered the hepatic feature of the metabolic syndrome and this has stimulated interest in its possible role in the atherosclerosis development. Clinical observations indicated that NAFLD might be an independent risk factor for coronary artery disease. Moreover, NASH may increase atherosclerotic and cardiovascular risks by local overexpression of inflammatory mediators, endothelial damage, and regulators of blood pressure. NASH development is correlated with hepatic progenitor cell activation and the release of proatherogenic adipokines. These aspects suggest the necessity for an early therapeutic intervention in NASH patients, not only for ameliorating the liver injury, but also for improving the systemic proatherogenic state.

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. Stary HC, Chandler AB, Glagov S et al (1994) A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb 14(5):840–856

    Article  PubMed  CAS  Google Scholar 

  2. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM (2000) Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 20(5):1262–1275

    Article  PubMed  CAS  Google Scholar 

  3. Gaudio E, Carpino G, Grassi M, Musca A (2006) Morphological aspects of atherosclerosis lesion: past and present. Clin Ter 157(2):135–142

    PubMed  CAS  Google Scholar 

  4. Donnelly P, Maurovich-Horvat P, Vorpahl M et al (2010) Multimodality imaging atlas of coronary atherosclerosis. JACC Cardiovasc Imaging 3(8):876–880

    Article  PubMed  Google Scholar 

  5. Finn AV, Kolodgie FD, Virmani R (2010) Correlation between carotid intimal/medial thickness and atherosclerosis: a point of view from pathology. Arterioscler Thromb Vasc Biol 30(2):177–181

    Article  PubMed  CAS  Google Scholar 

  6. Kolodgie FD, Burke AP, Nakazawa G, Virmani R (2007) Is pathologic intimal thickening the key to understanding early plaque progression in human atherosclerotic disease? Arterioscler Thromb Vasc Biol 27(5):986–989

    Article  PubMed  CAS  Google Scholar 

  7. Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R (1997) Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 336(18):1276–1282

    Article  PubMed  CAS  Google Scholar 

  8. Naghavi M, Libby P, Falk E et al (2003) From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II. Circulation 108(15):1772–1778

    Article  PubMed  Google Scholar 

  9. Naghavi M, Libby P, Falk E et al (2003) From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation 108(14):1664–1672

    Article  PubMed  Google Scholar 

  10. Virmani R, Burke AP, Farb A, Kolodgie FD (2006) Pathology of the vulnerable plaque. J Am Coll Cardiol 47(8 Suppl):C13–C18

    Article  PubMed  CAS  Google Scholar 

  11. Stone GW, Maehara A, Lansky AJ et al (2011) A prospective natural-history study of coronary atherosclerosis. N Engl J Med 364(3):226–235

    Article  PubMed  CAS  Google Scholar 

  12. Chiu JJ, Chien S (2011) Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev 91(1):327–387

    Article  PubMed  Google Scholar 

  13. Li YS, Haga JH, Chien S (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 38(10):1949–1971

    Article  PubMed  Google Scholar 

  14. Chiu JJ, Usami S, Chien S (2009) Vascular endothelial responses to altered shear stress: pathologic implications for atherosclerosis. Ann Med 41(1):19–28

    Article  PubMed  CAS  Google Scholar 

  15. Dimmeler S, Haendeler J, Zeiher AM (2002) Regulation of endothelial cell apoptosis in atherothrombosis. Curr Opin Lipidol 13(5):531–536

    Article  PubMed  CAS  Google Scholar 

  16. Hsiai TK, Cho SK, Wong PK, Ing M, Salazar A, Sevanian A, Navab M, Demer LL, Ho CM (2003) Monocyte recruitment to endothelial cells in response to oscillatory shear stress. FASEB J 17(12):1648–1657

    Article  PubMed  CAS  Google Scholar 

  17. Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12(3):204–212

    Article  PubMed  CAS  Google Scholar 

  18. Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 352(16):1685–1695

    Article  PubMed  CAS  Google Scholar 

  19. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417(6890):750–754

    Article  PubMed  CAS  Google Scholar 

  20. Zernecke A, Shagdarsuren E, Weber C (2008) Chemokines in atherosclerosis: an update. Arterioscler Thromb Vasc Biol 28(11):1897–1908

    Article  PubMed  CAS  Google Scholar 

  21. Butcher MJ, Galkina EV (2012) Phenotypic and functional heterogeneity of macrophages and dendritic cell subsets in the healthy and atherosclerosis-prone aorta. Front Physiol 3:44

    Article  PubMed  CAS  Google Scholar 

  22. Ley K, Miller YI, Hedrick CC (2011) Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 31(7):1506–1516

    Article  PubMed  CAS  Google Scholar 

  23. Moore KJ, Tabas I (2011) Macrophages in the pathogenesis of atherosclerosis. Cell 145(3):341–355

    Article  PubMed  CAS  Google Scholar 

  24. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5(12):953–964

    Article  PubMed  CAS  Google Scholar 

  25. Butcher M, Galkina E (2011) Current views on the functions of interleukin-17A-producing cells in atherosclerosis. Thromb Haemost 106(5):787–795

    Article  PubMed  CAS  Google Scholar 

  26. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604

    Article  PubMed  CAS  Google Scholar 

  27. Hansson GK, Robertson AK, Soderberg-Naucler C (2006) Inflammation and atherosclerosis. Annu Rev Pathol 1:297–329

    Article  PubMed  CAS  Google Scholar 

  28. Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346(16):1221–1231

    Article  PubMed  CAS  Google Scholar 

  29. Pacifico L, Nobili V, Anania C, Verdecchia P, Chiesa C (2011) Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk. World J Gastroenterol 17(26):3082–3091

    PubMed  Google Scholar 

  30. Bieghs V, Rensen PC, Hofker MH, Shiri-Sverdlov R (2012) NASH and atherosclerosis are two aspects of a shared disease: central role for macrophages. Atherosclerosis 220(2):287–293

    Article  PubMed  CAS  Google Scholar 

  31. Sookoian S, Gianotti TF, Rosselli MS, Burgueno AL, Castano GO, Pirola CJ (2011) Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 218(2):378–385

    Article  PubMed  CAS  Google Scholar 

  32. Targher G, Day CP, Bonora E (2011) Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363(14):1341–1350

    Article  Google Scholar 

  33. Adams LA, Angulo P (2005) Recent concepts in non-alcoholic fatty liver disease. Diabet Med 22(9):1129–1133

    Article  PubMed  CAS  Google Scholar 

  34. Villanova N, Moscatiello S, Ramilli S, Bugianesi E, Magalotti D, Vanni E, Zoli M, Marchesini G (2005) Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 42(2):473–480

    Article  PubMed  Google Scholar 

  35. Sookoian S, Pirola CJ (2008) Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 49(4):600–607

    Article  PubMed  Google Scholar 

  36. Targher G, Bertolini L, Padovani R, Rodella S, Tessari R, Zenari L, Day C, Arcaro G (2007) Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 30(5):1212–1218

    Article  PubMed  Google Scholar 

  37. Targher G, Bertolini L, Padovani R, Rodella S, Zoppini G, Pichiri I, Sorgato C, Zenari L, Bonora E (2010) Prevalence of non-alcoholic fatty liver disease and its association with cardiovascular disease in patients with type 1 diabetes. J Hepatol 53(4):713–718

    Article  PubMed  CAS  Google Scholar 

  38. Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M (2009) Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. Semin Thromb Hemost 35(3):277–287

    Article  PubMed  CAS  Google Scholar 

  39. Targher G, Bertolini L, Rodella S, Lippi G, Franchini M, Zoppini G, Muggeo M, Day CP (2008) NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring) 16(6):1394–1399

    Article  CAS  Google Scholar 

  40. Marra F, Bertolani C (2009) Adipokines in liver diseases. Hepatology 50(3):957–969

    Article  PubMed  CAS  Google Scholar 

  41. Ikejima K, Takei Y, Honda H et al (2002) Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 122(5):1399–1410

    Article  PubMed  CAS  Google Scholar 

  42. Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6(10):772–783

    Article  PubMed  CAS  Google Scholar 

  43. Nobili V, Carpino G, Alisi A, Franchitto A, Alpini G, De Vito R, Onori P, Alvaro D, Gaudio E (2012) Hepatic progenitor cells activation, fibrosis and adipokines production in pediatric nonalcoholic fatty liver disease. Hepatology. doi:10.1002/hep.25742

  44. Saxena NK, Ikeda K, Rockey DC, Friedman SL, Anania FA (2002) Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. Hepatology 35(4):762–771

    Article  PubMed  CAS  Google Scholar 

  45. Bertolani C, Sancho-Bru P, Failli P et al (2006) Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol 169(6):2042–2053

    Article  PubMed  CAS  Google Scholar 

  46. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, Ebenbichler CF, Patsch JR, Tilg H (2005) Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut 54(1):117–121

    Article  PubMed  CAS  Google Scholar 

  47. Beier JI, Guo L, von Montfort C, Kaiser JP, Joshi-Barve S, Arteel GE (2008) New role of resistin in lipopolysaccharide-induced liver damage in mice. J Pharmacol Exp Ther 325(3):801–808

    Article  PubMed  CAS  Google Scholar 

  48. Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121(6):2111–2117

    Article  PubMed  CAS  Google Scholar 

  49. Spencer M, Yao-Borengasser A, Unal R, Rasouli N, Gurley CM, Zhu B, Peterson CA, Kern PA (2010) Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. Am J Physiol Endocrinol Metab 299(6):E1016–E1027

    Article  PubMed  CAS  Google Scholar 

  50. Marzioni M, Alpini G, Saccomanno S et al (2007) Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis. Gastroenterology 133(1):244–255

    Article  PubMed  CAS  Google Scholar 

  51. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87(4):1409–1439

    Article  PubMed  CAS  Google Scholar 

  52. Ayala JE, Bracy DP, James FD, Burmeister MA, Wasserman DH, Drucker DJ (2010) Glucagon-like peptide-1 receptor knockout mice are protected from high-fat diet-induced insulin resistance. Endocrinology 151(10):4678–4687

    Article  PubMed  CAS  Google Scholar 

  53. Lee YS, Shin S, Shigihara T, Hahm E, Liu MJ, Han J, Yoon JW, Jun HS (2007) Glucagon-like peptide-1 gene therapy in obese diabetic mice results in long-term cure of diabetes by improving insulin sensitivity and reducing hepatic gluconeogenesis. Diabetes 56(6):1671–1679

    Article  PubMed  CAS  Google Scholar 

  54. Marra F, Gastaldelli A, Svegliati Baroni G, Tell G, Tiribelli C (2008) Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med 14(2):72–81

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eugenio Gaudio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gaudio, E., Nobili, V., Franchitto, A. et al. Nonalcoholic fatty liver disease and atherosclerosis. Intern Emerg Med 7 (Suppl 3), 297–305 (2012). https://doi.org/10.1007/s11739-012-0826-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11739-012-0826-5

Keywords

Navigation