The problem of non-alcoholic fatty liver disease, metabolic syndrome and atherosclerosis: from the unity of pathogenesis to the possibility of ursodeoxycholic acid correction
PDF (Русский)


non-alcoholic flatty liver disease, metabolic syndrome, atherosclerosis, cardiovascular risk, ursodeoxycholic acid

How to Cite

Gubergrits, N. B., Mozhyna, T. L., & Byelyayeva, N. V. (2020). The problem of non-alcoholic fatty liver disease, metabolic syndrome and atherosclerosis: from the unity of pathogenesis to the possibility of ursodeoxycholic acid correction. Herald of Pancreatic Club, 48(3), 91-100.

Abstract views: 40
PDF Downloads: 18


Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver pathologies, the prevalence of which is steadily increasing worldwide. Cardiovascular disease (CVD) is another group of common diseases that have similar pathophysiological mechanisms with NAFLD. CVD and NAFLD occur against the background of metabolic syndrome, systemic insulin resistance, oxidative stress, altered lipid metabolism. The course of both diseases predisposes to the development of endothelial dysfunction and formation/instability of atherosclerotic plaques. The progression of NAFLD is associated with an increase of the thickness of intima-media complex and calcification of coronary arteries, which is accompanied by an increased risk of subclinical and clinically significant atherosclerosis development. Patients with NAFLD have a high cardiovascular risk, the maximum increase of which should be expected in patients with severe fibrosis (F3–F4 on the NAFLD Fibrosis Score scale). Ursodeoxycholic acid reduces the severity of systemic inflammatory response and oxidative stress, improves lipid metabolism, increases the hypolipidemic effect of statins, reduces the degree of hyperglycemia and insulin resistance, inhibits the formation of atherosclerotic plaques, has vasodilating effect. The presence of significant pleiotropic properties in combination with apparent cytoprotective, choleretic, antiapoptic, anticholestatic, immunomodulatory activity allows to include ursodeoxycholic acid in NAFLD treatment, non-alcoholic steatohepatitis in order to reduce the clinical manifestations of atherosclerosis and prevent CVD progression.
PDF (Русский)


1. Adams L. A., Anstee Q. M., Tilg H., Targher G. Nonalcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut. 2017. Vol. 66. P. 1138–1153.
2. Ahmad T. R., Haeusler R. A. Bile acids in glucose metabolism and insulin signaling — mechanisms and research needs. Nat. Rev. Endocrinol. 2019. Vol. 15, No 12. P. 701–712.
3. Birkenfeld A. L., Shulman G. I. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014. Vol. 59. P. 713–723.
4. Brown J. M., Hazen S. L. The gut microbial endocrine organ: bacterially derived signals driving cardiometabolic diseases. Annu. Rev. Med. 2015. Vol. 66. P. 343–359.
5. Brunner K. T., Pedley A., Massaro J. M., Hoffmann U., Benjamin E. J., Long M. T. Increasing liver fat is associated with progression of cardiovascular risk factors. Liver Int. 2020. Vol. 10. P. 1111/liv.14472.
6. Chalasani N., Younossi Z., Lavine J. E., et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018. Vol. 67. P. 328–357.
7. Chung J., Kim K. H., Lee S. C., An S. H., Kwon K. Ursodeoxycholic acid (UDCA) exerts anti-atherogenic effects by inhibiting endoplasmic reticulum (ER) stress induced by disturbed flow. Mol. Cells. 2015. Vol. 38, No 10. P. 851–858.
8. Corey K. E., Misdraji J., Gelrud L., Zheng H., Chung R. T., Krauss R. M. Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile. Lipids Health Dis. 2014. Vol. 13. P. 100.
9. Coulon S., Francque S., Colle I., et al. Evaluation of inflammatory and angiogenic factors in patients with non-alcoholic fatty liver disease. Cytokine. 2012. Vol. 59. P. 442–449.
10. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology. 2012. Vol. 142. P. 711–725.
11. Ðanić M., Stanimirov B., Pavlović N., et al. Pharmacological applications of bile acids and their derivatives in the treatment of metabolic syndrome. Front. Pharmacol. 2018. Vol. 9. P. 1382.
12. DeFilippis A. P., Blaha M. J., Martin S. S., et al. Nonalcoholic fatty liver disease and serum lipoproteins: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis. 2013. Vol. 227. P. 429–436.
13. El Hadi H., Di Vincenzo A., Vettor R., Rossato M. Relationship between heart disease and liver disease: a two-way street. Cells. 2020. Vol. 9, No 3. P. 567.
14. Emre A., Terzi S., Celiker E., et al. Impact of nonalcoholic fatty liver disease on myocardial perfusion in nondiabetic patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Am. J. Cardiol. 2015. Vol. 116. P. 1810–1814.
15. European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 2016. Vol. 64. P. 1388–1402.
16. Francque S., Laleman W., Verbeke L., et al. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Lab. Invest. 2012. Vol. 92. P. 1428–1439.
17. Francque S. M., van der Graaff D., Kwanten W. J. Non-alcoholic fatty liver disease and cardiovascular risk: pathophysiological mechanisms and implications. J. Hepatol. 2016. Vol. 65. P. 425–443.
18. Fraser A., Harris R., Sattar N., Ebrahim S., Smith G. D., Lawlor D. A. Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women’s Heart and Health Study and meta-analysis. Diabetes Care. 2009. Vol. 32. P. 741–750.
19. Gill R. M., Belt P., Wilson L., Bass N. M., Ferrell L. D. Centrizonal arteries and microvessels in nonalcoholic steatohepatitis. Am. J. Surg. Pathol. 2011. Vol. 35. P. 1400–1404.
20. Guo K., Zhang L., Lu J., et al. Non-alcoholic fatty liver disease is associated with late but not early atherosclerotic lesions in Chinese inpatients with type 2 diabetes. J. Diabetes Complications. 2017. Vol. 31. P. 80–85.
21. Hallsworth K., Hollingsworth K. G., Thoma C., et al. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J. Hepatol. 2013. Vol. 58. P. 757–762.
22. Higuera-de la Tijera F., Servín-Caamaño A. I. Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets. World J. Hepatol. 2015. Vol. 7, No 10. P. 1297–1301.
23. Hu J., Hong W., Yao K. N., Zhu X. H., Chen Z. Y., Ye L. Ursodeoxycholic acid ameliorates hepatic lipid metabolism in LO2 cells by regulating the AKT/mTOR/SREBP-1 signaling pathway. World J. Gastroenterol. 2019. Vol. 25, No 12. P. 1492–1501.
24. Jaruvongvanich V., Wirunsawanya K., Sanguankeo A., Upala S. Nonalcoholic fatty liver disease is associated with coronary artery calcification: a systematic review and meta-analysis. Dig. Liver Dis. 2016. Vol. 48. P. 1410–1417.
25. Kang J. H., Cho K. I., Kim S. M., et al. Relationship between nonalcoholic fatty liver disease and carotid artery atherosclerosis beyond metabolic disorders in non-diabetic patients. J. Cardiovasc. Ultrasound. 2012. Vol. 20. P. 126–133.
26. Kasumov T., Edmison J. M., Dasarathy S., Bennett C., Lopez R., Kalhan S. C. Plasma levels of asymmetric dimethylarginine in patients with biopsy-proven nonalcoholic fatty liver disease. Metabolism. 2011. Vol. 60. P. 776–781.
27. Keskin M., Hayiroglu M. I., Uzun A. O., Guvenc T. S., Sahin S., Kozan O. Effect of nonalcoholic fatty liver disease on in-hospital and long-term outcomes in patients with ST-segment elevation myocardial infarction. Am. J. Cardiol. 2017. Vol. 120. P. 1720–1726.
28. Kim J., Lee D. Y., Park S. E., et al. Increased risk for development of coronary artery calcification in subjects with non-alcoholic fatty liver disease and systemic inflammation. PLoS One. 2017. Vol. 12. P. e0180118.
29. Kim J. K., Lee K. S., Lee D. K., et al. Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice. Exp. Mol. Med. 2014. Vol. 46, No 12. P. e127.
30. Kumar R., Priyadarshi R. N., Anand U. Non-alcoholic fatty liver disease: growing burden, adverse outcomes and associations. J. Clin. Transl. Hepatol. 2020. Vol. 8, No 1. P. 76–86.
31. Lazar M. V., Eapen M., Nair H. R., Siyad I., Gopalakrishna R. Correlation between insulin resistance and liver histology in patients with nonalcoholic steatohepatitis with and without obesity. Indian J Gastroenterol. 2020. Vol. 10. P. 1007/s12664-020-01024-z.
32. Leamy A. K., Egnatchik R. A., Young J. D. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease. Prog. Lipid. Res. 2013. Vol. 52. P. 165–174.
33. Ma J., Hwang S. J., Pedley A., et al. Bi-directional analysis between fatty liver and cardiovascular disease risk factors. J. Hepatol. 2017. Vol. 66. P. 390–397.
34. Mahfood Haddad T., Hamdeh S., Kanmanthareddy A., Alla V. M. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: a systematic review and meta-analysis. Diabetes Metab. Syndr. 2017. Vol. 11, Suppl. 1. Р. S209–216.
35. Mannisto V. T., Simonen M., Soininen P., et al. Lipoprotein subclass metabolism in nonalcoholic steatohepatitis. J. Lipid. Res. 2014. Vol. 55. P. 2676–2684.
36. Mantovani A., Byrne C. D., Bonora E., Targher G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care. 2018. Vol. 41. P. 372–382.
37. Martsevish S. Iu., Kutishenko N. P., Drozdova L. Iu., Lerman O. V., Nevzorova V. A., Reznik I. I., Shavkuta G. V., Iakhontov D. A., RACURS study group. Ursodeoxycholic acid-enhanced efficiency and safety of statin therapy in patients with liver, gallbladder, and/or biliary tract diseases: the RACURS study. Ter. Arkh. 2014. Vol. 86, No 12. P. 48–52.
38. Niederseer D., Wernly S., Bachmayer S., et al. Diagnosis of non-alcoholic fatty liver disease (NAFLD) is independently associated with cardiovascular risk in a large austrian screening cohort. J. Clin. Med. 2020. Vol. 9, No 4. P. E1065.
39. Ozel Coskun B. D., Yucesoy M., Gursoy S., et al. Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis. Eur. J. Gastroenterol. Hepatol. 2015. Vol. 27, No 2. P. 142–149.
40. Pacana T., Cazanave S., Verdianelli A., et al. Dysregulated hepatic methionine metabolism drives homocysteine elevation in diet-induced nonalcoholic fatty liver disease. PLoS One. 2015. Vol. 10. P. e0136822.
41. Pickhardt P. J., Hahn L., Munoz del Rio A., Park S. H., Reeder S. B., Said A. Natural history of hepatic steatosis: observed outcomes for subsequent liver and cardiovascular complications. Am. J. Roentgenology. 2014. Vol. 202. P. 752–758.
42. Pisto P., Santaniemi M., Bloigu R., Ukkola O., Kesaniemi Y. A. Fatty liver predicts the risk for cardiovascular events in middle-aged population: a population-based cohort study. BMJ Open. 2014. Vol. 4. P. e004973.
43. Puchner S. B., Lu M. T., Mayrhofer T., et al. High risk coronary plaque at coronary CT angiography is associated with nonalcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial. Radiology. 2015. Vol. 274. P. 693–701.
44. Sánchez-García A., Sahebkar A., Simental-Mendía M., Simental-Mendía L. E. Effect of ursodeoxycholic acid on glycemic markers: a systematic review and meta-analysis of clinical trials. Pharmacol. Res. 2018. Vol. 135. P. 144–149.
45. Siddiqui M. S., Fuchs M., Idowu M. O., et al. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin. Gastroenterol. Hepatol. 2015. Vol. 13. P. 1000–1008. e3.
46. Sinn D. H., Kang D., Chang Y., et al. Non-alcoholic fatty liver disease and progression of coronary artery calcium score: a retrospective cohort study. Gut. 2017. Vol. 66. P. 323–329.
47. Skrypnyk I. M., Dubrovins'ka T. V. Optimization of long-term treatment with rosuvastatin of patients with myocardial infarction in combination with non-alcoholic steatohepatitis. Lik. Sprava. 2014. Vol. 5-6. P. 113-121.
48. Sonmez A., Nikolic D., Dogru T., et al. Low- and high-density lipoprotein subclasses in subjects with nonalcoholic fatty liver disease. J. Clin. Lipidol. 2015. Vol. 9. P. 576–582.
49. Sookoian S, Pirola C. J. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J. Hepatol. 2008. Vol. 49. P. 600–607.
50. Sperling L. S., Mechanick J. I., Neeland I. J., et al. The CardioMetabolic Health Alliance: working toward a new care model for the metabolic syndrome. J. Am. Coll. Cardiol. 2015. Vol. 66. P. 1050–1067.
51. Stahl E. P., Dhindsa D. S., Lee S. K., Sandesara P. B., Chalasani N. P., Sperling L. S. Nonalcoholic fatty liver disease and the heart: JACC state-of-the-art review. J. Am. Coll. Cardiol. 2019. Vol. 73, No 8. P. 948–963.
52. Targher G., Byrne C. D., Lonardo A., Zoppini G., Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J. Hepatol. 2016. Vol. 65. P. 589–600.
53. Treeprasertsuk S., Leverage S., Adams L. A., Lindor K. D., St Sauver J., Angulo P. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int. 2012. Vol. 32. P. 945–950.
54. Tripodi A., Fracanzani A. L., Primignani M., et al. Procoagulant imbalance in patients with nonalcoholic fatty liver disease. J. Hepatol. 2014. Vol. 61. P. 148–154.
55. Troisi G., Crisciotti F., Gianturco V., et al. The treatment with ursodeoxycholic acid in elderly patients affected by NAFLD and metabolic syndrome: a case-control study. Clin. Ter. 2013. Vol. 164, No 3. P. 203–207.
56. VanWagner L. B., Wilcox J. E., Colangelo L. A., et al. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: a population-based study. Hepatology. 2015. Vol. 62. P. 773–783.
57. Wong R. J., Aguilar M., Cheung R., et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015. Vol. 148. P. 547–555.
58. Wong V. W., Wong G. L., Yeung J. C., et al. Longterm clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: a prospective cohort study. Hepatology. 2016. Vol. 63. P. 754–763.
59. Wu R., Hou F., Wang X., et al. Nonalcoholic fatty liver disease and coronary artery calcification in a northern Chinese population: a cross sectional study. Sci. Rep. 2017. Vol. 7. P. 9933.
60. Wu S., Wu F., Ding Y., Hou J., Bi J., Zhang Z. Association of non-alcoholic fatty liver disease with major adverse cardiovascular events: a systematic review and meta-analysis. Sci. Rep. 2016. Vol. 6. P. 33386.
61. Xiang Z., Chen Y. P., Ma K. F., et al. The role of ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review. BMC Gastroenterol. 2013. Vol. 13. P. 140.
62. Younossi Z., Anstee Q. M., Marietti M., et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol Hepatol. 2018. Vol. 15. P. 11–20.
63. Zhou Y. Y., Zhou X. D., Wu S. J., et al. Nonalcoholic fatty liver disease contributes to subclinical atherosclerosis: a systematic review and metaanalysis. Hepatology. Communications 2018. Vol. 2.