Pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver disease
Gastroenterology and Hepatology from Bed to Bench,
Vol. 15 No. 3 (2022),
20 June 2022
https://doi.org/10.22037/ghfbb.v15i3.2549
Abstract
Non-alcoholic fatty liver disease is one of the main liver diseases worldwide. The most common cause of death in patients with non-alcoholic fatty liver disease is cardiovascular disease. The relationship between these two conditions has been well established. Indeed, identical reasons may contribute to the development of cardiovascular disease and non-alcoholic fatty liver disease with lifestyle factors such as smoking, sedentariness, poor nutritional habits, and physical inactivity being major aspects. This review focuses on potential pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver. PubMed, EMBASE, Orphanet, MIDLINE, Google Scholar, and Cochrane Library were searched for articles published between 2006 and 2022. Relevant articles were selected using the following terms: “Non-alcoholic fatty liver disease,” “Сardiovascular diseases,” “Pathophysiological mechanisms.” The reference lists of all identified articles were searched for other relevant publications as well. The pathophysiological mechanisms of cardiovascular disorders in non-alcoholic fatty liver remain largely speculative and may include systemic low-grade inflammation, atherogenic dyslipidemia, abnormal glucose metabolism and hepatic insulin resistance, endothelial dysfunction, gut dysbiosis, as well as the associated cardiac remodeling, which are influenced by interindividual genetic and epigenetic variations. It is clear that the identification of pathophysiological mechanisms underlying cardiovascular disorders in non-alcoholic fatty liver disease will make the selection of therapeutic measures more optimal and effective.
- Non-alcoholic fatty liver disease, cardiovascular diseases, pathophysiological mechanisms.
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References
Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011;9:524-30.
Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84.
Ivashkin VT, Mayevskaya MV, Pavlov ChS, Tikhonov IN, Shirokova YeN, Buyeverov AO, et al. Diagnostics and treatment of non-alcoholic fatty liver disease: clinical guidelines of the Russian Scientific Liver Society and the Russian gastroenterological association. Rus J gastroenterol hepatol coloproctol 2016;26:24-42.
European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-402.
Polyzos SA, Kechagias S, Tsochatzis EA. Review article: non-alcoholic fatty liver disease and cardiovascular diseases: associations and treatment considerations. Aliment Pharmacol Ther 2021;54:1013-1025.
Lackner C. Prospects for a better diagnosis and prognosis of NAFLD: a pathologist´s view. Hepatoma Res 2021;7:27.
Shroff H, VanWagner LB. Cardiovascular disease in nonalcoholic steatohepatitis: Screening and management. Curr Hepatol Rep 2020;19:315-26.
Jichitu A, Bungau S, Stanescu AMA, Vesa CM, Toma MM, Bustea C, et al. Non-Alcoholic fatty liver disease and cardiovascular comorbidities: pathophysiological links, diagnosis, and therapeutic management. Diagnostics (Basel) 2021;11:689.
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;6:33386.
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis. J Hepatol 2016;65:589-600.
Bisaccia G, Ricci F, Mantini C, Tana C, Romani GL, Schiavone C, et al. Nonalcoholic fatty liver disease and cardiovascular disease phenotypes. SAGE Open Med 2020;8:2050312120933804.
Gehrke N, Schattenberg JM. Metabolic inflammation-A role for hepatic inflammatory pathways as drivers of comorbidities in nonalcoholic fatty liver disease? Gastroenterology 2020;158:1929-47.
Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 2010;52:1836-46.
Calder PC. Fatty acids and inflammation: the cutting edge between food and pharma. Eur J Pharmacol 2011;668:50-8.
Niederseer D, Wernly B, Aigner E, Stickel F, Datz C. NAFLD and cardiovascular diseases: Epidemiological, mechanistic and therapeutic considerations. J Clin Med 2021;10:467.
Hirase T, Node K. Endothelial dysfunction as a cellular mechanism for vascular failure. Am J Physiol Heart Circ Physiol 2012;302:499-505.
Gao X, Guo S, Zhang S, Liu A, Shi L, Zhang Y. Matrine attenuates endoplasmic reticulum stress and mitochondrion dysfunction in nonalcoholic fatty liver disease by regulating SERCA pathway. J Transl Med 2018;16:319.
Dusi V, Ghidoni A, Ravera A, De Ferrari GM, Calvillo L. Chemokines and heart disease: A network connecting cardiovascular biology to immune and autonomic nervous systems. Mediators Inflamm 2016;2016:5902947.
Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357-61.
Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
Halcox JP, Banegas JR, Roy C, Dallongeville J, De Backer G, Guallar E, et al. Prevalence and treatment of atherogenic dyslipidemia in the primary prevention of cardiovascular disease in Europe: EURIKA, a cross-sectional observational study. BMC Cardiovasc Disord 2017;17:160.
Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711-25.
Tourniaire F, Romier-Crouzet B, Lee JH, Marcotorchino J, Gouranton E, Salles J, et al. Chemokine expression in inflamed adipose tissue is mainly mediated by NF-κB. PLoS One 2013;8:66515.
Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 2006;116:115-24.
Ipsen DH, Lykkesfeldt J, Tveden-Nyborg P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease. Cell Mol Life Sci 2018;75:3313-27.
Dabravolski SA, Bezsonov EE, Baig MS, Popkova TV, Orekhov AN. Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases. Int J Mol Sci 2021;22:6949.
Patterson RE, Kalavalapalli S, Williams CM, Nautiyal M, Mathew JT, Martinez J, et al. Lipotoxicity in steatohepatitis occurs despite an increase in tricarboxylic acid cycle activity. Am J Physiol Endocrinol Metab 2016;310:484-94.
Lechner K, McKenzie AL, Kränkel N, Von Schacky C, Worm N, Nixdorff U, et al. High-risk atherosclerosis and metabolic phenotype: The roles of ectopic adiposity, atherogenic dyslipidemia, and inflammation. Metab Syndr Relat Disord 2020;18:176-85.
Jones JG. Hepatic glucose and lipid metabolism. Diabetologia 2016;59:1098-103.
Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020;41:2313-30.
Siddiqui MS, Fuchs M, Idowu MO, Luketic VA, Boyett S, Sargeant C, et al. Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile. Clin Gastroenterol Hepatol 2015;13:1000-8.
Rizzo M, Berneis K, Corrado E, Novo S. The significance of low-density-lipoproteins size in vascular diseases. Int Angiol 2006;25:4-9.
Saeed A, Feofanova EV, Yu B, Sun W, Virani SS, Nambi V, et al. Remnant-like particle cholesterol, low-density lipoprotein triglycerides, and incident cardiovascular disease. J Am Coll Cardiol 2018;72:156-69.
Dittrich J, Beutner F, Teren A, Thiery J, Burkhardt R, Scholz M, et al. Plasma levels of apolipoproteins C-III, A-IV, and E are independently associated with stable atherosclerotic cardiovascular disease. Atherosclerosis 2019;281:17-24.
Zewinger S, Reiser J, Jankowski V, Alansary D, Hahm E, Triem S, et al. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation. Nat Immunol 2020;21:30-41.
Libby P, Everett BM. Novel antiatherosclerotic therapies. Arterioscler Thromb Vasc Biol 2019;39:538-45.
Afonso MS, Lavrador MS, Koike MK, Cintra DE, Ferreira FD, Nunes VS, et al. Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation. J Nutr Biochem 2016;32:91-100.
Hwang DH, Kim JA, Lee JY. Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid. Eur J Pharmacol 2016;785:24-35.
Lai HTM, de Oliveira Otto MC, Lee Y, Wu JHY, Song X, King IB, et al. Serial plasma phospholipid fatty acids in the de novo lipogenesis pathway and total mortality, cause-specific mortality,
and cardiovascular diseases in the cardiovascular health study. J Am Heart Assoc 2019;8:012881.
Francque SM, van der Graaff D, Kwanten WJ. Non-alcoholic fatty liver disease and cardiovascular risk: Pathophysiological mechanisms and implications. J Hepatol 2016;65:425-43.
Shulman GI. Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease. N Engl J Med 2014;371:1131-41.
Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev 2018;98:2133-223.
Worm N. Beyond body weight-loss: Dietary strategies targeting intrahepatic fat in NAFLD. Nutrients 2020;12:1316.
Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical update: Cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease and heart failure in type 2 diabetes mellitus - mechanisms, management, and clinical considerations. Circulation 2016;133:2459-502.
Laakso M, Kuusisto J. Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol 2014;10:293-302.
Scholz GH, Hanefeld M. Metabolic vascular syndrome: New insights into a multidimensional network of risk factors and diseases. Visc Med 2016;32:319-26.
Kasumov T, Edmison JM, Dasarathy S, Bennett C, Lopez R, Kalhan SC. Plasma levels of asymmetric dimethylarginine in patients with biopsy-proven nonalcoholic fatty liver disease. Metabolism 2011;60:776-81.
de Carvalho SC, Muniz MT, Siqueira MD, Siqueira ER, Gomes AV, Silva KA, et al. Plasmatic higher levels of homocysteine in non-alcoholic fatty liver disease (NAFLD). Nutr J 2013;12:37.
Xu Y, Guan Y, Yang X, Xia Z, Wu J. Association of serum homocysteine levels with histological severity of NAFLD. J Gastrointestin Liver Dis 2020;29:51-8.
Tripodi A, Fracanzani AL, Primignani M, Chantarangkul V, Clerici M, Mannucci PM, et al. Procoagulant imbalance in patients with non-alcoholic fatty liver disease. J Hepatol 2014;61:148-54.
Coulon S, Francque S, Colle I, Verrijken A, Blomme B, Heindryckx F, et al. Evaluation of inflammatory and angiogenic factors in patients with non-alcoholic fatty liver disease. Cytokine 2012;59:442-9.
Tilg H, Zmora N, Adolph TE, Elinav E. The intestinal microbiota fuelling metabolic inflammation. Nat Rev Immunol 2020;20:40-54.
Garbuzenko DV. The role of intestinal microflora in the development of complications of hepatic cirrhosis-associated portal hypertension. Klin Med (Mosk) 2007;85:15-9.
Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol 2019;73:2089-105.
Zhang Y, Xu J, Wang X, Ren X, Liu Y. Changes of intestinal bacterial microbiota in coronary heart disease complicated with nonalcoholic fatty liver disease. BMC Genomics 2019;20:862.
Brandsma E, Kloosterhuis NJ, Koster M, Dekker DC, Gijbels MJJ, van der Velden S, et al. A proinflammatory gut microbiota increases systemic inflammation and accelerates atherosclerosis. Circ Res 2019;124:94-100.
Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature 2020;581:310-5.
Koeth RA, Lam-Galvez BR, Kirsop J, Wang Z, Levison BS, Gu X, et al. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest 2019;129:373-87.
Wang Z, Bergeron N, Levison BS, Li XS, Chiu S, Jia X, et al. Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J 2019;40:583-94.
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 2013;368:1575-84.
Qi J, You T, Li J, Pan T, Xiang L, Han Y, et al. Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med 2018;22:185-94.
Roncal C, Martínez-Aguilar E, Orbe J, Ravassa S, Fernandez-Montero A, Saenz-Pipaon G, et al. Trimethylamine-N-oxide (TMAO) predicts cardiovascular mortality in peripheral artery disease. Sci Rep 2019;9:15580.
Wu C, Xue F, Lian Y, Zhang J, Wu D, Xie N, et al. Relationship between elevated plasma trimethylamine N-oxide levels and increased stroke injury. Neurology 2020;94:667.
Chen YM, Liu Y, Zhou RF, Chen XL, Wang C, Tan XY, et al. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults. Sci Rep 2016;6:19076.
Zhu W, Gregory JC, Org E, Buffa JA, Gupta N, Wang Z, et al. Gut microbial metabolite tmao enhances platelet hyperreactivity and thrombosis risk. Cell 2016;165:111-24.
Roberts AB, Gu X, Buffa JA, Hurd AG, Wang Z, Zhu W, et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 2018;24:1407-17.
Reiner MF, Müller D, Gobbato S, Stalder O, Limacher A, Bonetti NR, et al. Gut microbiota-dependent trimethylamine-N-oxide (TMAO) shows a U-shaped association with mortality but not with recurrent venous thromboembolism. Thromb Res 2019;174:40-7.
Carlsson B, Lindén D, Brolén G, Liljeblad M, Bjursell M, Romeo S, et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2020;51:1305-20.
Del Campo JA, Gallego-Durán R, Gallego P, Grande L. Genetic and epigenetic regulation in nonalcoholic fatty liver disease (NAFLD). Int J Mol Sci 2018;19:911.
Li XL, Sui JQ, Lu LL, Zhang NN, Xu X, Dong QY, et al. Gene polymorphisms associated with non-alcoholic fatty liver
disease and coronary artery disease: a concise review. Lipids Health Dis 2016;15:53.
Byrne CD, Targher G. Non-alcoholic fatty liver disease-related risk of cardiovascular disease and other cardiac complications. Diabetes Obes Metab 2021;29.
Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, et al. Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals. Eur Heart J 2018;39:385-93.
Kasper P, Martin A, Lang S, Kütting F, Goeser T, Demir M, et al. NAFLD and cardiovascular diseases: a clinical review. Clin Res Cardiol 2021;110:921-37.
Simons N, Isaacs A, Koek GH, Kuč S, Schaper NC, Brouwers MCGJ. PNPLA3, TM6SF2, and MBOAT7 genotypes and coronary artery disease. Gastroenterology 2017;152:912-3.
Stols-Gonçalves D, Hovingh GK, Nieuwdorp M, Holleboom AG. NAFLD and atherosclerosis: Two sides of the same dysmetabolic coin? Trends Endocrinol Metab 2019;30:891-902.
Azevedo PS, Polegato BF, Minicucci MF, Paiva SA, Zornoff LA. Cardiac remodeling: Concepts, clinical impact, pathophysiological mechanisms and pharmacologic treatment. Arq Bras Cardiol 2016;106:62-9.
Zhou J, Bai L, Zhang XJ, Li H, Cai J. Nonalcoholic fatty liver disease and cardiac remodeling risk: Pathophysiological mechanisms and clinical implications. Hepatology 2021;74:2839-47.
Cai J, Zhang XJ, Ji YX, Zhang P, She ZG, Li H. Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases. Circ Res 2020;126:679-704.
Garbuzenko DV, Belov DV. Non-alcoholic fatty liver disease as an independent factor of cardiometabolic risk of cardiovascular diseases. Exp Clin Gastroenterol 2021;194:22–34.
VanWagner LB, Wilcox JE, Colangelo LA, Lloyd-Jones DM, Carr JJ, Lima JA, et al. Association of nonalcoholic fatty liver disease with subclinical myocardial remodeling and dysfunction: A population-based study. Hepatology 2015;62:773-83.
Styczynski G, Kalinowski P, Michałowski Ł, Paluszkiewicz R, Ziarkiewicz-Wróblewska B, Zieniewicz K, et al. Cardiac morphology, function, and hemodynamics in patients with morbid obesity and nonalcoholic steatohepatitis. J Am Heart Assoc 2021;10:017371.
Garbuzenko DV, Arefyev NO, Belov DV. Restructuring of the vascular bed in response to hemodynamic disturbances in portal hypertension. World J Hepatol 2016;8:1602-9.
Baffy G, Bosch J. Overlooked subclinical portal hypertension in non-cirrhotic NAFLD: Is it real and how to measure it? J Hepatol 2022;76:458–63.
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