The Pathophysiological Associations Between Obesity, NAFLD, and Atherosclerotic Cardiovascular Diseases

Abstract

Obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerotic cardiovascular diseases are common and growing public health concerns. Previous epidemiological studies unfolded the robust correlation between obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is a well-known risk factor for NAFLD, and both of them can markedly increase the odds of atherosclerotic cardiovascular diseases. On the other hand, significant weight loss achieved by lifestyle modification, bariatric surgery, or medications, such as semaglutide, can concomitantly improve NAFLD and atherosclerotic cardiovascular diseases. Therefore, certain pathophysiological links are involved in the development of NAFLD in obesity, and atherosclerotic cardiovascular diseases in obesity and NAFLD. Moreover, recent studies indicated that simultaneously targeting several mechanisms by tirzepatide and retatrutide leads to greater weight loss and markedly improves the complications of metabolic syndrome. These findings remind the importance of a mechanistic viewpoint for breaking the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. In this review article, we mainly focus on shared pathophysiological mechanisms, including insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, and endothelial dysfunction. Most of these pathophysiological alterations are primarily initiated by obesity. The development of NAFLD further exacerbates these molecular and cellular alterations, leading to atherosclerotic cardiovascular disease development or progression as the final manifestation of molecular perturbation. A better insight into these mechanisms makes it feasible to develop new multi-target approaches to simultaneously unhinge the deleterious chain of events linking obesity and NAFLD to atherosclerotic cardiovascular diseases.

Keywords

obesity  - cardiovascular diseases - insulin resistance - endothelial dysfunction - GLP1 signaling

Publication History

Received: 15 January 2024

Accepted: 02 February 2024

Article published online:
12 March 2024

• References

• 1 Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism 2019; 92: 6-10
• 2 Yeh TL, Hsu HY, Tsai MC. et al. Association between metabolically healthy obesity/overweight and cardiovascular disease risk: a representative cohort study in Taiwan. PloS One 2021; 16: e0246378
• 3 Zou B, Yeo YH, Nguyen VH. et al. Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999-2016. J Intern Med 2020; 288: 139-151
• 4 Paik JM, Kabbara K, Eberly KE. et al. Global burden of NAFLD and chronic liver disease among adolescents and young adults. Hepatology (Baltimore. Md) 2022; 75: 1204-1217
• 5 Ito T, Ishigami M, Zou B. et al. The epidemiology of NAFLD and lean NAFLD in Japan: a meta-analysis with individual and forecasting analysis, 1995-2040. Hepatol Int 2021; 15: 366-379
• 6 Ge X, Zheng L, Wang M. et al. Prevalence trends in non-alcoholic fatty liver disease at the global, regional and national levels, 1990-2017: a population-based observational study. BMJ Open 2020; 10: e036663
• 7 Dai H, Alsalhe TA, Chalghaf N. et al. The global burden of disease attributable to high body mass index in 195 countries and territories, 1990-2017: an analysis of the Global Burden of Disease Study. PLoS Med 2020; 17: e1003198
• 8 Henson JB, Simon TG, Kaplan A. et al. Advanced fibrosis is associated with incident cardiovascular disease in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2020; 51: 728-736
• 9 Ye Q, Zou B, Yeo YH. et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020; 5: 739-752
• 10 Kim Y, Han E, Lee JS. et al. Cardiovascular risk is elevated in lean subjects with nonalcoholic fatty liver disease. Gut Liver 2022; 16: 290-299
• 11 Aminian A, Al-Kurd A, Wilson R. et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA 2021; 326: 2031-2042
• 12 Volpe S, Lisco G, Fanelli M. et al. Once-weekly subcutaneous semaglutide improves fatty liver disease in patients with type 2 diabetes: a 52-week prospective Real-life study. Nutrients 2022; 14: 4673
• 13 Kolkailah A, Aharonovich A, Lingvay I. et al. Effects of once-weekly semaglutide on coronary outcomes in patients with type 2 diabetes mellitus with or at high risk for cardiovascular disease: insights from the SUSTAIN-6 trial. Eur J Prevent Cardiol 2022; 29: zwac056-042
• 14 Wong VW, Wong GL, Chan RS. et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease. J Hepatol 2018; 69: 1349-1356
• 15 Sinn DH, Kang D, Cho SJ. et al. Weight change and resolution of fatty liver in normal weight individuals with nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2021; 33: e529-e534
• 16 Meneses D, Olveira A, Corripio R. et al. The benefit of bariatric surgery on histological features of metabolic associated fatty liver disease assessed through noninvasive methods. Obes Surg 2022; 32: 2682-2695
• 17 Hartman ML, Sanyal AJ, Loomba R. et al. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care 2020; 43: 1352-1355
• 18 Jastreboff AM, Aronne LJ, Ahmad NN. et al. Tirzepatide once weekly for the treatment of obesity. N Eng. J Med 2022; 387: 205-216
• 19 Weghuber D, Barrett T, Barrientos-Pérez M. et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022; 387: 2245-2257
• 20 Jastreboff AM, Kaplan LM, Frías JP. et al. Triple-hormone-receptor agonist retatrutide for obesity – a phase 2 trial. N Eng. J Med 2023; 389: 514-526
• 21 Sargeant JA, Gray LJ, Bodicoat DH. et al. The effect of exercise training on intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review and meta-analysis. Obes Rev 2018; 19: 1446-1459
• 22 Zhang M, Hu T, Zhang S. et al. Associations of different adipose tissue depots with insulin resistance: a systematic review and meta-analysis of observational studies. Sci Rep 2015; 5: 18495
• 23 Cho Y, Hong N, Kim KW. et al. The effectiveness of intermittent fasting to reduce body mass index and glucose metabolism: a systematic Review and meta-analysis. J Clin Med 2019; 8: 1645
• 24 Rao R, Yanagisawa R, Kini S. Insulin resistance and bariatric surgery. Obes Rev 2012; 13: 316-328
• 25 Jiao N, Baker SS, Nugent CA. et al. Gut microbiome may contribute to insulin resistance and systemic inflammation in obese rodents: a meta-analysis. Physiol Genom 2018; 50: 244-254
• 26 Ye J. Mechanisms of insulin resistance in obesity. Front Med 2013; 7: 14-24
• 27 Marchesini G, Brizi M, Morselli-Labate AM. et al. Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 1999; 107: 450-455
• 28 Lomonaco R, Bril F, Portillo-Sanchez P. et al. Metabolic impact of nonalcoholic steatohepatitis in obese patients with type 2 diabetes. Diabetes Care 2016; 39: 632-638
• 29 Seppälä-Lindroos A, Vehkavaara S, Häkkinen 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
• 30 Bugianesi E, Gastaldelli A, Vanni E. et al. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 2005; 48: 634-642
• 31 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: 3313-3327
• 32 Zheng F, Cai Y. Concurrent exercise improves insulin resistance and nonalcoholic fatty liver disease by upregulating PPAR-γ and genes involved in the beta-oxidation of fatty acids in ApoE-KO mice fed a high-fat diet. Lipids Health Dis 2019; 18: 6
• 33 Smith GI, Shankaran M, Yoshino M. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J Clin Invest 2020; 130: 1453-1460
• 34 Chen Y, Feng R, Yang X. et al. Yogurt improves insulin resistance and liver fat in obese women with nonalcoholic fatty liver disease and metabolic syndrome: a randomized controlled trial. Am J Clin Nutr 2019; 109: 1611-1619
• 35 Honma M, Sawada S, Ueno Y. et al. Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. Int J Obes (Lond) 2018; 42: 1544-1555
• 36 Lyu K, Zhang Y, Zhang D. et al. A membrane-bound diacylglycerol species induces PKCε-mediated hepatic insulin resistance. Cell Metab 2020; 32: 654-664.e5
• 37 Ding X, Wang X, Wu J. et al. Triglyceride-glucose index and the incidence of atherosclerotic cardiovascular diseases: a meta-analysis of cohort studies. Cardiovasc Diabetol 2021; 20: 76
• 38 Gast KB, Tjeerdema N, Stijnen T. et al. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PloS One 2012; 7: e52036
• 39 Meza CA, La Favor JD, Kim DH. et al. Endothelial dysfunction: is there a hyperglycemia-induced imbalance of NOX and NOS?. Int J Mol Sci 2019; 20: 3775
• 40 Ouwens DM, Boer C, Fodor M. et al. Cardiac dysfunction induced by high-fat diet is associated with altered myocardial insulin signalling in rats. Diabetologia 2005; 48: 1229-1237
• 41 Erqou S, Adler AI, Challa AA. et al. Insulin resistance and incident heart failure: a meta-analysis. Eur J Heart Fail 2022; 24: 1139-1141
• 42 Tang N, Ma J, Tao R. et al. The effects of the interaction between BMI and dyslipidemia on hypertension in adults. Sci Rep 2022; 12: 927
• 43 Hasan B, Nayfeh T, Alzuabi M. et al. Weight loss and serum lipids in overweight and obese adults: a systematic review and meta-analysis. J Clin Endocrinol Metab 2020; 105: dgaa673
• 44 Murad MH, Hazem A, Coto-Yglesias F. et al. The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis. BMC Endocr Disord 2012; 12: 2
• 45 Mora S, Glynn RJ, Hsia J. et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010; 121: 1069-1077
• 46 Chen KN, He L, Zhong LM. et al. Meta-analysis of dyslipidemia management for the prevention of ischemic stroke recurrence in China. Front Neurol 2020; 11: 483570
• 47 Bril F, Sninsky JJ, Baca AM. et al. Hepatic steatosis and insulin resistance, but not steatohepatitis, promote atherogenic dyslipidemia in NAFLD. J Clin Endocrinol Metab 2016; 101: 644-652
• 48 Amor AJ, Pinyol M, Solà E. et al. Relationship between noninvasive scores of nonalcoholic fatty liver disease and nuclear magnetic resonance lipoprotein abnormalities: a focus on atherogenic dyslipidemia. J Clin Lipidol 2017; 11: 551-561.e557
• 49 Dowla S, Aslibekyan S, Goss A. et al. Dyslipidemia is associated with pediatric nonalcoholic fatty liver disease. J Clin Lipidol 2018; 12: 981-987
• 50 Speliotes EK, Massaro JM, Hoffmann U. et al. Fatty liver is associated with dyslipidemia and dysglycemia independent of visceral fat: the Framingham Heart Study. Hepatology 2010; 51: 1979-1987
• 51 Hodson L, Gunn PJ. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol 2019; 15: 689-700
• 52 Lambert JE, Ramos-Roman MA, Browning JD. et al. Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 2014; 146: 726-735
• 53 van Bloemendaal L, Ten Kulve JS, la Fleur SE. et al. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol 2014; 221: T1-T16
• 54 Yang X, Zhang M, Lu Z. et al. Novel small molecule glucagon-like peptide-1 receptor agonist S6 stimulates insulin secretion from rat islets. Front Pharmacol 2021; 12: 664802
• 55 Rodrigues T, Borges P, Mar L. et al. GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes. Pharmacol Res 2020; 161: 105198
• 56 Lincoff AM, Brown-Frandsen K, Colhoun HM. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Eng. J Med 2023; 389: 2221-2232
• 57 Punjabi M, Arnold M, Rüttimann E. et al. Circulating glucagon-like peptide-1 (GLP-1) inhibits eating in male rats by acting in the hindbrain and without inducing avoidance. Endocrinology 2014; 155: 1690-1699
• 58 Bernosky-Smith KA, Stanger DB, Trujillo AJ. et al. The GLP-1 agonist exendin-4 attenuates self-administration of sweetened fat on fixed and progressive ratio schedules of reinforcement in rats. Pharmacol Biochem Behav 2016; 142: 48-55
• 59 Zhou R, Lin C, Cheng Y. et al. Liraglutide alleviates hepatic steatosis and liver injury in T2MD rats via a GLP-1R dependent AMPK pathway. Front Pharmacol 2020; 11: 600175
• 60 Gao Z, Song GY, Ren LP. et al. β-catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet. Eur J Histochem 2020; 64: 3160
• 61 Bandyopadhyay S, Das S, Samajdar SS. et al. Role of semaglutide in the treatment of nonalcoholic fatty liver disease or non-alcoholic steatohepatitis: a systematic review and meta-analysis. Diabetes Metab Syndr 2023; 17: 102849
• 62 Hagerich K, Durkee M, Goldstein MG. Tirzepatide once weekly for the treatment of obesity. N Eng J Med 2022; 387: 1433
• 63 Ajaz S, McPhail MJ, Gnudi L. et al. Mitochondrial dysfunction as a mechanistic biomarker in patients with non-alcoholic fatty liver disease (NAFLD). Mitochondrion 2021; 57: 119-130
• 64 Zhang X, Zhang J, Sun H. et al. Defective phosphatidylglycerol remodeling causes hepatopathy, linking mitochondrial dysfunction to hepatosteatosis. Cell Mol Gastroenterol Hepatol 2019; 7: 763-781
• 65 Rector RS, Thyfault JP, Uptergrove GM. et al. Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis and contributes to the natural history of non-alcoholic fatty liver disease in an obese rodent model. J Hepatol 2010; 52: 727-736
• 66 Chella Krishnan K, Kurt Z, Barrere-Cain R. et al. Integration of multi-omics data from mouse diversity panel highlights mitochondrial dysfunction in non-alcoholic fatty liver disease. Cell Syst 2018; 6: 103-115.e107
• 67 Yang XX, Wang X, Shi TT. et al. Mitochondrial dysfunction in high-fat diet-induced nonalcoholic fatty liver disease: The alleviating effect and its mechanism of Polygonatum kingianum. Biomed Pharmacother 2019; 117: 109083
• 68 Ortiz M, Soto-Alarcón SA, Orellana P. et al. Suppression of high-fat diet-induced obesity-associated liver mitochondrial dysfunction by docosahexaenoic acid and hydroxytyrosol co-administration. Dig Liver Dis 2020; 52: 895-904
• 69 Chistiakov DA, Shkurat TP, Melnichenko AA. et al. The role of mitochondrial dysfunction in cardiovascular disease: a brief review. Ann Med 2018; 50: 121-127
• 70 Tajes M, Díez-López C, Enjuanes C. et al. Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells. Cell Biosci 2021; 11: 89
• 71 Ribeiro Junior RF, Dabkowski ER, Shekar KC. et al. MitoQ improves mitochondrial dysfunction in heart failure induced by pressure overload. Free Radic Biol Med 2018; 117: 18-29
• 72 Glanz VY, Sobenin IA, Grechko AV. et al. The role of mitochondria in cardiovascular diseases related to atherosclerosis. Front Biosci (Elite Ed) 2020; 12: 102-112
• 73 Shanmugam K, Ravindran S, Kurian GA. et al. Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. Oxid Med Cell Longev 2018; 9173436
• 74 Guo C, Wang J, Jing L. et al. Mitochondrial dysfunction, perturbations of mitochondrial dynamics and biogenesis involved in endothelial injury induced by silica nanoparticles. Environ Pollut 2018; 236: 926-936
• 75 Saltiel AR, Olefsky JM. Inflammatory mechanisms linking obesity and metabolic disease. J Clin Invest 2017; 127: 1-4
• 76 Cohen E, Margalit I, Shochat T. et al. Markers of chronic inflammation in overweight and obese individuals and the role of gender: a cross-sectional study of a large cohort. J Inflam Res 2021; 14: 567-573
• 77 Mărginean CO, Meliţ LE, Huțanu A. et al. The adipokines and inflammatory status in the era of pediatric obesity. Cytokine 2020; 126: 154925
• 78 Alzamil H. Elevated serum TNF-α is related to obesity in type 2 diabetes mellitus and is associated with glycemic control and insulin resistance. J Obes 2020; 2020: 5076858
• 79 Yu E, Hsu H-Y, Huang C-Y. et al. Inflammatory biomarkers and risk of atherosclerotic cardiovascular disease. Open Med 2018; 13: 208-213
• 80 Lund MAV, Thostrup AH, Frithioff-Bøjsøe C. et al. Low-grade inflammation independently associates with cardiometabolic risk in children with overweight/obesity. Nutr Metab Cardiovasc Dis 2020; 30: 1544-1553
• 81 Su Z, Efremov L, Mikolajczyk R. Differences in the levels of inflammatory markers between metabolically healthy obese and other obesity phenotypes in adults: a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis 2023; S0939-4753(23)00348-4
• 82 Fuchs A, Samovski D, Smith GI. et al. Associations among adipose tissue immunology, inflammation, exosomes and insulin sensitivity in people with obesity and nonalcoholic fatty liver disease. Gastroenterology 2021; 161: 968-981.e912
• 83 Duan Y, Pan X, Luo J. et al. Association of inflammatory cytokines with non-alcoholic fatty liver disease. Front Immunol 2022; 13: 880298
• 84 Al Rifai M, Silverman MG, Nasir K. et al. The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2015; 239: 629-633
• 85 Gao X, Li Y, Ma Z. et al. Obesity induces morphological and functional changes in female reproductive system through increases in NF-κB and MAPK signaling in mice. Reprod Biol Endocrinol 2021; 19: 148
• 86 Renovato-Martins M, Moreira-Nunes C, Atella GC. et al. Obese adipose tissue secretion induces inflammation in preadipocytes: role of toll-like receptor-4. Nutrients 2020; 12: 2828
• 87 Kim EJ, Kim BH, Seo HS. et al. Cholesterol-induced non-alcoholic fatty liver disease and atherosclerosis aggravated by systemic inflammation. PloS One 2014; 9: e97841
• 88 Ye L, Chen X, Wang M. et al. Curcumin analogue C66 attenuates obesity-induced myocardial injury by inhibiting JNK-mediated inflammation. Biomed Pharmacother 2021; 143: 112121
• 89 Uddandrao VS, Chandrasekaran P, Saravanan G. et al. Phytoformulation with hydroxycitric acid and capsaicin protects against high-fat-diet-induced obesity cardiomyopathy by reducing cardiac lipid deposition and ameliorating inflammation and apoptosis in the heart. J Trad Complement Med 2023; . https://www.sciencedirect.com/science/article/pii/S2225411023000883
• 90 Gao S, Xue X, Yin J. et al. Danlou tablet inhibits the inflammatory reaction of high-fat diet-induced atherosclerosis in ApoE knockout mice with myocardial ischemia via the NF-κB signaling pathway. J Ethnopharmacol 2020; 263: 113158
• 91 Gutiérrez-Cuevas J, Sandoval-Rodríguez A, Monroy-Ramírez HC. et al. Prolonged-release pirfenidone prevents obesity-induced cardiac steatosis and fibrosis in a mouse NASH model. Cardiovasc Drugs The 2021; 35: 927-938
• 92 Canfora EE, Meex RCR, Venema K. et al. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol 2019; 15: 261-273
• 93 Yassour M, Lim MY, Yun HS. et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med 2016; 8: 176
• 94 Monga Kravetz A, Testerman T, Galuppo B. et al. Effect of gut microbiota and PNPLA3 rs738409 variant on nonalcoholic fatty liver disease (NAFLD) in obese youth. J Clin Endocrinol Metab 2020; 105: e3575-e3585
• 95 Chen YH, Chiu CC, Hung SW. et al. Gnotobiotic mice inoculated with Firmicutes, but not Bacteroidetes, deteriorate nonalcoholic fatty liver disease severity by modulating hepatic lipid metabolism. Nutr Res 2019; 69: 20-29
• 96 Iino C, Endo T, Mikami K. et al. Significant decrease in faecalibacterium among gut microbiota in nonalcoholic fatty liver disease: a large BMI- and sex-matched population study. Hepatol Int 2019; 13: 748-756
• 97 Zhang Y, Xu J, Wang X. et al. Changes of intestinal bacterial microbiota in coronary heart disease complicated with nonalcoholic fatty liver disease. BMC Genom 2019; 20: 862
• 98 de Wouters d'Oplinter A, Rastelli M, Van Hul M. et al. Gut microbes participate in food preference alterations during obesity. Gut Microbes 2021; 13: 1959242
• 99 Kazankov K, Jørgensen SMD, Thomsen KL. et al. The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 2019; 16: 145-159
• 100 Vrieze A, Van Nood E, Holleman F. et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143: 913-916.e917
• 101 Beale AL, O'Donnell JA, Nakai ME. et al. The gut microbiome of heart failure with preserved ejection fraction. J Am Heart Assoc 2021; 10: e020654
• 102 Sun W, Du D, Fu T. et al. Alterations of the gut microbiota in patients with severe chronic heart failure. Front Microbiol 2021; 12: 813289
• 103 Pakhomov N, Baugh JA. The role of diet-derived short-chain fatty acids in regulating cardiac pressure overload. Am J Physiol Heart Circ Physiol 2021; 320: H475-H486
• 104 Zhao M, Zhao L, Xiong X. et al. TMAVA, a metabolite of intestinal microbes, is increased in plasma from patients with liver steatosis, inhibits γ-butyrobetaine hydroxylase, and exacerbates fatty liver in mice. Gastroenterology 2020; 158: 2266-2281.e2227
• 105 Organ CL, Li Z, Sharp TE. et al. Nonlethal inhibition of gut microbial trimethylamine N-oxide production improves cardiac function and remodeling in a murine model of heart failure. J Am Heart Assoc 2020; 9: e016223
• 106 Burz SD, Monnoye M, Philippe C. et al. Fecal microbiota transplant from human to mice gives insights into the role of the gut microbiota in non-alcoholic fatty liver disease (NAFLD). Microorganisms 2021; 9: 199
• 107 Rodriguez J, Hiel S, Neyrinck AM. et al. Discovery of the gut microbial signature driving the efficacy of prebiotic intervention in obese patients. Gut 2020; 69: 1975-1987
• 108 Wang P, Li D, Ke W. et al. Resveratrol-induced gut microbiota reduces obesity in high-fat diet-fed mice. Int J Obes (Lond) 2020; 44: 213-225
• 109 Farin W, Oñate FP, Plassais J. et al. Impact of laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy on gut microbiota: a metagenomic comparative analysis. Surg Obes Relat Dis 2020; 16: 852-862
• 110 Paganelli FL, Luyer M, Hazelbag CM. et al. Roux-Y gastric bypass and sleeve gastrectomy directly change gut microbiota composition independent of surgery type. Sci Rep 2019; 9: 10979
• 111 Calabrese FM, Disciglio V, Franco I. et al. A low glycemic index mediterranean diet combined with aerobic physical activity rearranges the gut microbiota signature in NAFLD patients. Nutrients 2022; 14: 1773
• 112 Sharpton SR, Maraj B, Harding-Theobald E. et al. Gut microbiome-targeted therapies in nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression. Am J Clin Nutr 2019; 110: 139-149
• 113 Pinheiro TA, Barcala-Jorge AS, Andrade JMO. et al. Obesity and malnutrition similarly alter the renin-angiotensin system and inflammation in mice and human adipose. J Nutr Biochem 2017; 48: 74-82
• 114 Fu Z, Wang F, Liu X. et al. Soluble (pro)renin receptor induces endothelial dysfunction and hypertension in mice with diet-induced obesity via activation of angiotensin II type 1 receptor. Clin Sci (Lond) 2021; 135: 793-810
• 115 Faloia E, Gatti C, Camilloni MA. et al. Comparison of circulating and local adipose tissue renin-angiotensin system in normotensive and hypertensive obese subjects. J Endocrinol Invest 2002; 25: 309-314
• 116 Engeli S, Böhnke J, Gorzelniak K. et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005; 45: 356-362
• 117 Park SY, Karki S, Saggese SM. et al. Angiotensin II-mediated vasoconstriction of the visceral adipose tissue vasculature is linked to systemic hypertension in obesity. FASEB J 2017; 31: 684.686-684.686
• 118 Oliveras A, Molina L, Goday A. et al. Effect of bariatric surgery on cardiac structure and function in obese patients: role of the renin-angiotensin system. J Clin Hypertens (Greenwich) 2021; 23: 181-192
• 119 Oliveras A, Galceran I, Goday A. et al. Improvement of arterial stiffness one month after bariatric surgery and potential mechanisms. J Clin Med 2021; 10: 691
• 120 Yoneda M, Hotta K, Nozaki Y. et al. Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease. Liver Int 2009; 29: 1078-1085
• 121 Goh GB, Pagadala MR, Dasarathy J. et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int 2015; 35: 979-985
• 122 Li Y, Xiong F, Xu W. et al. Increased serum angiotensin II is a risk factor of nonalcoholic fatty liver disease: a prospective pilot study. Gastroenterol Res Pract 2019; 5647161
• 123 Sturzeneker MCS, de Noronha L, Olandoski M. et al. Ramipril significantly attenuates the development of non-alcoholic steatohepatitis in hyperlipidaemic rabbits. Am J Cardiovasc Dis 2019; 9: 8-17
• 124 Hirose A, Ono M, Saibara T. et al. Angiotensin II type 1 receptor blocker inhibits fibrosis in rat nonalcoholic steatohepatitis. Hepatology 2007; 45: 1375-1381
• 125 Frantz ED, Penna-de-Carvalho A, Batista Tde M. et al. Comparative effects of the renin-angiotensin system blockers on nonalcoholic fatty liver disease and insulin resistance in C57BL/6 mice. Metab Syndr Relat Disord 2014; 12: 191-201
• 126 Lee KC, Hsieh YC, Yang YY. et al. Aliskiren reduces hepatic steatosis and epididymal fat mass and increases skeletal muscle insulin sensitivity in high-fat diet-fed mice. Sci Rep 2016; 6: 18899
• 127 Kim KM, Roh JH, Lee S. et al. Clinical implications of renin-angiotensin system inhibitors for development and progression of non-alcoholic fatty liver disease. Sci Rep 2021; 11: 2884
• 128 Wu Y, Ma KL, Zhang Y. et al. Lipid disorder and intrahepatic renin-angiotensin system activation synergistically contribute to non-alcoholic fatty liver disease. Liver In 2016; 36: 1525-1534
• 129 Yang M, Ma X, Xuan X. et al. Liraglutide attenuates non-alcoholic fatty liver disease in mice by regulating the local renin-angiotensin system. Front Pharmacol 2020; 11: 432
• 130 Song LN, Liu JY, Shi TT. et al. Angiotensin-(1-7), the product of ACE2 ameliorates NAFLD by acting through its receptor Mas to regulate hepatic mitochondrial function and glycolipid metabolism. FASEB J 2020; 34: 16291-16306
• 131 Cao X, Song LN, Zhang YC. et al. Angiotensin-converting enzyme 2 inhibits endoplasmic reticulum stress-associated pathway to preserve nonalcoholic fatty liver disease. Diabetes Metab Res Rev 2019; 35: e3123
• 132 Cao X, Yang F, Shi T. et al. Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis activates Akt signaling to ameliorate hepatic steatosis. Sci Rep 2016; 6: 21592
• 133 Zhang X, Wong GL, Yip TC. et al. Angiotensin-converting enzyme inhibitors prevent liver-related events in nonalcoholic fatty liver disease. Hepatology 2021; 76: 469-482
• 134 Tai C, Gan T, Zou L. et al. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular events in patients with heart failure: a meta-analysis of randomized controlled trials. BMC Cardiovasc Disord 2017; 17: 257
• 135 van Vark LC, Bertrand M, Akkerhuis KM. et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012; 33: 2088-2097
• 136 McAlister FA. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are beneficial in normotensive atherosclerotic patients: a collaborative meta-analysis of randomized trials. Eur Heart J 2012; 33: 505-514
• 137 Evans M, Carrero JJ, Szummer K. et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in myocardial infarction patients with renal dysfunction. J Am Coll Cardiol 2016; 67: 1687-1697
• 138 Sim HW, Zheng H, Richards AM. et al. Beta-blockers and renin-angiotensin system inhibitors in acute myocardial infarction managed with inhospital coronary revascularization. Sci Rep 2020; 10: 15184
• 139 Liu T, Wen H, Li H. et al. Oleic acid attenuates Ang II (Angiotensin II)-induced cardiac remodeling by inhibiting FGF23 (Fibroblast Growth Factor 23) expression in mice. Hypertension 2020; 75: 680-692
• 140 Tian Y, Luo J, Xu Q. et al. Macrophage depletion protects against endothelial dysfunction and cardiac remodeling in angiotensin II hypertensive mice. Clin Exp Hypertens 2021; 43: 699-706
• 141 Ding J, Tang Q, Luo B. et al. Klotho inhibits angiotensin II-induced cardiac hypertrophy, fibrosis, and dysfunction in mice through suppression of transforming growth factor-β1 signaling pathway. Eur J Pharmacol 2019; 859: 172549
• 142 Meijles DN, Cull JJ, Markou T. et al. Redox regulation of cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) controls p38-MAPK (Mitogen-Activated Protein Kinase) and orchestrates cardiac remodeling to hypertension. Hypertension 2020; 76: 1208-1218
• 143 Leifheit-Nestler M, Kirchhoff F, Nespor J. et al. Fibroblast growth factor 23 is induced by an activated renin-angiotensin-aldosterone system in cardiac myocytes and promotes the pro-fibrotic crosstalk between cardiac myocytes and fibroblasts. Nephrol Dial Transplant 2018; 33: 1722-1734
• 144 Yang C, Wu X, Shen Y. et al. Alamandine attenuates angiotensin II-induced vascular fibrosis via inhibiting p38 MAPK pathway. Eur J Pharmacol 2020; 883: 173384
• 145 Kwaifa IK, Bahari H, Yong YK. et al. Endothelial dysfunction in obesity-induced inflammation: molecular mechanisms and clinical implications. Biomolecules 2020; 10: 291
• 146 Steven S, Dib M, Hausding M. et al. CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice. Cardiovasc Res 2018; 114: 312-323
• 147 Muñoz M, López-Oliva ME, Rodríguez C. et al. Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity. Redox Biol 2020; 28: 101330
• 148 Huby AC, Antonova G, Groenendyk J. et al. Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation 2015; 132: 2134-2145
• 149 Huby AC, Otvos L, Belin de Chantemèle EJ. Leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in obese female mice. Hypertension 2016; 67: 1020-1028
• 150 Stepp DW, Boesen EI, Sullivan JC. et al. Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat. Am J Physiol Heart Circ Physiol 2007; 293: H2537-H2542
• 151 Hartopo AB, Fachiroh J, Puspitawati I. et al. Serum endothelin-1 level positively correlates with waist and hip circumferences in stable coronary artery disease patients. Rev Cardiovasc Med 2021; 22: 919-924
• 152 Iantorno M, Schinzari F, Mores N. et al. Changes in vasodilator reactivity and vasoconstrictor tone in metabolically healthy obesity and the metabolic syndrome. Circulation 2015; 132: A18950-A18950
• 153 Jenkins HN, Williams LJ, Dungey A. et al. Elevated plasma endothelin-1 is associated with reduced weight loss post vertical sleeve gastrectomy. Surg Obes Relat Dis 2019; 15: 1044-1050
• 154 Narayan J, Das HS, Nath P. et al. Endothelial dysfunction, a marker of atherosclerosis, is independent of metabolic syndrome in NAFLD patients. Int J Hepatol 2020; 1825142
• 155 Al-Hamoudi W, Alsadoon A, Hassanian M. et al. Endothelial dysfunction in nonalcoholic steatohepatitis with low cardiac disease risk. Sci Rep 2020; 10: 8825
• 156 Sapmaz F, Uzman M, Basyigit S. et al. Steatosis grade is the most important risk factor for development of endothelial dysfunction in NAFLD. Medicine (Baltimore) 2016; 95: e3280
• 157 Theofilis P, Vordoni A, Nakas N. et al. Endothelial dysfunction in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Life (Basel) 2022; 12: 718
• 158 Lugo-Gavidia LM, Burger D, Matthews VB. et al. Role of microparticles in cardiovascular disease: implications for endothelial dysfunction, thrombosis, and inflammation. Hypertension 2021; 77: 1825-1844
• 159 Benincasa G, Coscioni E, Napoli C. Cardiovascular risk factors and molecular routes underlying endothelial dysfunction: Novel opportunities for primary prevention. Biochem Pharmacol 2022; 202: 115108
• 160 Xu Y, Arora RC, Hiebert BM. et al. Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Imaging 2014; 15: 736-746
• 161 Ras RT, Streppel MT, Draijer R. et al. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol 2013; 168: 344-351
• 162 Furuta K, Guo Q, Pavelko KD. et al. Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis. J Clin Invest 2021; 131 -e143690 . PMID: 33476308; PMCID: PMC7954604
• 163 Guo Q, Furuta K, Lucien F. et al. Integrin β(1)-enriched extracellular vesicles mediate monocyte adhesion and promote liver inflammation in murine NASH. J Hepatol 2019; 71: 1193-1205
• 164 Pasarín M, La Mura V, Gracia-Sancho J. et al. Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD. PloS One 2012; 7: e32785
• 165 Nozaki Y, Fujita K, Wada K. et al. Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution. BMC Gastroenterol 2015; 15: 177
• 166 Persico M, Masarone M, Damato A. et al. "Non alcoholic fatty liver disease and eNOS dysfunction in humans". BMC Gastroenterol 2017; 17: 35
• 167 Sheldon RD, Meers GM, Morris EM. et al. eNOS deletion impairs mitochondrial quality control and exacerbates Western diet-induced NASH. Am J Physiol Endocrinol Metab 2019; 317: E605-E616
• 168 Albadawy R, Agwa SHA, Khairy E. et al. Circulatory endothelin 1-regulating RNAs panel: promising biomarkers for non-invasive NAFLD/NASH diagnosis and stratification: clinical and molecular pilot study. Genes (Basel) 2021; 12: 1813
• 169 Okamoto T, Koda M, Miyoshi K. et al. Antifibrotic effects of ambrisentan, an endothelin-A receptor antagonist, in a non-alcoholic steatohepatitis mouse model. World J Hepatol 2016; 8: 933-941
• 170 Simons N, Bijnen M, Wouters KAM. et al. The endothelial function biomarker soluble E-selectin is associated with nonalcoholic fatty liver disease. Liver Int 2020; 40: 1079-1088
• 171 Laird CT, Hassanein W, O'Neill NA. et al. P- and E-selectin receptor antagonism prevents human leukocyte adhesion to activated porcine endothelial monolayers and attenuates porcine endothelial damage. Xenotransplantation 2018; 25: e12381
• 172 Bae CR, Zhang H, Kwon YG. The endothelial dysfunction blocker CU06-1004 ameliorates choline-deficient l-amino acid diet-induced non-alcoholic steatohepatitis in mice. PloS One 2020; 15: e0243497
• 173 Eslam M, Newsome PN, Sarin SK. et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 2020; 73: 202-209
• 174 Eslam M, Sarin SK, Wong VW. et al. The Asian pacific association for the study of the liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol Int 2020; 14: 889-919
• 175 Moon JH, Kim W, Koo BK. et al. Metabolic dysfunction-associated fatty liver disease predicts long-term mortality and cardiovascular disease. Gut Liver 2022; 16: 433
• 176 Yoo TK, Lee MY, Kim SH. et al. Comparison of cardiovascular mortality between MAFLD and NAFLD: a cohort study. Nutr Metab Cardiovasc Dis 2023; 33: 947-955
• 177 Kim H, Lee CJ, Ahn SH. et al. MAFLD predicts the risk of cardiovascular disease better than NAFLD in asymptomatic subjects with health check-ups. Digest Dis Sci 2022; 67: 4919-4928
• 178 Lee H, Lee YH, Kim SU. et al. Metabolic dysfunction-associated fatty liver disease and incident cardiovascular disease risk: a nationwide cohort study. Clin Gastroenterol hHepatol 2021; 19: 2138-2147.e2110
• 179 Lin S, Huang J, Wang M. et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver Int 2020; 40: 2082-2089
• 180 Carreres L, Jílková ZM, Vial G. et al. Modeling diet-induced NAFLD and NASH in rats: a comprehensive review. Biomedicines 2021; 9: 378
• 181 Sabir U, Irfan HM. , Alamgeer et al. Reduction of hepatic steatosis, oxidative stress, inflammation, ballooning and insulin resistance after therapy with safranal in NAFLD animal model: a new approach. J Inflam Res 2022; 15: 1293-1316
• 182 Eng JM, Estall JL. Diet-induced models of non-alcoholic fatty liver disease: food for thought on sugar, fat, and cholesterol. Cells 2021; 10: 1805
• 183 Zakaria Z, Othman ZA, Suleiman JB. et al. Hepatoprotective effect of bee bread in metabolic dysfunction-associated fatty liver disease (MAFLD) rats: impact on oxidative stress and inflammation. Antioxidants (Basel, Switzerland) 2021; 10: 2031
• 184 Cioffi F, Giacco A, Petito G. et al. Altered mitochondrial quality control in rats with metabolic dysfunction-associated fatty liver disease (MAFLD) induced by high-fat feeding. Genes (Basel) 2022; 13: 315
• 185 Huang Y, Wang C, Wang M. et al. Oroxin B improves metabolic-associated fatty liver disease by alleviating gut microbiota dysbiosis in a high-fat diet-induced rat model. Eur J Pharmacol 2023; 951: 175788