Liver-derived lipoproteins and inflammation: from pathophysiology to pharmacological targets in metabolic liver disease

Abstract

Low density lipoproteins (LDL) reduction remains the key goal for reducing the risk of atherosclerotic cardiovascular diseases (CVD) in people with high residual risk and metabolic complications including liver disease. Notwithstanding, epidemiological projections support a key role of liver-derived apolipoprotein B (ApoB) containing lipoproteins, namely very low density lipoproteins (VLDL) and their “remnants” (TG), undergoing the activity of lipases, in eliciting atherosclerotic inflammatory sequelae of a comparable order of magnitude to that of LDL. Disparate experimental evidence supports that triglycerides (TG), residual cholesterol content, or the large apolipoprotein set on the surface of these lipoproteins can elicit a number of plausible immune-inflammatory mechanisms that foster the vascular atherosclerotic process. Therapeutic options that convincingly lowered the plasma levels of liver-derived ApoB containing lipoproteins, either by reducing the hepatic synthesis or by improving the peripheral lipolysis of the lipid content, did not exert robust CVD risk reduction, and the effect on inflammation was questionable. Understanding the mechanisms linking liver-derived lipoproteins with chronic inflammation will provide pathophysiological insights for the identification of new therapeutic targets for people at high CVD risk and with metabolic complications. In this perspective, this topic is of immediate interest for the prevention of CVD in patients affected by non-alcoholic fatty liver disease (NAFLD) and, even more, for NAFLD patients with diabetes, insulin resistance, or other comorbidities (metabolic-associated fatty liver disease). This review resumes the principal physio-pathological insights regarding the metabolism of liver-derived lipoproteins and provides an update on the current pharmacological options that can be considered for improving CVD prevention in metabolic liver diseases.

Keywords

Very Low Density Lipoproteins / postprandial lipemia / inflammation / apolipoprotein B

References

[1] Targher G,Bonora E.Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease.N Engl J Med2010;363:1341-50

[2] Fracanzani AL,Pisano G.Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up.Atherosclerosis2016;246:208-13

[3] Byrne CD.NAFLD: a multisystem disease.J Hepatol2015;62:S47-64

[4] Eslam M,George J.International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.Gastroenterology2020;158:1999-2014.e1

[5] Shulman GI.Ectopic fat in insulin resistance, dyslipidemia, and cardiometabolic disease.N Engl J Med2014;371:1131-41

[6] Adiels M,Taskinen MR.Diabetic dyslipidaemia.Curr Opin Lipidol2006;17:238-46

[7] Adiels M,Borén J.Fatty liver, insulin resistance, and dyslipidemia.Curr Diab Rep2008;8:60-4

[8] Björnson E,Taskinen MR.Kinetics of plasma triglycerides in abdominal obesity.Curr Opin Lipidol2017;28:11-8

[9] Bellosta S,Alieva AS,Corsini A.Cholesterol lowering biotechnological strategies: from monoclonal antibodies to antisense therapies. A pre-clinical perspective review.Cardiovasc Drugs Ther2022;

[10] Baragetti A,Casula M.Proprotein Convertase Subtilisin-Kexin type-9 (PCSK9) and triglyceride-rich lipoprotein metabolism: facts and gaps.Pharmacol Res2018;130:1-11

[11] Nordestgaard BG.A Test in context: lipid profile, fasting versus nonfasting.J Am Coll Cardiol2017;70:1637-46

[12] Masuda D.Postprandial hyperlipidemia and remnant lipoproteins.J Atheroscler Thromb2017;24:95-109 PMCID:PMC5305681

[13] Berry SE,Drew DA.Human postprandial responses to food and potential for precision nutrition.Nat Med2020;26:964-73 PMCID:PMC8265154

[14] Sharrett AR,Chambless LE.Metabolic and lifestyle determinants of postprandial lipemia differ from those of fasting triglycerides: the Atherosclerosis Risk In Communities (ARIC) study.Arterioscler Thromb Vasc Biol2001;21:275-81

[15] Dubois C,Juhel C.Effects of graded amounts (0-50 g) of dietary fat on postprandial lipemia and lipoproteins in normolipidemic adults.Am J Clin Nutr1998;67:31-8

[16] Pirillo A,Catapano AL.Postprandial lipemia as a cardiometabolic risk factor.Curr Med Res Opin2014;30:1489-503

[17] FoodData Central [Internet]. Available from: https://fdc.nal.usda.gov/ [Last accessed on 27 Jun 2022]

[18] BDA | Food Composition Database for Epidemiological Studies in Italy [Internet]. Available from: http://www.bda-ieo.it/wordpress/en/ [Last accessed on 27 Jun 2022]

[19] Sun L,Gonzalez FJ.The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer.Nat Rev Gastroenterol Hepatol2021;18:335-347.

[20] Hegele RA,Chapman MJ.The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.lancet Diabetes Endocrinol2014;2:655-666 PMCID:PMC4201123

[21] Johansen CT.Genetic bases of hypertriglyceridemic phenotypes.Curr Opin Lipidol2011;22:247-253

[22] Hansen SEJ,Varbo A.Low-grade inflammation in the association between mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis: a study of more than 115000 individuals from the general population.Clin Chem2019;65:321-332

[23] Mach F,Catapano AL.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur Heart J2020;41:111-188

[24] Ginsberg HN,Chapman MJ.Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.Eur Heart J2021;42:4791-4806 PMCID:PMC8670783

[25] Tada H,Inazu A,Kawashiri M aki.Remnant lipoproteins and atherosclerotic cardiovascular disease.Clin Chim Acta2019;490:1-5

[26] Salinas CAA.Remnant lipoproteins: are they equal to or more atherogenic than LDL?.Curr Opin Lipidol2020;31:132-139

[27] Nakajima K,Tokita Y.Postprandial lipoprotein metabolism: VLDL vs chylomicrons.Clin Chim Acta2011;412:1306-1318 PMCID:PMC3265327

[28] Sniderman AD.Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL-lowering therapy: implications for clinical practice.J Clin Lipidol2008;2:36-42

[29] Ference BA,Ginsberg HN.Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk.JAMA2017;318:947-956 PMCID:PMC5710502

[30] Bini S,Di Costanzo A,Pecce V.The interplay between angiopoietin-Like proteins and adipose tissue: another piece of the relationship between adiposopathy and cardiometabolic diseases?.Int J Mol Sci2021;22:1-16 PMCID:PMC7828552

[31] Minicocci I,Cantisani V.Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.J Lipid Res2013;54:3481-3490 PMCID:PMC3826694

[32] Ekstedt M,Nasr P.Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.Hepatology2015;61:1547-1554

[33] Angulo P,Dam-Larsen S.Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease.Gastroenterology2015;149:389-397 PMCID:PMC4516664

[34] Tsutsumi T,Kawaguchi T.MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: generalized estimating equation approach.Hepatol Res2021;51:1115-1128

[35] Moreton JR.Atherosclerosis and alimentary hyperlipemia.Science1947;106:190-191

[36] Moreton JR.Physical state of lipids and foreign substances producing atherosclerosis.Science1948;107:371-373

[37] Schwartz EA.Lipolysis of triglyceride-rich lipoproteins, vascular inflammation, and atherosclerosis.Biochim Biophys Acta2012;1821:858-866

[38] Higgins LJ.Inflammation associated with the postprandial lipolysis of triglyceride-rich lipoproteins by lipoprotein lipase.Curr Atheroscler Rep2009;11:199-205

[39] Ting HJ,Schaff UY.Triglyceride-rich lipoproteins prime aortic endothelium for an enhanced inflammatory response to tumor necrosis factor-α.Circ Res2007;100:381-390

[40] Zewinger S,Jankowski V.Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation.Nat Immunol2020;21:30-41

[41] Doi H,Oka H.Remnant lipoproteins induce proatherothrombogenic molecules in endothelial cells through a redox-sensitive mechanism.Circulation2000;102:670-676

[42] De Sousa JC,Ayrault-Jarrier M.Association between coagulation factors VII and X with triglyceride rich lipoproteins.J Clin Pathol1988;41:940-944

[43] Mattavelli E,Baragetti A.Molecular immune-inflammatory connections between dietary fats and atherosclerotic cardiovascular disease: which translation into clinics?.Nutrients2021;13 PMCID:PMC8625932

[44] Ajuwon K.Palmitate activates the NF-kappaB transcription factor and induces IL-6 and TNFalpha expression in 3T3-L1 adipocytes.J Nutr2005;135:1841-1846

[45] Lee J,Youn H.Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1.J Biol Chem2004;279:16971-16979

[46] Ciesielska A,Kwiatkowska K.TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling.Cell Mol Life Sci2021;78:1233-1261 PMCID:PMC7904555

[47] Lee JY,Lee WH.Differential modulation of Toll-like receptors by fatty acids: preferential inhibition by n-3 polyunsaturated fatty acids.J Lipid Res2003;44:479-486

[48] Veglia F,Blasi M.Fatty acid transport protein 2 reprograms neutrophils in cancer.Nature2019;569:73-78 PMCID:PMC6557120

[49] Zheng S,Li Z.Posttreatment of Maresin1 Inhibits NLRP3 inflammasome activation via promotion of NLRP3 ubiquitination.FASEB J2020;34:11944-11956

[50] Viola JR,Jansen Y.Resolving lipid mediators maresin 1 and resolvin D2 prevent atheroprogression in mice.Circ Res2016;119:1030-1038

[51] Adam AC,Moren M.High dietary arachidonic acid levels induce changes in complex lipids and immune-related eicosanoids and increase levels of oxidised metabolites in zebrafish (Danio rerio).Br J Nutr2017;117:1075-1085 PMCID:PMC5481881

[52] Holladay CS,Spangelo BL.Arachidonic acid stimulates interleukin-6 release from rat peritoneal macrophages in vitro: evidence for a prostacyclin-dependent mechanism.Prostaglandins Leukot Essent Fatty Acids1993;49:915-922

[53] Shen Z,Ji Z.Arachidonic acid induces macrophage cell cycle arrest through the JNK signaling pathway.Lipids Health Dis2018;17:26 PMCID:PMC5807765

[54] Wellenstein MD.Fatty acids corrupt neutrophils in cancer.Cancer Cell2019;35:827-829

[55] Alsina-Sanchis E,Moll I,Rodriguez-Vita J.Intraperitoneal oil application causes local inflammation with depletion of resident peritoneal macrophages.Mol Cancer Res2021;19:288-300

[56] Christ A,Latz E.Western diet and the immune system: an inflammatory connection.Immunity2019;51:794-811

[57] Astrup A,Bier DM.Saturated fats and health: a reassessment and proposal for food-based recommendations: JACC state-of-the-art review.J Am Coll76:844-857

[58] Sheedy FJ,Rayner KJ.CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation.Nat Immunol2013;14:812-820 PMCID:PMC3720827

[59] Tall AR.Cholesterol, inflammation and innate immunity.Nat Rev Immunol2015;15:104-116 PMCID:PMC4669071

[60] Duewell P,Rayner KJ.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature2010;464:1357-1361 PMCID:PMC2946640

[61] Bekkering S,Joosten LAB,Netea MG.Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes.Arterioscler Thromb Vasc Biol2014;34:1731-1738

[62] Christ A,Lauterbach MAR.Western diet triggers NLRP3-dependent innate immune reprogramming.Cell2018;172:162-175.e14 PMCID:PMC6324559

[63] Toutouzas K,Koutagiar I.Vascular inflammation and metabolic activity in hematopoietic organs and liver in familial combined hyperlipidemia and heterozygous familial hypercholesterolemia.J Clin Lipidol2018;12:33-43

[64] Bernelot Moens SJ,Schnitzler JG.Remnant cholesterol elicits arterial wall inflammation and a multilevel cellular immune response in humans.Arterioscler Thromb Vasc Biol2017;37:969-975

[65] Raposeiras-Roubin S,Oliva B.Triglycerides and residual atherosclerotic risk.J Am Coll Cardiol2021;77:3031-3041 PMCID:PMC8215641

[66] Chait A,Vaisar T,Goldberg IJ.Remnants of the triglyceride-rich lipoproteins, diabetes, and cardiovascular disease.Diabetes2020;69:508-516 PMCID:PMC7085249

[67] Borén J,Krauss RM.Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.Eur Heart J2020;41:2313-2330 PMCID:PMC7308544

[68] Mahely R,Rall S.Lipoproteins of special significance in atherosclerosis: insights provided by studies of type III hyperlipoproteinemia.Ann N Y Acad Sci1985;454:209-221

[69] Norata GD,Raselli S.Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies.Atherosclerosis2007;193:321-327

[70] Schnitzler JG,Tiessens F.Nile red quantifier: a novel and quantitative tool to study lipid accumulation in patient-derived circulating monocytes using confocal microscopy.J Lipid Res2017;58:2210-2219 PMCID:PMC5665660

[71] Klop B,Mamo JC,Castro Cabezas M.Understanding postprandial inflammation and its relationship to lifestyle behaviour and metabolic diseases.Int J Vasc Med2012;2012:1-11 PMCID:PMC3179890

[72] Aboumsallem JP,Mishra M.Cholesterol-lowering gene therapy prevents heart failure with preserved ejection fraction in obese type 2 diabetic mice.Int J Mol Sci2019;20:2222 PMCID:PMC6539537

[73] Pourcet B.Alternative macrophages in atherosclerosis: not always protective!.J Clin Invest2018;128:910-912 PMCID:PMC5824921

[74] Rasmussen KL,Nordestgaard BG.Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals.Alzheimers Dement2018;14:71-80

[75] Bonacina F,Wang G.Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation.Nat Commun2018;9:3083 PMCID:PMC6079066

[76] Liberale L,Montecucco F.Pathophysiological relevance of macrophage subsets in atherogenesis.Thromb Haemost2017;117:7-18

[77] Westerterp M,Wang M.Deficiency of ATP-binding cassette transporters A1 and G1 in macrophages increases inflammation and accelerates atherosclerosis in mice.Circ Res2013;112:1456-65 PMCID:PMC3839866

[78] Baragetti A,Catapano AL.Effect of lipids and lipoproteins on hematopoietic cell metabolism and commitment in atherosclerosis.Immunometabolism2021;3 PMCID:PMC7610604

[79] Kaplan R,Hernandez M.Regulation of the angiopoietin-like protein 3 gene by LXR.J Lipid Res2003;44:136-143

[80] Zheng J,Umikawa M,Zhang CC.Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche.Blood2011;117:470-479 PMCID:PMC3031476

[81] Chadwick AC,Lv W.Reduced blood lipid levels with in vivo CRISPR-Cas9 base editing of ANGPTL3.Circulation2018;137:975-977 PMCID:PMC5830171

[82] Zhang CC,Ge G.Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells.Nat Med2006;12:240-245 PMCID:PMC2771412

[83] Collaboration CTT (CTT).Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.Lancet2010;376:1670-1681 PMCID:PMC2988224

[84] Athyros VG,Bilianou H.The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement.Metabolism2017;71:17-32

[85] Chalasani N,Kesterson J,Hall SD.Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity.Gastroenterology2004;126:1287-1292

[86] Cohen DE,Chalasani N.An assessment of statin safety by hepatologists.Am J Cardiol2006;97:77C-81C

[87] Kaplan DE,Mehta R.Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis.Gastroenterology2019;156:1693-1706.e12

[88] Kim RG,Prokop LJ.Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis.Clin Gastroenterol Hepatol2017;15:1521-1530 PMCID:PMC5605397

[89] Thomson MJ,Khungar V.Prevalence and factors associated with statin use among patients with nonalcoholic fatty liver disease in the TARGET-NASH study.Clin Gastroenterol Hepatol2022;20:458-460 PMCID:PMC8464616

[90] Torres-Peña JD,Fuentes-Jiménez F.Statins in non-alcoholic steatohepatitis.Front Cardiovasc Med2021;8:777131 PMCID:PMC8652077

[91] Shepherd J,Lorimer AR,Packard CJ.Fenofibrate reduces low density lipoprotein catabolism in hypertriglyceridemic subjects.Arteriosclerosis1985;5:162-168

[92] Ginsberg HN.Changes in lipoprotein kinetics during therapy with fenofibrate and other fibric acid derivatives.Am J Med1987;83:66-70

[93] Pawlak M,Staels B.Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.J Hepatol2015;62:720-733

[94] Kooistra T,De Vries-Van Der Weij J.Fenofibrate reduces atherogenesis in ApoE*3Leiden mice: evidence for multiple antiatherogenic effects besides lowering plasma cholesterol.Arterioscler Thromb Vasc Biol2006;26:2322-30

[95] Okopień B,Herman ZS.Effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance.J Clin Endocrinol Metab2006;91:1770-1778

[96] Krysiak R,Okopieñ B.Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance.Pharmacol Rep2013;65:1311-1316

[97] Ginsberg H,Lovato L.Effects of combination lipid therapy in type 2 diabetes mellitus.N Engl J Med2010;362:1563-1574 PMCID:PMC2879499

[98] Scott R,Fulcher G.Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.Diabetes Care2009;32:493-498 PMCID:PMC2646035

[99] Deprince A,Staels B.Dysregulated lipid metabolism links NAFLD to cardiovascular disease.Mol Metab2020;42:101092 PMCID:PMC7600388

[100] Seko Y,Umemura A.Effect of pemafibrate on fatty acid levels and liver enzymes in non-alcoholic fatty liver disease patients with dyslipidemia: a single-arm, pilot study.Hepatol Res2020;50:1328-1336

[101] Hatanaka T,Saito N.Impact of pemafibrate in patients with hypertriglyceridemia and metabolic dysfunction-associated fatty liver disease pathologically diagnosed with non-alcoholic steatohepatitis: a retrospective, single-arm study.Intern Med2021;60:2167-2174 PMCID:PMC8355409

[102] Phase 3 CV outcomes study with pemafibrate stopped early - PACE-CME [Internet]. Available from: https://pace-cme.org/2022/04/11/phase-3-cv-outcomes-study-with-pemafibrate-stopped-early/ [Last accessed on 27 Jun 2022]

[103] Shearer GC,Harris WS.Fish oil -- how does it reduce plasma triglycerides?.Biochim Biophys Acta2012;1821:843-851 PMCID:PMC3563284

[104] Oscarsson J.Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.Lipids Health Dis2017;16:149 PMCID:PMC5553798

[105] Bhatt DL,Miller M.Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.

[106] Gaudet D,Tremblay K.Targeting APOC3 in the familial chylomicronemia syndrome.N Engl J Med2014;371:2200-06

[107] Witztum JL,Freedman SD.Volanesorsen and triglyceride levels in familial chylomicronemia syndrome.N Engl J Med2019;381:531-542

[108] Ahmad Z,Hamon S.Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia.Circulation2019;140:470-486 PMCID:PMC6686956

[109] Gaudet D,Baum SJ.Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.Eur Heart J2020;41:3936-3945 PMCID:PMC7750927

[110] Marso SP,Brown-Frandsen K.Liraglutide and cardiovascular outcomes in type 2 diabetes.Drug Ther Bull2016;54:101

[111] Nogueira JP,Béliard S.Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes.Arterioscler Thromb Vasc Biol2012;32:1039-1044

[112] Parlevliet ET,Geerling JJ.GLP-1 receptor activation inhibits VLDL production and reverses hepatic steatosis by decreasing hepatic lipogenesis in high-fat-fed APOE*3-Leiden mice.PLoS One2012;7:e49152 PMCID:PMC3487842

[113] Mantovani A,Beatrice G,Lonardo A.Glucagon-Like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials.Metabolites2021;11:1-13 PMCID:PMC7911747

[114] Geerling JJ,Van Der Zon GC.Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice.Diabetes2014;63:880-891

[115] Rigamonti E,Staels B.Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men.Arterioscler Thromb Vasc Biol2008;28:1050-1059

[116] Kirchgessner TG,Ostrowski J.Beneficial and adverse effects of an LXR agonist on human lipid and lipoprotein metabolism and circulating neutrophils.Cell Metab2016;24:223-233

[117] Younossi ZM,Loomba R.Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial.Lancet2019;394:2184-2196

[118] Intercept announces withdrawal of EMA marketing authorization application for obeticholic acid for advanced liver fibrosis due to NASH - intercept pharmaceuticals, Inc. Available from: https://ir.interceptpharma.com/news-releases/news-release-details/intercept-announces-withdrawal-ema-marketing-authorization [Last accessed on 27 Jun 2022]

[119] Lazarus JV,Anstee QM.Advancing the global public health agenda for NAFLD: a consensus statement.Nat Rev Gastroenterol Hepatol2021;19:60-78

[120] Diabetes [Internet]. Available from: https://www.who.int/health-topics/diabetes#tab=tab_1 [Last accessed on 27 Jun 2022]

[121] Sabatine MS,Keech AC.Evolocumab and clinical outcomes in patients with cardiovascular disease.N Engl J Med2017;376:1713-1722

[122] Ridker PM,Thuren T.CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med2017;377:1119-31

[123] Bouabdallaoui N,Tardif JC.Lessons from COLCOT and LoDoCo2: colchicine for secondary prevention in coronary artery disease.Eur Heart J2021;42:2800-1

[124] Opstal TSJ,Fiolet ATL.Colchicine attenuates inflammation beyond the inflammasome in chronic coronary artery disease: a LoDoCo2 proteomic substudy.Circulation2020;142:1996-8

[125] Ridker PM.Mortality differences associated with treatment responses in CANTOS and FOURIER: insights and implications.Circulation2018;137:1763-1766