Mechanisms of protective effects of astaxanthin in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease is a major contributor to chronic liver disease worldwide, and 10%-20% of nonalcoholic fatty liver progresses to nonalcoholic steatohepatitis (NASH). Astaxanthin is a kind of natural carotenoid, mainly derived from microorganisms and marine organisms. Due to its special chemical structure, astaxanthin has strong antioxidant activity and has become one of the hotspots of marine natural product research. Considering the unique chemical properties of astaxanthin and the complex pathogenic mechanism of NASH, astaxanthin is regarded as a significant drug for the prevention and treatment of NASH. Thus, this review comprehensively describes the mechanisms and the utility of astaxanthin in the prevention and treatment of NASH from seven aspects: antioxidative stress, inhibition of inflammation and promotion of M2 macrophage polarization, improvement in mitochondrial oxidative respiration, regulation of lipid metabolism, amelioration of insulin resistance, suppression of fibrosis, and liver tumor formation. Collectively, the goal of this work is to provide a beneficial reference for the application value and development prospect of astaxanthin in NASH.

Keywords

Nonalcoholic fatty liver disease / astaxanthin / fibrosis / insulin resistance / mitochondrial dysfunction / oxidative stress

References

[1] Rinella ME,Sanyal AJ,Abdelmalek MF.participants of the AASLD/EASL WorkshopReport on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD.J Hepatol2019;71:823-33

[2] Caldwell S.The natural history of non-alcoholic fatty liver disease.Dig Dis2010;28:162-8

[3] Friedman SL,Rinella M.Mechanisms of NAFLD development and therapeutic strategies.Nat Med2018;24:908-22 PMCID:PMC6553468

[4] Kulik L.Epidemiology and management of hepatocellular carcinoma.Gastroenterology2019;156:477-91.e1 PMCID:PMC6340716

[5] Younossi ZM,Abdelatif D,Henry L.Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology2016;64:73-84

[6] Zhou JH,Wang WX.Epidemiological features of NAFLD from 1999 to 2018 in China.Hepatology2020;71:1851-64

[7] Zhu JZ,Wang YM,Yu CH.Prevalence of nonalcoholic fatty liver disease and economy.Dig Dis Sci2015;60:3194-202

[8] Wong RJ,Cheung R.Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States.Gastroenterology2015;148:547-55

[9] Buzzetti E,Tsochatzis EA.The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD).Metabolism2016;65:1038-48

[10] Basaranoglu M.From fatty liver to fibrosis: A tale of “second hit”.World J of Gastroenterol2013;19:1158 PMCID:PMC3587471

[11] Ni Y,Nagashimada M.Lycopene prevents the progression of lipotoxicity-induced nonalcoholic steatohepatitis by decreasing oxidative stress in mice.Free Radical Bio Med2020;152:571-82

[12] Schuppan D.Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches.J Gastroenterol Hepatol2013;28 Suppl 1:68-76

[13] Farrell GC.Nonalcoholic fatty liver disease: From steatosis to cirrhosis.Hepatology2006;43:S99-S112

[14] Lavine JE.Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents.JAMA2011;305:1659

[15] Bril F,Kalavalapalli S.Role of vitamin E for nonalcoholic steatohepatitis in patients with type 2 diabetes: A randomized controlled trial.Diabetes Care2019;42:1481-8

[16] Sanyal AJ,Kowdley KV.Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis.New Engl J Med2010;362:1675-85 PMCID:PMC2928471

[17] Ambati RR,Ravi S.Astaxanthin: sources, extraction, stability, biological activities and its commercial applications-a review.Mar Drugs2014;12:128-52 PMCID:PMC3917265

[18] Krinsky NI.Antioxidant functions of carotenoids.Free Radic Biol Med1989;7:617-35

[19] Rishton GM.Natural products as a robust source of new drugs and drug leads: past successes and present day issues.Am J Cardiol2008;101:43d-9d

[20] Guerin M,Olaizola M.Haematococcus astaxanthin: applications for human health and nutrition.Trends Biotechnol2003;21:210-6

[21] Spiller GA.Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: a randomized clinical trial.J Med Food2003;6:51-6

[22] Fassett RG.Astaxanthin in cardiovascular health and disease.Molecules2012;17:2030-48 PMCID:PMC6268807

[23] Hussein G,Goto H,Watanabe H.Astaxanthin, a carotenoid with potential in human health and nutrition.J Nat Prod2006;69:443-9

[24] Kishimoto Y,Uto-Kondo H.Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages.Eur J Nutr2010;49:119-26

[25] Lobos P,Cordova A.Astaxanthin protects primary hippocampal neurons against noxious effects of a beta-oligomers.Neural Plast2016;2016:3456783 PMCID:PMC4791503

[26] Sila A,Kamoun Z.Astaxanthin from shrimp by-products ameliorates nephropathy in diabetic rats.Eur J Nutr2015;54:301-7

[27] Visioli F.Astaxanthin in cardiovascular health and disease: mechanisms of action, therapeutic merits, and knowledge gaps.2017;8:39-63

[28] Sutti S,Locatelli I.Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH.Hepatology2014;59:886-97

[29] Polimeni L,Baratta F.Oxidative stress: new insights on the association of non-alcoholic fatty liver disease and atherosclerosis.World J Hepatol2015;7:1325-36 PMCID:PMC4450196

[30] Del Ben M,Baratta F.Serum cytokeratin-18 is associated with NOX₂-Generated oxidative stress in patients with nonalcoholic fatty liver.Int J Hepatol2014;2014:784985 PMCID:PMC3941779

[31] Del Ben M,Carnevale R et al.NOX₂-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non-alcoholic fatty liver disease.BMC Gastroenterol2014;14:1-8 PMCID:PMC4014405

[32] Betteridge DJ.What is oxidative stress?.Metabolism2000;49:3-8

[33] Touyz RM.Reactive oxygen species, vascular oxidative stress, and redox signaling in hypertension - What is the clinical significance?.Hypertension2004;44:248-52

[34] Chen G,Nagata N,Ota T.Micronutrient antioxidants and nonalcoholic fatty liver disease.Int J Mol Sci2016;17:1379 PMCID:PMC5037659

[35] Meinke MC,Tscherch K.Influence of dietary carotenoids on radical scavenging capacity of the skin and skin lipids.Eur J Pharm Biopharm2013;84:365-73

[36] Barros MP,Colepicolo P.Astaxanthin and peridinin inhibit oxidative damage in Fe(2+)-loaded liposomes: scavenging oxyradicals or changing membrane permeability?.Biochem Biophys Res Commun2001;288:225-32

[37] Palozza P.Astaxanthin and canthaxanthin are potent antioxidants in a membrane model.Arch Biochem Biophys1992;297:291-5

[38] Zhang ZW,Liu T.Mitochondrion-permeable antioxidants to treat ROS-burst-mediated acute diseases.Oxid Med Cell Longev2016;2016:6859523 PMCID:PMC4663357

[39] Jorgensen K.Carotenoid scavenging of radicals. Effect of carotenoid structure and oxygen partial pressure on antioxidative activity.Z Lebensm Unters Forsch1993;196:423-9

[40] Lim BP,Terao J,Suzuki T.Antioxidant activity of xanthophylls on peroxyl radical-mediated phospholipid peroxidation.Biochim Biophys Acta1992;1126:178-84

[41] Nakagawa K,Miyazawa T.Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes.Br J Nutr2011;105:1563-71

[42] Rao A, Raghunath Reddy RL, Baskaran V, Sarada R, Ravishankar GA. Characterization of microalgal carotenoids by mass spectrometry and their bioavailability and antioxidant properties elucidated in rat model.J Agric Food Chem2010;58:8553-9

[43] Choi HD,Chang MJ,Shin WG.Effects of astaxanthin on oxidative stress in overweight and obese adults.Phytother Res2011;25:1813-8

[44] Santos SD,Firmino GO.Shrimp waste extract and astaxanthin: rat alveolar macrophage, oxidative stress and inflammation.J Food Sci2012;77:H141-6

[45] Franceschelli S,Ferrone A.Astaxanthin treatment confers protection against oxidative stress in U937 cells stimulated with lipopolysaccharide reducing O2- production.PLoS One2014;9:e88359 PMCID:PMC3919765

[46] Lee SJ,Lee KS.Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I (kappa) B kinase-dependent NF-kappaB activation.Mol Cells2003;16:97-105

[47] Kim YJ,Yokozawa T.Protection against oxidative stress, inflammation, and apoptosis of high-glucose-exposed proximal tubular epithelial cells by astaxanthin.J Agric Food Chem2009;57:8793-7

[48] Abdelzaher LA,Suzuki T,Takashina M.Astaxanthin alleviates oxidative stress insults-related derangements in human vascular endothelial cells exposed to glucose fluctuations.Life Sci2016;150:24-31

[49] Campoio TR,Otton R.Oxidative stress in human lymphocytes treated with fatty acid mixture: role of carotenoid astaxanthin.Toxicol In Vitro2011;25:1448-56

[50] Wan J,Teixeira-Clerc F.M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease.Hepatology2014;59:130-42

[51] Ni Y,Zhuge F.Astaxanthin prevents and reverses diet-induced insulin resistance and steatohepatitis in mice: A comparison with vitamin E.Sci Rep2015;5:17192 PMCID:PMC4658633

[52] Jia Y,Kim J,Lee SJ.Astaxanthin reduces hepatic lipid accumulations in high-fat-fed C57BL/6J mice via activation of peroxisome proliferator-activated receptor (PPAR) alpha and inhibition of PPAR gamma and Akt.J Nutr Biochem2016;28:9-18

[53] Ni Y,Zhuge F.The gut microbiota and its metabolites, novel targets for treating and preventing non-alcoholic fatty liver disease.Mol Nutr Food Res2020;64:e2000375

[54] Ferro D,Pastori D.New insights into the pathogenesis of non-alcoholic fatty liver disease: gut-derived lipopolysaccharides and oxidative stress.Nutrients2020;12 PMCID:PMC7551294

[55] Lumeng CN.Inflammatory links between obesity and metabolic disease.J Clin Invest2011;121:2111-7 PMCID:PMC3104776

[56] Macedo RC,Marin DP.Astaxanthin addition improves human neutrophils function: in vitro study.Eur J Nutr2010;49:447-57

[57] Fan CD,Fu XT.Astaxanthin attenuates homocysteineinduced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage.Front Physiol2017;8:1041 PMCID:PMC5733103

[58] Wang XJ,Fu XT.Reversal of homocysteine-induced neurotoxicity in rat hippocampal neurons by astaxanthin: evidences for mitochondrial dysfunction and signaling crosstalk.Cell Death Discov2018;4:50 PMCID:PMC6197197

[59] Kim SH,Kim H.Astaxanthin Inhibits Mitochondrial Dysfunction and Interleukin-8 Expression in Helicobacter pylori-Infected Gastric Epithelial Cells.Nutrients2018;10 PMCID:PMC6164770

[60] Yu T,Chen Y,Deuster PA.Astaxanthin inhibits mitochondrial dysfunction and interleukin-8 expression in helicobacter pylori-infected gastric epithelial cells.J Cell Physiol2019;234:13292-302 PMCID:PMC6164770

[61] Mano CM,Cardozo KHM,Bechara EJH.Astaxanthin Restrains Nitrative-Oxidative Peroxidation in Mitochondrial-Mimetic Liposomes: A Pre-Apoptosis model.Mar Drugs2018;16:126 PMCID:PMC5923413

[62] Shanmugapriya K,Kang HW.In vitro antitumor potential of astaxanthin nanoemulsion against cancer cells via mitochondrial mediated apoptosis.Int J Pharm2019;560:334-46

[63] Lee DH,Lee YJ.Astaxanthin protects against MPTP/MPP+-induced mitochondrial dysfunction and ROS production in vivo and in vitro.Food Chem Toxicol2011;49:271-80 PMCID:PMC3010303

[64] Choi AM,Levine B.Autophagy in human health and disease.N Engl J Med2013;368:651-62

[65] Harano Y,Toyama T.Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver.Liver Int2006;26:613-20

[66] Singh R,Wang Y.Autophagy regulates lipid metabolism.Nature2009;458:1131-5 PMCID:PMC2676208

[67] Jones JR,Kim KA.Deletion of PPAR gamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance.Proc Natl Acad Sci USA2005;102:6207-12 PMCID:PMC556131

[68] Venkatachalam MA,Lan R,Saikumar P.Acute kidney injury: a springboard for progression in chronic kidney disease.Am J Physiol Renal Physiol2010;298:F1078-94 PMCID:PMC2867413

[69] Augusti PR,Somacal S.Astaxanthin prevents changes in the activities of thioredoxin reductase and paraoxonase in hypercholesterolemic rabbits.J Clin Biochem Nutr2012;51:42-9 PMCID:PMC3391862

[70] Ryu SK,Fujioka K,Pashkow FJ.Effect of an oral astaxanthin prodrug (CDX-085) on lipoprotein levels and progression of atherosclerosis in LDLR(-/-) and ApoE(-/-) mice.Atherosclerosis2012;222:99-105

[71] Deng ZY,Wang SF,Chen Y.Effects of astaxanthin on blood coagulation, fibrinolysis and platelet aggregation in hyperlipidemic rats.Pharm Biol2017;55:663-72 PMCID:PMC6130668

[72] Samuel VT.The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux.J Clin Invest2016;126:12-22 PMCID:PMC4701542

[73] Ye J.Mechanisms of insulin resistance in obesity.Front Med2013;7:14-24 PMCID:PMC3936017

[74] Yang Y,Park YK.Histone deacetylase 9 plays a role in the antifibrogenic effect of astaxanthin in hepatic stellate cells.J Nutr Biochem2017;40:172-7

[75] Bhuvaneswari S.Astaxanthin prevents loss of insulin signaling and improves glucose metabolism in liver of insulin resistant mice.Can J Physiol Pharmacol2012;90:1544-52

[76] Bhuvaneswari S,Sreeja S.Astaxanthin reduces hepatic endoplasmic reticulum stress and nuclear factor-kappaB-mediated inflammation in high fructose and high fat diet-fed mice.Cell Stress Chaperones2014;19:183-91 PMCID:PMC3933623

[77] Kisseleva T.Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis.J Gastroenterol Hepatol2007;22 Suppl 1:S73-8

[78] Baghy K,Kovalszky I.Decorin-TGFbeta axis in hepatic fibrosis and cirrhosis.J Histochem Cytochem2012;60:262-8 PMCID:PMC3351239

[79] Yang Y,Park YK,Lee JY.Astaxanthin prevents TGFbeta1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells.Biochim Biophys Acta2015;1850:178-85

[80] Shen M,Lu J.Protective effect of astaxanthin on liver fibrosis through modulation of TGF-beta1 expression and autophagy.Mediators Inflamm2014;2014:954502 PMCID:PMC4016904

[81] Hernandez-Gea V,Rozenfeld R.Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues.Gastroenterology2012;142:938-46 PMCID:PMC3439519

[82] Zhao Q,Zhao ZH,Wang K.Epigenetic modifications in hepatic stellate cells contribute to liver fibrosis.Tohoku J Exp Med2013;229:35-43

[83] Dai W,He L.Genistein inhibits hepatocellular carcinoma cell migration by reversing the epithelial-mesenchymal transition: partial mediation by the transcription factor NFAT1.Mol Carcinog2015;54:301-11

[84] Villanueva A,Llovet JM.Linking molecular classification of hepatocellular carcinoma and personalized medicine: preliminary steps.Curr Opin Oncol2008;20:444-53 PMCID:PMC3678124

[85] Gradelet S,Berges R,Astorg P.Dietary carotenoids inhibit aflatoxin B1-induced liver preneoplastic foci and DNA damage in the rat: role of the modulation of aflatoxin B1 metabolism.Carcinogenesis1998;19:403-11

[86] Tripathi DN.Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: role of Nrf2, p53, p38 and phase-II enzymes.Mutat Res2010;696:69-80

[87] Khor TO,Prawan A.Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer.Cancer Prev Res (Phila)2008;1:187-91 PMCID:PMC3580177

[88] Lee JH,Shu L.Dietary phytochemicals and cancer prevention: Nrf2 signaling, epigenetics, and cell death mechanisms in blocking cancer initiation and progression.Pharmacol Ther2013;137:153-71 PMCID:PMC3694988

[89] Song X,Zhang L.Changes in cell ultrastructure and inhibition of JAK1/STAT3 signaling pathway in CBRH-7919 cells with astaxanthin.Toxicol Mech Methods2012;22:679-86

[90] Li J,Xia Y.Astaxanthin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma cells via inhibition of NF-Kappa b P65 and Wnt/Beta-Catenin in vitro.Mar Drugs2015;13:6064-81 PMCID:PMC4626679

[91] Shao Y,Yang J,Li J.Astaxanthin inhibits proliferation and induces apoptosis and cell cycle arrest of mice H22 hepatoma cells.Med Sci Monit2016;22:2152-60 PMCID:PMC4922829

[92] Menendez JA.Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis.Nat Rev Cancer2007;7:763-77

[93] Postic C.The role of the lipogenic pathway in the development of hepatic steatosis.Diabetes Metab2008;34:643-8

[94] Ohno T,Shirakami Y.Preventive effects of astaxanthin on diethylnitrosamine-induced liver tumorigenesis in C57/BL/KsJ-db/db obese mice.Hepatol Res2016;46:E201-9

[95] Saxena NK,Nagalingam A.Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma.Gastroenterology2010;139:1762-73 PMCID:PMC2967590