The Association of Non Viral Liver Diseases from NAFLD to NASH to HCC with the Pandemic of Obesity, Type 2 Diabetes, or Diabesity & Metabolic Syndrome Etiopathogenetic Correlation along with Utilization for Diagnostic & Therapeutic Purposes-A Systematic Review

Kulvinder Kochar Kaur (Kaur Centre For Human Reproduction, 721, G.T.B. Nagar, Jalandhar, Punjab, 144001, India)
Gautam Allahbadia (Ex-Rotunda-A Centre for Human Reproduction, 672, Kalpak Garden, Bandra(W)-Mumbai, 400040, India)
Mandeep Singh (Swami Satyanand Hospital, Jalandhar, Punjab, India)


Earlier we have been reviewing the etiopathogenesis (EP) of obesity, type2 Diabetes mellitus (T2DM), Metabolic Syndrome (MetS), Non Alcoholic Fatty Acid Liver Disease (NAFLD) non alcoholic steatohepapititis (NASH), along with its propagation to Hepatocellular carcinoma (HCC) in addition to their therapies exhaustively. T2DM continues to be a major health issue with reaching epidemic to pandemic proportions. Liver disease includes a spectrum of liver injury varying from isolated steatosis known as Non Alcoholic Fatty Acid Liver Disease (NAFLD) to HCC. Clinically it has been observed that the coexistence of NAFLD as well as T2DM is prevalent. T2DM aids in the biological events that results in escalation of robustness of NAFLD that constitutes the primary etiology of chronic liver diseases. In the past 2 decades the incidence of nonviral NAFLD/NASH, obtained HCC has been escalating at a fast pace. In view of no appropriate agents for therapy of NAFLD/NASH, a thiazolidenedione group of drug pioglitazone used for T2DM therapy is utilized occasionally.
Thus here we conducted a systematic review utilizing search engine pubmed, google scholar; web of science; embase; Cochrane review libraryutilizingtheMeSHterms like T2DM; MetS; NAFLD; NASH; HCC;WAT; BAT; VisceralAT; Obesity; BMI; Adipocytokines; adiponectin;leptin; resistin; visfatin; irisin; Hepatokines; angiopoietin like protein 2; hepatosscin; retinol binding protein 4; treatment like pioglitazone;liraglutide; elafibranor CVC (cerviciroc); obeticholic acid; aramchol;selonosertib; simtuzumab; Oxidative stress(OS); insulin resistance (IR) from 1980’s to 2021 till date. We found a total of 1050 articles out of which we selected 236 articles for this review. No meta-analysis was done. Hence diagnosis avoidance in addition to treatment of the generation as well as propagation of NAFLD/NASH are significant areas needing tackling. Thus here we have summarized the EP of NAFLD/NASH, as well as NAFLD/NASH, obtained HCC along with the present advantageous therapies under trial,for NAFLD/NASH. Moreover how adipocyte obtained adipokines along with liver obtained hepatokines might work as both diagnostic in addition to therapeutic targets from NAFLD to HCC.



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[1] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Kochar Kaur -K,Allahabadia GN,Singh M(2016).An update on Aetiopathogenesis and management of Obesity.Obes Control Ther3(1):1-17. Diabetes Res Clin Pract 2014;103:137-49.

[2] Kochar Kaur -K,Allahabadia GN,Singh M(2013)Current management of obesity in an infertile female.Recent Advances -and Future Prospectives.Drugs J Pharm Nutr Soc;3:1-13.

[3] Kochar Kaur -K,Allahabadia GN,Singh M .Therapeutic Utilization of Neuro Imaging Studies in Obesity for Optimal Utilization of Drugs used in Treatment for Obesity-Lessons Learnt from Bariatric Surgery. -J Ageing Restor Med (JARM)n2019;2(2):89-97.

[4] Kochar Kaur -K,Allahabadia GN,Singh M . Existing and prospective pathways for intervention in treatment of obesity in a novel way-a review; -MOJ Drug Des Develop Ther. 2018;2(3):95-105. DOI: 10.15406/mojddt.2018.02.00035.

[5] Kochar Kaur -K,Allahabadia GN,Singh M .Advances in BAT physiology for understanding and translating into Pharmacotherapies for obesity and comorbidities. MOJ Drug Des Develop Ther. 2018;2(5:166-176. DOI:10.15406/mojddt.2018.02.00057.

[6] Kochar Kaur -K,Allahabadia GN,Singh M. Targeting macrophage polarization for therapy of diabesity–the feasibility of early improvement of insulin sensitivity and insulin resistance-a comprehensive systematic review. J Diab Metab Disorder Control. 2021;8(1):6-25.

[7] Kochar Kaur -K,Allahabadia GN,Singh M. Are we at the verge of finding a new efficacious pharmacotherapy for obesity in the form of agonism at triple drug receptors: glucagon, Glucagon like peptide1 (GLP1), glucose dependent insulin tropic peptide (GIP). MOJ Drug Des Develop Ther. 2019;3(1):22-27.

[8] Kochar Kaur -K,Allahabadia GN,Singh M. Targeting Orexin Neurons for Treatment of Obesity is It Feasible in Human Being-A Systematic Review. Journal of Neurology Research Reviews & Reports. J Neurol Res Rev Rep, 2019; 1(1): 1-9.

[9] Kochar Kaur -K,Allahabadia GN,Singh M .Importance of simultaneous treatment of obesity and diabetes mellitus: A sequelae to the understanding of diabesity-A review.Obes Res Open J. 2019; 6(1): 1-10. DOI: 10.17140/OROJ-6-136.

[10] Kochar Kaur -K,Allahabadia GN,Singh M . Role of Adipocyte Impairment in Heart Failure Induction in Subjects that are Obese along with Prediabetes and Overt Diabetes Mellitus - A Systematic Review. International Journal of Cardiology and Cardiovascular Disorder2021; 2(1) :1-21.

[11] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. A Mini Review on Development of Newer Therapies for Non Alcoholic Fatty Acid Liver Disease with Emphasis on Vitamin D and its Receptor and Allyl Isothiocyanate (AITC)”. Acta Scientific Nutritional Health 2019; 3(12) :1-5.

[12] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. An Update on Further Progression of NAFLD, NASH with Prospective Therapies Like L-Carnitine (LC), Nicotinamide Ribose (NR) Combination, as well as Apical Sodium Dependent Bile Acids Transporter (ASBT) or Volixibat and Silybin as Alternatives. Int J Clin Med Cases. 2020 Jan;3(3):138. DOI: 10.31021/ijcmc.20203138-29/1/2020 jan 29.

[13] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Have Probiotics and Synbiotics passed the test of time to be implemented in management of obesity and related metabolic disorders-a comprehensive review. Adv Obes Weight Manag Control. 2019;9(1):21-28. DOI: 10.15406/aowmc.2019.09.00269.

[14] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Will Probiotics Provide the Answer for Therapy of Non-alcoholic Fatty Liver Disease (NAFLD)? – A Systematic Review. Biochem Physiol -2020;9: 257.

[15] Kulvinder Kochar Kaur,Allahbadia GN,Singh M.. Rosmarinic Acid-A New Hope for Liver Diseases Like Cirrhosis, Hepatocellular Carcinoma-NeedsTranslation to Humans”. EC Endocrinology and Metabolic Research 2019;4(6 ): 289-301.

[16] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. How do we apply advances in knowledge of Hepatic Macrophages in treating Liver Diseases especially non alcoholic -fatty liver disease( NAFLD), non alcoholic steatohepapititis( NASH), with the increasing incidence of Diabesity-A Systematic Review.EC Endocrinology and Metabolic Research published in2020.

[17] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Mechanisms that associate extension of Nonalcoholic fatty liver diseases(NAFLD) to NASH (Nonalcoholic steatohepatitis) and further progressing to cirrhosis and Hepatocellular carcinoma(HCC) in addition to few proposed biomarkers for poor prognosis.J Gynaecol 2021;1(16):1-18.

[18] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. How can we optimize therapy of Non Alcoholic Fatty Acid Liver Disease-A Short Communication on role of Astragaloside IV and other prospective agents”. Clinical Research and Clinical Case Reports, 2021;1(3):1-4; DOI: http;//

[19] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Paradoxical Additional Role of SGLT2 Inhibitors Beyond Glycosuria in Controlling Obesity, NAFLD Treatment, Pancreatic β Cell Protection Besides Therapy for Diabetes Mellitus, CVOT and Renoprotection-A Minireview”. Acta Scientific Gastrointestinal Disorders 4.7 (2021): 15-26.

[20] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. ’An update on management of Nonalcoholic Fatty Liver Disease &Nonalcoholic Steatohepapititis-Is -the time ripe for achieving -resolution of NAFLD &NASH soon’’.2021Under review.

[21] Khan MAB,Hashim MJ,King JK,Govender RD,Mustafa H,AlKaabi J. -Epidemiology of type2 Diabetes mellitus- Global burden of disease and forecasted trends.J Epidemiol Glob Health 2020;10:107-11.

[22] Masmiquel L,Leiter LA,Vidal J,Bain S,Petrie J,-Franek E,etal.LEADER 5: Prevalenceand cardiometabolic impact ofobesity in cardiovascular high risk patients with type2 Diabetes mellitus:baseline global date from the LEADER trial. Cardiovasc Diabetol 2016;10:29.

[23] Ng ACT,Delgado V,Borlaug BA,Bax JJ.Diabesity :the combined burden of obesity -and Diabetes on heart disease and the role of imaging .Nat Rev Cardiol 2021;108:291-304.

[24] Gonzalez-Gross M,Melendez A.Sedentarism,active lifestyle and sport:impact on health and -obesity prevention.Nutr Hosp2013;5:89-98.

[25] Younossi ZM .Nonalcoholic fatty liver disease a global public healthperspective. J Hepatol 2019.;70: 531-44.

[26] Sunny NE,Bril F,Cusi K. Mitochondrial Adaptation in non alcoholic -fatty liver disease:novel mechanisms and treatmentstrategies. Trends -Endocrinol Metab 2017; 28:250-60.

[27] Abd-El-Khader SM, El-Den Ashwamy EM. Nonalcoholic fatty -liver disease:the diagnosis and management. World JHepatol 2015; 7:846-58.

[28] Arulanadan A,Loomba R.Non invasing testing -for NASH and NASH with advanced fibrosis:are we there yet?Curr Hepatol Res 2015;14: 109-18.

[29] Chalasani N, Younossi ZM, Lavine AE,Charlton M, Cusi K, RinellaM, -etal .The diagnosis and management of - non alcoholic fatty liver disease: practice guidance from the -American -Association for thestudy of - Liver disease. -Hepatology -2018;67: 328-57.

[30] Kim H, Lee DS,An TH,Park HJ,Kim WK,Bae KH,Oh KJ.Metabolic spectrum of liver failure in type2 - Diabetes and obesity:From NAFLD to NASH to HCC.Int J Mol Sci 2021;22:4295.

[31] Mahjoubin-TehranM,DeVentisA.Mikhailidis DP,Atkin SL,Mantzoros CS,Jamialahmadi T, -etal . Nonalcoholic fatty liver disease and steatohepatitis:state of the art on effective therapeutics based on the gold standard method for diagnosis. Mol Metab 2020;13:101049.

[32] Loomba R.Adams LA.The 20% rule of NASHprogression:the natural history of -advanced fibrosisand cirrhosis caused by NASH. Hepatology 2019;70: 1885-88.

[33] Wong SW,Ting YW,Chan WL. Epidemiology of -non alcoholic fatty liver disease related Hepatocellular carcinoma and its implications.JGH Open 2018;2: 235-41.

[34] BenhammouJN,Lin J,Hussain SK, El-Kabany M.Emerging risk factors for non alcoholic fatty liver disease - -associated Hepatocellular carcinoma. Hepatoma Res -2020;6:35.

[35] Huang DQ,El-SeragHB, Loomba R. Global Epidemiology of NAFLD- related HCC:Trends ,predictions,riskfactors and prevention. Nat Rev -Gastroenterol -Hepatol 2021;18:223-38.

[36] Anstee QM,McPherson S,Day CP.How big a problem -is Nonalcoholic fatty liver disease?BMJ2011;343:d3897.

[37] Tomah S,Alkhoury N,Hamdy O. Nonalcoholic fatty liver disease and type2 Diabetes:where do Diabetologists stand? Clin Diabetes Endocrinol 2020;6:9.

[38] Jarvis H,Craig D,Barker R,Spiers G,Stow D, Anstee QM, -etal .Metabolic risk factors -and incident advanced liver disease in Nonalcoholic fatty liver disease(NAFLD) :a systematic review and -meta-analysis of -population -based observational studies.PLoS Med 2020;17:e1003100.

[39] Miya narsky L,Manchem Y,Shibolet O. Treatment of Hepatocellular carcinoma:steps forward but but still a long way to go. World JHepatol 2015; 7:566-74.

[40] Goto K,Roca Suarez AA,Wrench F,Baumert TF,Lupberger J.Virus and Hepatocellular carcinoma:when the host loses its grip. Int J MolSci 2020;21):3057.

[41] Enomoto H,Ueno Y,Hiasa Y,Nishikawa H,Hige S,Taki kawa Y, -etal .Japan etiology of LiverCirrhosis Study Group in the 54th annual meeting of JSH.The transition in the -etiologies of -Hepatocellular carcinoma-complicated LiverCirrhosis in anationwide survey of Japan.J Gastroenterol -2021;56:158-67.

[42] Kinoda T, Goto K,Hirotsu Y,Masuzaki R,Moriyama M,Omata M. Molecular mechanisms :connections -between Nonalcoholic fatty liver disease, steatohepapititis and Hepatocellular carcinoma. Int J MolSci 2020;21):1525.

[43] Kim WK,Bae KH, Lee SC,Oh KJ.The latest insights into adipokines in -Diabetes. J Clin Med - - 2019; 8:1874.

[44] David Hojland L,Kykkesfeldt J,Tveden Nyborg . Molecular mechanisms of hepatic lipid accumulation in Nonalcoholic fatty liver disease. Cell Mol Life Sci -2018;75: 3313-327.

[45] Donnelly KL,Smith CI,Schwazenberg SJ,Jessurun J,Boldt MD,Parks EJ.Sources of fatty acids stored in liver and secreted via lipoprotein in patients with - non alcoholic fatty liver disease. J Clin Invest 2005;115:1343-51.

[46] Michele AB, David EC. Triglyceride metabolismin the liver .Compr Physiol -2017;8: 1-8.

[47] Draison F,Moulin P,Beylot M.Contribution of -hepatic Denovo lipogenesis and resterification of plasma non esterified fatty acids to plasma Triglyceride synthesis in Nonalcoholic fatty liver disease. Diabetes -Metab -2003;29:478-85.

[48] Chiu S,Mulligan K,Schwartz JM.Dietary arbohydrate and fatty liver disease: Denovo lipogenesis. Curr -Opin Clin Nutr Metab Care 2018;21:277-82.

[49] Linden AG,LiS,Choi HW,Fang F,Fukasawa U, Ueda K, -etal .Interplay between ChREBP and SREBP1c coordinates -postprandial glycolysis and lipogenesis -in livers of mice.J Lipid Res -2018;59: 475-87.

[50] Day CP,James OF. Steatohepapititis:A tale of two hits? Gastroenterology 1998;114:842-45.

[51] Arrese M,Cabrera D,Kalergis AM,Feldstein AE. Innate immunity and inflammation in NAFLD/ NASH.Dig Dis Sci 2016;61:1294-1303.

[52] Fukut H.Gut- liver axis in liver cirrhosis :how to manage leaky gut and endotoxaemia. World J Hepatol 2015; 7:425-42.

[53] JuC,Tacke F. Hepatic Macrophages in homeostasis and -liver diseases:from pathogenesis to novel therapeutic strategies. Cell Mol Immunol 2016;13: 316-27.

[54] Chakaroun RM,Massier L,Kovacs P.Gut microbiome, intestinal permeability - and tissue bacteria in metabolic disease:perpetrators or bystanders? Nutrients -2020;12:1082.

[55] Carpino G,Del Ben M,Pastori D,Carnevale R,Baratta F,Overi D, -etal .Increased liver localization of lipopolysaccharides in human and experimental NAFLD. Hepatology 2020;72: 470-85.

[56] Harte AL,Da Silva NF,Creely SJ,McGeeKC,Billyyard T,Youssef-Elabd EM, -etal .Elevated endotoxin levels in non alcoholic fatty liver disease.J Inflamm2010;7:15.

[57] Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007;56(7):1761-72.

[58] Kudo H,Takahara T,Yata Y,Kawai K,Zhang W,Sugiyama T. Lipopolysaccharides triggered TNFα-induced apoptosis in murine model of non alcoholic steatohepapititis model.J Hepatol 2009;51:168-75.

[59] Ma J,Zhou Q,Li H. Gut microbiota and Nonalcoholic fatty liver disease:insights on mechanisms and therapy. Nutrients -2017;9:1124.

[60] Jin C,Engstler AJ,Ziegenhardt D,Bishoff SC,Trautwein C.Bergheim I.Loss of -lipopolysaccharides binding protein attenuates -the development of diet induced - non alcoholic fatty liver disease in mice.J Gastroenterol Hepatol -2017;32:708-15.

[61] Lawrence T.The nuclear factor κB pathway in inflammation.Cold Spring HarbaPerspect Biol 2009;1:a001651.

[62] Lancaster GI,Langley KG,Berglund NA,Kammoun HL,Reibe S,EstevezE, et al.Evidence that TLR4 is not a receptor for saturatedfatty acids but mediates lipid-induced inflammation by reprogramming -macrophagemetabolism. Cell Metab 2018;27:1096-110.

[63] Sumida Y,Yoneda M.Current -and future Pharmacologic therapies for NAFLD/ NASH. J Gastroenterol -2018;27:1096-110.

[64] Masarone M,RosatoV,DallioM,Gravina AG,Aglitti A,LoguercioC, et al.Role of Oxidative stress in the pathogenesis of NAFLD. Oxid Med Cell Longev -2018;2018:9547613.

[65] Simoes ICM,Fontes A,Pinton P,Zischka H,WieckowskiMR. Mitochondria in non alcoholic fatty liver

[66] disease. Int J Biochem Cell Biol 2018;95:93-99.

[67] Serfaty L,Lemoine M.Definition and natural history of metabolic steatosis: Clinical aspects of NAFLD, NASH and cirrhosis. Diabetes -Metab -2008;34:634-37.

[68] Palmieri B,SblendorioV. Oxidative stress detection:what for ?Part II.Eur Rev Med Pharmacol Sci2007;11:27-54.

[69] Forrester SJ,Kikuchi DS,Hernandes MS,XuQ,Griendling KK. Reactive oxygen species in Metabolic -and -inflammatorysignaling.Circ Res 2018;122:877-902.

[70] Chen Z,Tian R,She Z,Cai J,LiH. Role of Oxidative stress in the pathogenesis of NAFLD.. Free Rad Biol Med -2020;152:116-41.

[71] Thuy LTT,Hai H,Kawada N.Role of cytoglobin ,a novel radical scavenger -in stellate cell activation and hepatic fibrosis -.Clin Mol Hepatol 2020; 26:280-93.

[72] Ilyasova D,Scarborough P,Spasojevic I.Urinary biomarkers of Oxidative stress. Clin Chim Acta 2012;7:219-27.

[73] Damiano S,Sozio C,La Rosa G,Santillo M.NOX dependent signaling dysreulation in severe COVID -19.Clues to effective treatment.Front -Cell Inf -Microbiol -2020; 10:608435.

[74] Angelico F,Loffredo L,Pignatelli P,Augelletti T,Carnevale R,Pacella A, et al. Weight loss is associated -with -improved endothelial dysfunction via NOX2 –generated Oxidative stress down regulation in patients with Metabolic Syndrome.Intern Energ -Med -2012;7:219-27.

[75] Del Ben M,Polimeni L, Carnevale R,Bartimoccia S,Baratta F,Nocella C, et al. NOX2 –generated Oxidative stress is associated -with - severity of ultrasound -liver steatosis - inpatients with -non alcoholic fatty liver disease.BMC Gastroenterol -2014;14:81.

[76] Dong Y,Yuan Y.Accelerated inflammation and Oxidative stressinduced by LPS in acute lung injury.:inhibition by ST1926. Int J Mol Med -2018;41(5):3405-21.

[77] Loffredo L,Zicani AM,Perri L, Carnevale R,Nocella C, Angelico F, et al.Does Nox2 over activation in children with Nonalcoholic fatty liver disease? Antioxid -Redox Signal -2019;30:1325-330.

[78] Kim SY, Jeong JM,Kim SJ,Seo W, Kim MH,Choi WM, et al. Proinflammatory Hepatic Macrophages generate ROS -through NADPH-oxidase -via endocytosis of -monomeric - TLR4-MD2 complex.Nat Commun2017 ;8:2247.

[79] Buzzzetti E, Pinzani M, Tsochatzis EA . The multiple hit pathogenesis of Nonalcoholic fatty liver disease (NAFLD). Metab Clin Exp 2016; 65: 451-64.

[80] Chalasani N, Younossi ZM, Lavine AE, Diehl AM,Brunt EM,Cusi K, et al. American Gastroenterological - Association, American -Association for thestudy of - Liver disease, American -Association forGastroenterology;The diagnosis and management of -non alcoholic fatty liver disease:practice guidelines -by the American Gastroenterological - Association, American -Association for thestudy of - Liver disease, American -Association forGastroenterology. Gastroenterology 2012;142:1592-609.

[81] Tziomalos K,Athyros VG,KaragiannisA. Nonalcoholic fatty liver disease in type2 Diabetes: pathogenesis -and treatment options. -Curr Vasc Pharmacol - 2012;10:162-72.

[82] Kulvinder Kochar Kaur, Gautam Allahbadia, Mandeep Singh . ’Attempt to utilize Classification of Type2 Diabetes mellitus subgroups provided by Ahlqvist to generate individualized treatment methods based on the actions on insulin resistance & βcell function :A move forward to more effective diabetes control from start &avoid End StageDamage ‘’.2021 Under review.

[83] Dasarathy S, Dasarathy J,Khayami A,Yerian LM,Sergent R,McCollough AJ. Randomized controlled trial -of omega3 fatty acids -in the - treatment - of non alcoholic steatohepapititis -in type2 Diabetes mellitus. Hepatology 2013; 58:518a.

[84] Alam F,Islam MA,Mohammed M,Ahmad I,Kamal MA,Donelly R, et al. Efficacy and safety of Pioglitazone monotherapy in type2 Diabetes mellitus.:a systematic review and -meta-analysis of Randomized controlled trials.Sci Rep -2019;9:5389.

[85] Lebovitz HE. Thiazolidenediones :The forgotten Diabetic medications .Curr -Diab Rep 2019;19:151.

[86] Schernather G,Currie CJ, Schernather GH.Do we still need Pioglitazone for the treatment - of type2 Diabetes mellitus?a risk benefit critique in 2013. Diabetes

[87] Care 2013; 36:S155-S161.

[88] Vieira R,Souto SB,Sanchez-Lopez E,Machado AL,Severino P,Jose S, et al. Sugar lowering drugs for -type2 Diabetes mellitus and Metabolic Syndrome-review of classical and newcompounds.Pt1-Pharmaceuticals -2019;12:152.

[89] Tyagi SM,Gupta P,Sai niAS,Kaushal C,Sharma S.The Peroxisome Proliferator adenineActivated Receptor:a family of nuclear -Receptors --role in various diseases.J Adv Pharm Technol Res 2011;2:236-40.

[90] Choi SS,Park J, Choi JH.Revisiting PPAR -γ -as a target -for the treatment of Metabolic disorders .BMB Rep - -2014;47:599-608.

[91] Fonseca V.Effect of thiazolidenediones on body -weight -in patients type2 Diabetes mellitus.Am J Med -2003;115:42S-48S.

[92] Kang JG,Park CY.The actions of -PPAR -γ -agonists on the various -target organs .Korean J Obes -2011;20:161-69.

[93] Kawai T,Funae O,Shimada A,Tabata -M,Hirata T,Atsumi Y, et al. Effects of pre treatment with low dose metformin on metabolic - parameters and -weight gain by -Pioglitazonein Japanese -patients -with type2 Diabetes.Int -Med -2008;47:1181-188.

[94] Musso G,Cassander M,Paschetta E,Gambino R. Thiazolidenediones and advanced liverfibrosis -in non alcoholic steatohepatitis -:a meta-analysis.JAMA Int -Med -2017;177:633-40.

[95] Bril F,Kalavalapalli S,Clark VC,Lomonaco R,Soldevila-Pico C,Liu IC, et al.Response to Pioglitazonein - patients -with -non alcoholic steatohepatitis - with vs without type2 Diabetes. Clin Gastroenterol Hepatol -2018;16:558-66.

[96] Yuan G,Zhang ML,Gong ZJ.Effects of PPAR –g agonist Pioglitazoneon rat -hepatic fibrosis. World JGastroenterol2004;10:1047-51.

[97] Shah RA,Kowdley KV. Obeticholic acid for the treatment of non alcoholic steatohepapititis.Expert Rev Gastroenterol Hepatol -2020;14:311-21.

[98] Verbeke L,Mannaerts I,Shierwagen R,Govaore O,Klein S,Vander Elst I, et al.FXR against Obeticholic acid reduces -hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep -2016;6:33453.

[99] Li T,Francl JM,Boehme S,Chang JY. Regulation of cholesterol and Bile acid homeostasis by the cholesterol7α hydroxylase / steroid -response -element binding protein 2/micro RNA-33a in mice. Hepatology 2013; 58:1111-121.

[100] Pelliciari R, Costantino G, Camaioni E,Sadeghpour BM,Entrena A,Willson TM, etal . Bile acid derivatives -as ligands of the -Farsenoid X receptor:synthesis,evaluation and structure Activity relationship -of a series of body and side chain modified analogues -of -chenodeoxycholic acid. J Med Chem - -2004; 47:4559-69.

[101] Mudaliar S,Henry RR,SanyalAJ,Morrow L,Marshall HU,Kipnes M, etal .Efficacy and safety of the -Farsenoid X receptor agonist Obeticholic acid in patients -withtype2 Diabetes mellitus and -of -non alcoholic fatty liver disease. Gastroenterology -2013; 145:574-82.

[102] Hameed B, Terrault NA,Gill RM,Loomba R, Chalasani N,Hoofnage JH, etal .The NASH Clinical research network. Clinical and metabolic effects associated -with -weight changes -and - Obeticholic acid in non alcoholic steatohepatitis. Aliment -Pharmacol -Ther 2018;47: 645-56.

[103] Hindson J. Obeticholic acid for the treatment of non alcoholic steatohepapititis. Nat Rev Gastroenterol Hepatol 2020; 17:65.

[104] Berger J,Moller DE.The mechanisms of action of PPARs. Annu Rev Med -2002;53: 409-35.

[105] Connolly JJ,Ooka K,Lim JK,Future Pharmacotherapy -for non alcoholic steatohepapititis( NASH):review in phase 2 and 3 trials.J Clin Transl Hepatol 2018; 6:264-75.

[106] Pawlak M,Lefebvre P,Staels B. Molecular mechanisms of PPARα action and its impact on lipid metabolism , inflammation and fibrosis -in non alcoholic steatohepatitis. -J Hepatol 2015;62: 720-33.

[107] Musso G,Gambino R,Cassader M,Pagano G.A meta-analysis for the randomized -trials -for the treatment of non alcoholic -Fatty Acid Liver Disease. Hepatology 2010; 52:79-104.

[108] Bojic LA,Huff MW. Peroxisome Proliferator Activated Receptorδ:A multifaceted -metabolic player.Curr Opin Lipiodol 2013;24: 171-7.

[109] Karpe F,Ehrenborg EE.PPARδ in humans:genetic -and Pharmacologic evidence for a significant Metabolic -function. Curr Opin Lipiodol 2009;20: 333-6.

[110] Riserus U,Sprecher D,Johnson T,Olson E,Hirschberg S,Liu A, etal. Activation of Peroxisome Proliferator Activated Receptorδ( PPAR -δ)promotes reversal of multiple metabolic abnormalities ,reduces Oxidative stress,and increases fatty acid oxidation in moderately obese men. Diabetes 2008;57: 332-9.

[111] Ratziu V,Harrison SA,Francque S,Bedossa P,Lahert P,Serfaty L, etal .GOLDEN 505 Investigator Study Group. Elafibranor,an agonist of -the Peroxisome Proliferator Activated Receptor α,and δ induces resolution of non alcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150:1147-59.

[112] Briand F,Heymes C,Bonada L,Angles T,Charpentier J,Branchereau M, etal.A 3week non alcoholic steatohepapititis mouse model -shows Elafibranor benefits -on hepatic inflammation and cell death. Clin Transl Sci 2020; 13:529-38.

[113] Tolbol KS,Kristiansen MN,Hansen HH,Veidal SS,Rigbolt KT, etal. Metabolic and hepatic effects of Liraglutide, Obeticholic acid and Elafibranor in diet induced obese -mouse model of biopsy confirmed non alcoholic steatohepatitis. -World JGastroenterol2018;24:179-94.

[114] Briand F,Maupoint J, BrousseauE,Breyner N,Bouchet M,Costard C, etal. Elafibranor improves diet induced non alcoholic steatohepatitis associated -with heart failure with preserved ejection fraction -in golden Syrian hamsters. Metabolism 2021; 117:154707.

[115] Cariou B,Hanf R,Lambert –Porcheron S,Zair Y,Sauvinet V, etal.Dual Peroxisome Proliferator Activated Receptor α,and δ agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese -subjects. Diabetes Care 2013; 36:2923-930.

[116] Cariou B, Zair Y,Staels B,Bruckert E. Effects of - the new dual PPARα / δ agonist GFT505 on lipid and glucosehomeostasis in abdominally obese - patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 2011; 34:2008-14.

[117] Jeong SW. Non alcoholic fatty liver disease:A Drug revolution is coming. Diabetes Metab J 2020;44:640-57.

[118] Irruarrizaga-Lejarreta M,Varela –Rey M, Fernandez-RamosD, Martinez-A rranz I,Delgado TC, etal.Role of Aramchol in steatohepapititis and - -fibrosis in mice . Hepatol Commun2017;1: 911-27.

[119] Dobrzyn A,Ntambi JM. Stearoyl-Co A Desaturase as a new drug for obesity treatment. ObesRev 2005;6:169-74.

[120] Goldiner I,Van der Velde AE,Vandenberghe KE,Van wijland MA,Halpern Z,Gilat T, etal.ABCA1 – dependent but apoA1 independent - cholesterol efflux -mediated by fatty acids -bile acid conjugates(-FABACs).Biochem J 2006;396:529-36.

[121] Safaldi K,Konikoff FM,Mahmaid M,Zelber –Sagi S,Halpern N,Gilat T etal.The fatty acids -bile acid conjugate Aramchol reduces liver fat content in Non Alcoholic Fatty Acid Liver Disease. Clin Gastroenterol Hepatol 2014; 12:2085-91.

[122] Gentiella R,Pechtner V,Corcos A,Consoli A. Glucagon like peptide 1 receptor -agonists in type2 - Diabetes treatment :are they all the same? Diabetes -Metab Res Rev 2019; 35:e3070.

[123] Greiner TU,Backhed F.Microbial regulation of GLP-1 and L-cell biology . -Mol Metab 2016;15:753-58.

[124] Michalowska J,Miller-Kasprzak E,Bogdanski P. Incretin -hormones in obesity -and related cardiometabolic disorders;the Clinical perspective. Nutrients -2021;13:351.

[125] Armstrong MJ,Gaunt P,Aithal GP,Barton D,Hull D,Parker R, etal .LEAN trial team .Liraglutidesafety and efficacy in for patients with non alcoholic steatohepatitis(LEAN):a multicenter ,double blinded , a -randomized,placebo- controlled -phase 2 -study . Lancet 2016; 387:679--90.

[126] DeFronzo RA,Ratner R,Han J,Kim D,Fineman M etal. Effects of Exenatide ( Extendin-4)on glycemic control and weight control over 30weeks in metformin treated patients with type2 - Diabetes. Diabetes Care 2005; 28:1092-100.

[127] Crane J,McGowan B.The GLP-1 agonists, Liraglutide,as a pharmacotherapy for obesity.Ther Adv Chronic Dis - 2016; 7:92-107.

[128] Davies MJ,Aronne LJ,Caterson ID,Thomsen AB,Jacobsen PB,Marso SP. Liraglutide and cardiovascular outcomes -in adults for obesity:a posthoc analysis from the SCALE -Diabetes randomized controlled trials. Diabetes Obes Metab 2018;20:734-39.

[129] AdamsJM,Pei H,Sandoval DA,SeelyRJ,Chang RB,-Liberles SD, etal. Liraglutide modulates appetite and body weight through Glucagon like peptide 1 receptor -expressing glutamatergic neurons. Diabetes -2018;67:1538-48.

[130] Mantovani A,Petracca G,Beatrice G,Csermely A,Lonardo A,Targher G. Glucagon like peptide 1 receptor -agonists for treatment of Non Alcoholic Fatty Acid Liver Disease and Non Alcoholic steatohepapititis:an updated meta-analysis of randomized controlled trials. Metabolites -2021;11:73.

[131] Kapodistria K,Tsilibary EP,KotsopouloE,Moustardas P,Kitsiou P. Liraglutide,A human Glucagon like peptide 1 analogue ,stimulates AKT dependent -survival signaling.J Cell Mol Med 2018;22:2970-980.

[132] HeQ,Sha S,Sun L,Zhang J,Dong M. GLP-1 analogueimproves - hepatic lipidaccumulation by inducing -autophagy via AMPK/ mTOR pathway. Biochem -Biophys Res Commun -2016;476:196-203.

[133] Chalasani N, Younossi ZM, Lavine AE, Diehl AM,Brunt EM,Cusi K,Sanyal AJ. The diagnosis and management of -non alcoholic fatty liver disease:practice guidelines -by the American Gastroenterological - Association, American -Association for thestudy of - Liver disease, American -Association for Gastroenterology. Hepatology 2012;302:G225-G235.

[134] Nelson CH,Etchevers K,Yi S,Breckenridge D,Hepner M,Patel U etal.Pharmacokinetic ,safety and tolerability of Selonsertib,an apoptosis signal regulating kinase 1(ASK1) Inhibitor), following first -in human single and multiple ascending doses in healthy subjects.Clin Pharmacokinet 2020;59:1109-17.

[135] Budas G,Karnic S,Johnson T,Shafideh T,Watkins S , Breckenridge D, etal. Reduction of Liver steatosis and fibrosis -with an ASK1 Inhibitor in murine model of NASH is accompanied by improvements in cholesterol, the bile acid and lipid metabolism.J Hepatol -2016;64:S170.

[136] Loomba R, Lawitz EJ,Mantry PS, Jayakumar A, Caldwell SH,Arnold H etal.The - ASK1 Inhibitor Selonsertib in - patients with Non Alcoholic steatohepapititis:a randomized phase 2 - trial. Hepatology 2018;67:549-59.

[137] Dickson I.No antifibrotic effects of Selonsertib in NASH. Nat Rev Gastroenterol Hepatol 2020; 17:260.

[138] Puente A,Fortea JL,Cabezas J,Arias Loste MT,Iruzubieta P,Llerena S, etal.LOXL2;A new target in antifibrogenic therapy. Int J MolSci 2019;20:1634.

[139] Rodriguez HM,Vaysberg M,Mikels A,McCauley S,Velayo AC,Garcia C, etal.Modulation of lysyl oxidase –like 2 enzymatic activity by an allosteric antibody Inhibitor.J Biol Chem 2010;285:20964-20974.

[140] Lipson KE,Wong C,Teng Y,Spong S.CTGF is a central mediator of tissue remodeling and its inhibition can reverse the fibrosis.Fibrogenesis T issue Repair 2012;5:S 24.

[141] Harrison SA, Abdelmalek MF, Caldwell SH,Shiffman ML, Diehl AM,Ghalib R etal.Simutuzumab -is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by ) -non alcoholic steatohepapititis. Gastroenterology 2018;155:1140-53.

[142] Marra F, Tacke F.Roles of chemokines - in liver disease. Gastroenterology 2014;147:577-94.

[143] Kim BM,Abdelfattah AM,Vasan R,Fuchs BC,Choi MY. Hepatic Stellate cells -secrete Cc15 to induce hepatic steatosis.Sci Rep 2018;8:7499.

[144] Friedman SL, Sanyal AJ, Goodman SM, Lefebvre E,Gottwald M,Fischer L, Ratziu V.Efficacy and safety -study of cenicriviroc for treatment of -non alcoholic steatohepatitis in adult subjects with Liver fibrosis:CENTAUR Phase 2b study design.Contemp Clin Trials2016; 47:356-65.

[145] Friedman SL, Ratziu V,Harrison SA, Abdelmalek MF, Aithal GP,Caballeria J, etal .A randomized,placebo- controlledtrial of cenicriviroc for the treatment of -non alcoholic steatohepatitis with fibrosis. Hepatology 2018; 67:1754-67.

[146] Anstee QM,Neuschwander –Tetri BA,Wong VW, Abdelmalek MF, Younossi ZM,Yuan J, etal. - Cenicriviroc for the treatment of -liver fibrosis in adults with - of -non alcoholic steatohepatitis:AURORA phase 3 -study design. Contemp Clin Trials2020; 89:105922.

[147] Boutari C,Perakakis N,Mantzoros CS. Association of Adipokines with development of , non alcoholic fatty liver disease.Endocrinol Metab 2018;33:33-43.

[148] Polyzos SA,Kountouras J, Mantzoros CS.Leptin in non alcoholic steatohepatitis:a narrative review. Metabolism -2015;64:60-78.

[149] Jamali R,Arj A,Razavizade M,Aarabi MH.Prediction of non alcoholic fatty liver disease via a novel panel of serum Adipokines.Medicine - 2016;95:e2630.

[150] Polyzos SA,Kountouras J,Anastasilakis AD,Geldari EV, Mantzoros CS. Irisin in -patients -with -non alcoholic fatty liver disease . Metabolism -2014;63:207-17.

[151] Zhang SR,Fan ZM. Ghrelin- ghrelin-O-Acetyl transferase system -in the pathogenesis of non alcoholic fatty liver disease. World J Gastroenterol2015;21:3214-22.

[152] Arvaniti VA,Thomopoulos KC,Tsamandas A,Makri M,Psyrorogiannis A,Vafiadis G, etal .Serum adiponectin -levels in different types of non alcoholic fatty liver disease: correlation with - -steatosis,necro inflammation and -fibrosis.Acta Gastroenterol Belg -2008;71:355-60.

[153] Garinis GA,Fruci B,Mazaa A,DeSienna M,Abenavoli A,Gulletta E, etal.Metformin -versus dietary -treatment of -non alcoholic steatohepatitis.Int J Obes -2010;34:1255-64.

[154] Ryan MJ,Dudash HJ,Docherty M,Geronilla KB,-Baker BA,Haff GG, etal. Vitamin E and Csupplementation -reduces Oxidative stress improves antioxidant tenzymes -and positive muscle work -in chronically loaded muscles -of aged rats .Exp Gerontol -2010;45:882-95.

[155] Balmer ML,Siegrist K,Zimmermann A,Dufour JF.Effect of ursodeoxycholic acid in combination with Vitamin E on Adipokines and apoptosis in patients with non alcoholic steatohepatitis. Liver Int -2009; 29:1184-88.

[156] Otabe S,Yuan X,Fukutani T,Wada N,Hashinaga T,Nakayama H, etal.Over expression of human -adiponectin -in transgenic mice - results in suppre ssion of fat accumulation and prevention of premature death -by high calorie diet. Am J Physiol Endocrinol Metab -2007;293:E210-E218.

[157] Sharma D,Wang J,Fu PP, Sharma S,Nagalingam A,Mells A, etal. Adiponectin antagonizes the oncogenic actions of leptin in Hepatocellular carcinogenesis.Hepatology 2010; 52:1713-22.

[158] Kelesidis T, Kelesidis I,Chou Z, Mantzoros CS.Narrative review:The role of leptin in human -physiology:emerging Clinical applications .Ann Intern Med 2010;152:93-100.

[159] Unger RH.Lipotoxic diseases, Annu -Rev Med 2002;53:319-36.

[160] Ikejima K,Honda H,Yoshikawa M,Hirose M,Kitamura T,Takei Y, etal.Leptinaugments inflammatoryand profibrogenic -responses in the murine liver induced by hepatoxic chemicals. Hepatology 2001; 34:288-97.

[161] Polyzos SA,Aronis KN,Kountouras J,Raptis DD,Vasiloglu MF, Mantzoros CS. Circulating leptin in non alcoholic fatty liver disease:a systematic review and -meta-analysis. Diabetologia - -2016;59:30-43.

[162] Muse ED,Obici S,Bhanot S,Monia BP,McKay RA,Rajala MW, etal.Role of resistin -in diet induced hepatic insulin resistance.J Clin Invest -2004; 114:232-39.

[163] Bertolani C,Sancho Bru P,Failli P,Batallier R,Aleffi S,DeFranco R, etal. Resistin as an intra hepatic cytokine : Over expression during chronic injury and induction of proinflammatory action in -hepatic stellate -cells.Am J Pathol -2006; 169:2042-53.

[164] Jamali R, Razavizade M, Arj A,Aarabi MH. Serum adipokines might predict liver histology findings -in - non alcoholic fatty liver disease. World J Gastroenterol2016;22:5096-103.

[165] Rasouli N,Yao-BorengaaserA,Miles LM,Elbein SC,Kern PA.Increased plasma Adiponectin in response to Pioglitazone does not result from Increased gene expression . Am J Physiol Endocrinol Metab -2006;290:E42-E46.

[166] Delporte C. Structure -and physiological actions of -ghrelin.Scientifica 2013; 2013:518909.

[167] Purnell JQ,Weigle DS,Breen P,Cummings DE. Ghrelin levels correlate with insulinlevels, insulin resistance,and high density lipoprotein cholesterol,but not with gender ,menopausal status -or cortisol -levels in humans. J Clin Endocrinol Metab -2003;88:5674-79.

[168] LiY,Hai J, Li L,Chen X,Peng H,Cao M, etal. Administration -of Ghrelin improves inflammation, Oxidative stress,and apoptosis during -and after non alcoholic fatty liver disease development.Endocrine 2013;43:376-86.

[169] Mao Y,Cheng J,YuF,LiH,GuoC,Fan X. Ghrelin attenuated lipotoxicity via autophagy induction .Cell Physiol Biochem -2015;37:563-76.

[170] Schnyder S,Handschin C. Skeletal muscle as an endocrine organ:PGC-1α,myokines and exercise.Bone -2015;80:115-25.

[171] Kulvinder Kochar Kaur,Allahbadia GN,Singh M. Therapeutic Applications of the Recent Understanding of Brown or “Beige” Adipocyte Physiology. Adv Tech Biol Med -2015; 3: 128. DOI: 10.4172/2379-1764.1000128.

[172] Zhang Y,Li R,Meng Y,LiS,Donelan W,Zhao Y,etal. Irisin stimulates browning of white adipocytes through -mitogen activated protein kinase p38MAP Kinase and ERKMAP Kinase Signaling. Diabetes -2014;63:514-25.

[173] Polyzos SA,Mathew H, Mantzoros CS. Irisin:A true, circulating hormone. Metabolism 2015;64:1611-18.

[174] Perez –Soleto D,Roca –RivadaA,BaamondeI,Baltar J,Castro AI,Dominguez E, etal.Lack of adipocytes-Fndc5/ Irisin expression -and secretion reduces thermogenesis and enhancesadipogenesis.Sci Rep -2017;7:16289.

[175] Muir AJ,Levy C,Janssen HLA,Montano-Loza AJ,-Shiffman ML, Caldwell S, etal. Simutuzumab for primary - sclerosing -cholangitis: phase 2 study results with insights -on the natural history of -disease. Hepatology 2019; 69:684-98.

[176] Chen P,Chung FM,Chang DM,Tsai JC,Huang HF,Shin SJ, etal.Elevated plasma levels of visfatin/preB cell colony-enhancing factor in treated patients with type2 - Diabetes. -J Clin Endocrinol Metab -2006;91:295-9.

[177] Mousavi Z,Ganji A,Farrokh Tehrani D,Bahari A,Esmeil Zadeh A,Delghadi M. Correlation of visfatinlevels with non alcoholic fatty liver in Metabolic Syndrome.J Islam Republic Iran 2017;31:28.

[178] KadoglouNP, Tsanikidis H,Kapelozou A,Vrabas I,Vitta I,Krayannacos PE, etal.Effect of -ofrosiglitazone -and metformin treatment - on apelin, visfatin ghrelin levels in -patients with type2 - Diabetes .Metabolism 2010;59:373-79.

[179] Kim E,Voatour P. Hepatocellular carcinoma:Old friends and new tricks.Exp Mol Med2020; 52:1898-1907.

[180] CholankerilG,Patel R,,Khurana S,Satapathy SK. Hepatocellular carcinoma in non alcoholic steatohepatitis:current -knowledge and implications for management. World JHepatol 2017; 9:-533-43.

[181] Jing YY,Han Z,Sun K,Zhang SS,Hou J,Liu Y, etal. Toll like receptor 4 signaling promotes epithelial –mesenchymal transition in human - Hepatocellular carcinoma induced by lipopolysaccharides.BMC Med 2012;10:98.

[182] Li H, Li Y, LiuD, LiuJ.LPS promotes epithelial –mesenchymal transition and activation of -TLR4/JNK signaling.Tumor -Biol -2014;35:10429-35.

[183] Gupta H,Youn GS,Shin MJ,Suk KT. Gut microbiota in Hepatocarcinogenesis. Microorganisms -2019;7:121.

[184] Saxena NK,FuPP,Nagalingam A, Wang J,Handy J,Cohen C, etal. Adiponectin modulates -c –jun N terminal kinase -and mammalian target of rapamycin -and inhibits Hepatocellular carcinoma. Gastroenterology -2010;139:1762-73.

[185] Al-Gayyar AM,Abbas A,Hamdan AM.Chemopreventive -and hepatoprotective -role of Adiponectin(SULF2 Inhibitor) in Hepatocellular carcinoma.Biol Chem 2016;397:257-67.

[186] Kamada Y,Matsumoto H,Tamura S,Fukushima J,Kiso S,Fukui K, etal.Hypo Adiponectinemia accelerates hepatic tumorformation - -in non alcoholic steatohepatitis mouse model.J -HepatoL -2007;47:556-64.

[187] Shen J,Yeh CC,Wang Q,Gurvich I,Siegel AB, etal. Plasma Adiponectin and Hepatocellular carcinoma survival -among patients without liver transplantation.Anticancer Res 2016;36:5307-14.

[188] Wei R,Hu Y,Dong F,Xu X,Hu A,Gao G. Hepatoma -cell-derived leptin down regulates -the immunosuppressive function of regulatory T cells -to enhance the anti tumor activity of CD 8+T cells -.Immunol Cell Biol -2016;94:388-99.

[189] Stefanou N,Papanilkolaou V,Furukawa Y,Nakamura Y,Tsezou A. Leptin as acritical regulator of Hepatocellular carcinoma development through modulation of human telomerase -reverse transcriptase.BMC Cancer -2010;10:442.

[190] Levielle M,Estall JL. Mitochondrial dysfunctionin the transition - from -NASHto HCC. Metabolites -2019;9:233.

[191] Nakagawa H,Umemura A,Taniguchi K,Font –Burgada J,Dhar D,Ogata H, etal.ER Stress -cooperates with hypernutrition to trigger TNF dependent -spontaneous HCC development. Cancer Cell - 2014;26:331-43.

[192] Von Loeffelholz H,Horn P,Birkenfeld AL,Claus RA,Metzing BU,Docke S, etal.Predictor of liver fat -in preoperative patients with non alcoholic fatty liver disease. J Invest Surg -2016;29:266-74.

[193] Peter A,Kovarova M,Staiger H,Mechann J,Schick F,Konigsrainer A, etal.The Hepatokines Fetuin A and -Fetuin B -are upregulated in the state of hepatic steatosis and may differently impact -on glucosehomeostasis in humans. Am J Physiol Endocrinol Metab -2018;314:E266-E273.

[194] Cui Z,Xuan R,Yang Y.Serum Fetuin A level is associated -with non alcoholic fatty liver disease in Chinese population.Oncotarget -2017; 8:-107149-107156.

[195] Mukhuty A,Fouzder C,Mukherjee S,Malick C,Mukhopadhyay S,Ray S, etal. Fetuin A secretion from Pancreatic βcells - -adversely affects -its function and elicits inflammation. Biochem -Biophys Res Commun -2017;491:1118-24.

[196] -Dasgupta S,Bhattacharya S,Biswas A,Majumdar SS, Mukhopadhyay S,Ray S, etal. -Nuclear factor kappa Bmediates -lipid-induced Fetuin A expression in hepatocytes -that improve adipocyte -function effecting insulin resistance.Biochem J - 2010;429:451-62.

[197] Mori K,Emoto M, Araki T,Yokoyama H,LeeH,Taramura M, etal. -Effects of Pioglitazone on Serum Fetuin A levels -in -patients with type2 - Diabetes. Metabolism 2008;57:1248-52.

[198] Ochi A, Mori K,Emoto M, Nakatani N, Morioka T,Motoyama K, -etal.Direct inhibitory -Effects of Pioglitazone on -hepatic -Fetuin A expression.PLoS One -2014;9:e88704.

[199] Li L,Gu X,Fang M,JiJ,YiC,Gao C.The diagnostic value of Serum fucosylated Fetuin A in hepatitis Bvirus related liver diseases. Clin - Chem LabMed -2016;54:693-701.

[200] Pan X,Kaminga AC,Chen J,Luo M, LuoJ. Fetuin A and -Fetuin B - in non alcoholic fatty liver disease:a meta-analysis and -meta regression. Int JEnviron Res -Public Health2020;17:2735.

[201] Meex RC,Hoy AJ,Morris A,Brown RD,LoJC,Burke M, etal. -Fetuin B -is a -secreted hepatocyte factor -linking steatosis to impaired glucose metabolism. Cell Metab 2015;22:1078-89.

[202] Zhou W, Yang -J,Zhu J, Wang -Y,Wu Y,Xu L, etal. -Fetuin B - aggravates -liver X receptor mediated -hepatic steatosis -through AMPK in Hep G2 cells in mice .Am J Transl Res -2019;11:1498-1509.

[203] Ebert T,Linder N,Schaudinn - A,Busse H,Berger J,Lichtinghagen R, etal. -Association of -Fetuin B - with markers of liver fibrosis in non alcoholic fatty liver disease .Endocrine 2017;58:246-52.

[204] Zhong G,Kirkwood J,Won KJ,Tjota N,Jeong H,Isoherranen N. Characterization of Vitamin A metabolome -in human livers with and -without non alcoholic fatty liver disease.J Pharmacol -Exp Ther 2019;370: 92-103.

[205] Perduca M,Nicolis S.Mannuci B,Galliano M,Monaco HL.Human plasma Retinol Binding protein -4(RBP4) is also a fatty acid Binding protein. Biochim -Biophys Acta Mol Cell Biol Lipids 2018;1863:458 -66.

[206] Wang X,Chen X, Zhang H,Pang J,Lin J, Xu X, etal. Circulating -Retinol Binding protein 4is associated -with development -and regression of non alcoholic fatty liver disease. Diabetes Metab 2020;46: 119-28.

[207] Graham TE, Yang Q,Bluher M,Hammarstedt A,Ciaraldi TP,Henry RR, etal. Retinol Binding protein 4 and insulin resistance in lean ,obese and diabetic -subjects. NEngl J -Med 2006;354:2552-63.

[208] Petta S,Tripodo C,Grimaudo S,Cabibi D,Camma C,DiCristina A, etal.High liver RBP4 protein content -is -associated -with histological features in patients with genotype1 chronic hepatitis C and with non alcoholic steatohepatitis. Dig -Liver Dis-2011;43:404-10.

[209] Bahr MJ,Boeker KH,Manns MP,Tietge UJ.Decreased hepatic - RBP4 -secretion -is correlated with - -reduced levels -hepatic - glucose -production but is not -associated -with insulin resistance in patients with cirrhosis.Clin -Endocrinol -2009;70:60-5.

[210] Hara H,Uchida S,Yoshi mura H.Aoki M,Toyoda Y,Sakai K, etal.Isolation and -Characterization ofa novel liver specific gene, Hepassocin,upregulated -during liver regeneration. Biochim -Biophys Acta -2000;1492:31-44.

[211] Abdelmeomen G,Khodeir S,Zaki AN,Kasaab M,Abou Saif S,Abd Elasam S.Over expressionof -Hepassocin in diabetic -patients with non alcoholic fatty liver disease may facilitate increased -hepatic lipid accumulation. Endocrin Metab Immune Disord Drug Targets - 2019;19: 185-8.

[212] Wu HT,Lu FH,OuHY,Su YC,Hung HC, Wu JS, etal.The role of Hepassocin in the development of non alcoholic fatty liver disease. -J Hepatol 2013;59: 1065-72.

[213] Cheng KP, OuHY, Hung HC,LiCH,Fan KC, Wu JS, etal. Unsaturated fatty acids increase the expression of Hepassocin through a Signal -Transducers and Activators of Transcription3 dependent pathway in HepG2 cells.Lipids - 2018;53:863-69.

[214] Jung TW, Chung YH,Kim HC, Abd -El-Aty AM, Jeong JH.Hyper lipidemia-induced -Hepassocin in the liver contributes -to insulin resistance in skeletal muscle. - MolCell Endocrinol2018; 470:26-33.

[215] YuHT, Yu M,Li CY,Zhan YQ,Xu WX, Li -YH , etal. Specific - expression of -and regulation -of Hepassocin - in the liver and down regulation -of the correlation of -HNF1 alpha with decreased levels of Hepassocin in human Hepatocellular carcinoma. J Biol Chem 2009;284:133335-1313347.

[216] Li CY,Cao CZ, Xu WX, Cao MM, Yang F,Dong L, etal. Recombinant human -Hepassocin -stimulates -proliferation of hepatocytes -in vivo and improves survival -in -Hepatocellular carcinoma.Gut - 2010;59:817-26.

[217] Yan J, Yu Y, Wang N, Chang Y,Ying H, Liu W, etal.LFIRE1/HFREP-1,a liver Specific - gene is frequently -down regulated and has growth suppressor activity in Hepatocellular carcinoma. Oncogene -2004;230:1939-49.

[218] Pan J,Parlee SD,Brunel FM, Li P,LuW,Perez-Tilve D, etal.Optimization of peptide inhibitors of β-Klotho as antagonists of Fibroblast -growth -factor 19 and -21.ACS Pharmacol Transl Sci -2020;3:976-86.

[219] Wu AL,Coulter S,Liddle C,Wong A,Eastham-Anderson J,French DM, etal.FGF19 regulates cell proliferation, glucose and bile acid metabolism via FGFR4 -dependent and independent pathways. PLoS One -2011;6:e17868.

[220] Jiao N,Baker SS,Chapa-Rodriques A, Liu W,Nugent CA,Tsompana M, etal.Suppressed hepatic bile acid signaling despite elevated production of primary -and secondary bile acids in NAFLD.Gut -2018;67:1881-91.

[221] Li Y,Zhang W,Doughtie A,Cui G, Li X,Pandit H, etal.Upregulation of Fibroblast -growth -factor 19 and its receptor associates -with -progression from -fatty liver to Hepatocellular carcinoma. Oncotarget -2016; 7:-52329-52339.

[222] Chen L, Liu H, Liu J,Zhu Y,Xu L,HeH, etal.Klotho endows hepatoma cells -with resistance to anoikis -via VEGFR 2/PAK1 activation in -Hepatocellular carcinoma. PLoS ONE -2013;8:e58413.

[223] Gong Q,HuZ, Zhang F,Cui A, Chen X,Jiang H, etal. Fibroblast -growth -factor 21 improves insulin sensitivity by inhibiting mammalian target of rapamycin complex1 in mice . Hepatology 2017; 64:425-38.

[224] Hong ES,Lim C,Choi HY,Lee YK.KuEJ,Moon JH, etal.Plasma of Fibroblast -growth -factor 21 levels increase with ectopic fat accumulation -and its receptor levels -are decreased in the visceral fat of in -patients with type2 - Diabetes .BMJ Open Diabetes Res Care 2019;7:e00076.

[225] Flisiak-IackiewiczM, Bobrus-Chociej A, Wasilewska M, Tarasow E,WojtowskaM, Lebenszejn DM.Can Hepatokines be regarded as novel noninvasive serum biomarkers -of intraHepatic liver -content in obese -children?Adv Med Sci -2019;64:30484.

[226] Rusli F,Deelen J,Andriyani E,Boekschoten MV,Lute C,Van den Akker EB, etal. Fibroblast -growth -factor 21 reflects liver fat accumulation - and dysregulation of signaling pathways in the liver -of C57BL/6J mice.Sci Rep - 2016; 6:30484.

[227] Yang M,Xu D, Liu Y,Guo X, Li W, Guo C, etal. Combined serum -biomarkers in noninvasive -diagnosis of non alcoholic steatohepapititis. PLoS ONE -2015;10:e131664.

[228] Yang C, Lu W,Lin T,You P,YeM,Huang Y, etal. Activation - of liver FGF21 -in Hepatocarcinogenesis and during Hepatic stress .BMC -Gastroenterol 2013; 13:67.

[229] Kong FJ,MaLL,LiG,Chen YX,Zhou JQ,Circulating betatrophin levels an d gestational Diabetes mellitus:a systematic review and -meta-analysis -. PLoS ONE -2017;12:e016994.

[230] Lee YH, Lee SG, Lee CJ,Kim SH,Song YM,Yoon MR, etal. Association between betatrophin/ANGPTL8 and non alcoholic fatty liver disease:animal and human studies. Sci Rep - 2016; 6:24013.

[231] Zhang R.The -ANGPTL3-4-8 model ,a molecular -mechanism for triglyceride trafficking .Open Biol -2016; 6:150272.

[232] Yin Y,Ding X,Peng L,Hou Y,Ling Y,GuM, etal.Increased serum ANGPTL8 concentrations in patients -with pre Diabetes and -type2 - Diabetes.J Diabetes Res 2017; 2017:8293207.

[233] Gusarova V,Alexa CA,Na E,Stevis BE,Xin Y,-Bonner-Weir S, etal. ANGPTL8/ betatrophin does notcontrol Pancreatic βcells - expansion.Cell -2014; 159:691-6.

[234] Zhang L,Shannon CE, TM,Abdul –Ghani MA,-Fourcaudot M,Norton L.Regulation of ANGPTL8 in liver -and adipose tissue by nutritional and hormonal signals and the effect on glucosehomeostasis in mice. Am J Physiol Endocrinol Metab -2020;318:E613-E624.

[235] Chen YQ,Pottanat TG,Siegel RW,Ehsani M,Qian YQ,Zhen EY, etal. Angiopoietin –Like Protein- 8 differentially regulates ANGPTL 3 and ANGPTL 4 during postprandial -partitioning of fatty acids.J Lipid Res - 2020;61:1203-20.

[236] Dijk W,Kersten S.Regulation of -Lipid metabolism by Angiopoietin –Like Protein’s . Curr Opin Lipiodol 2016;27: 249-56.

[237] Yoshida K,Shimizugawa T,Ono M,Furukawa H. Angiopoietin –Like Protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res - 2002;43:1770-72.

[238] Ng KT,Xu A,Cheng Q,Guo DY,Lim ZX,Sun CK, etal. Clinical relevanc e -and therapeutic potential -of -Angiopoietin –Like Protein 4 in Hepatocellular carcinoma.Mol Cancer 2014;13:96.



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