Non-Alcoholic Fatty Liver Disease (NAFLD) and its Recent Therapeutic Strategies

Nikunja Kishor Mishra; Amiyakanta Mishra; Rosy Priyadarshini

doi:10.52711/2321-5836.2023.00022

Research Journal of Pharmacology and Pharmacodynamics

ISSN

2321-5836 (Online)
0975-4407 (Print)

Submit Article

Non-Alcoholic Fatty Liver Disease (NAFLD) and its Recent Therapeutic Strategies

Author(s): Nikunja Kishor Mishra, Amiyakanta Mishra, Rosy Priyadarshini

Email(s): montu.mph@gmail.com

DOI: 10.52711/2321-5836.2023.00022

Address: Nikunja Kishor Mishra*, Amiyakanta Mishra, Rosy Priyadarshini
College of Pharmaceutical Sciences, Puri (Affiliated to Biju Patnaik University of Technology), Baliguali, Puri - Konark Marine Drive Road, Puri - 752004, Odisha, India.
*Corresponding Author

Published In: Volume - 15, Issue - 3, Year - 2023

View HTML

View PDF

ABSTRACT:
Non-alcoholic fatty liver disease (NAFLD) is a serious health issue globally. It includes a broad spectrum of alteration from simple steatosis to steatohepatitis and cirrhosis. Obesity and type-2 diabetes mellitus (T2DM) are the major factors that are associated with progression of NAFLD. The disease has been proven to have a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear; however some of many pathophysiological mechanisms that are involved in the development of NAFLD include fatty-acid accumulation in hepatic parenchyma, impaired mitochondrial metabolism, inflammation, oxidative stress, oxygen free radicals. Liver biopsy is the diagnostic gold-standard for NAFLD, but multiple non-invasive techniques like serological biomarkers and radiological techniques have established a new field for research. Since several inter-related pathways are involved in the pathological process, a single therapeutic agent is not helpful. Therefore, a combination therapy towards multiple targets could control the NAFLD. Various new targeted therapies includes apoptosis signal regulating kinase-1(ASK1) inhibitor, FXR (Farnesoid X receptor)-agonists, Caspase Inhibition, SCD-1(Stearoyl coenzyme A desaturase -1) enzyme inhibitors, SIRT1 (Sirtuin1) activator, CCR2 (chemokine receptor 2) and CCR5 (chemokine receptor 5) inhibitors, DPP-4 (Dipeptidyl peptidase-4) inhibitors and NOX (NADPH oxidase)-1/4 inhibitors that are currently under investigation. The treatment for patients with NAFLD is mainly based on loss of body weight and adjuvant management by using insulin sensitizer, anti-oxidants and reducing inflammation. The development of a healthy lifestyle and moderate exercise may be pillars for the treatment of NAFLD.

Keywords:

Cite this article:
Nikunja Kishor Mishra, Amiyakanta Mishra, Rosy Priyadarshini. Non-Alcoholic Fatty Liver Disease (NAFLD) and its Recent Therapeutic Strategies. Research Journal of Pharmacology and Pharmacodynamics. 2023; 15(3):119-6. doi: 10.52711/2321-5836.2023.00022

Cite(Electronic):
Nikunja Kishor Mishra, Amiyakanta Mishra, Rosy Priyadarshini. Non-Alcoholic Fatty Liver Disease (NAFLD) and its Recent Therapeutic Strategies. Research Journal of Pharmacology and Pharmacodynamics. 2023; 15(3):119-6. doi: 10.52711/2321-5836.2023.00022 Available on: https://rjppd.org/AbstractView.aspx?PID=2023-15-3-5

REFERENCE:
1.    Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64: 73-84. doi: 10.1002/hep.28431.
2.    Lomonaco R, Chen J, Cusi K. An endocrine perspective of nonalcoholic fatty liver disease (NAFLD). Ther Adv Endocrinol Metab. 2011; 2(5):211–25. doi: 10.1177/2042018811419157.
3.    Brunt EM, Kleiner DE, Wilson LA, Belt P, NeuschwanderTetri BA, Network NCR. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011; 53:810–20. doi: 10.1002/hep.24127.
4.    Hjelkrem M, Stauch C, Shaw J, Harrison SA. Validation of the non-alcoholic fatty liver disease activity score. Aliment Pharmacol Ther. 2011; 34:214–8. doi: 10.1111/j.1365-2036.
5.    Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007; 45(4):846–54. doi: 10.1002/hep.21496.
6.    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004; 40(6):1387–95. doi: 10.1002/hep.20466.
7.    Chalasani N, Younossi Z, LaVine JE, Charlton M, Cusi K, Rinella M, Harrison SA, Brunt EM, Sanyal AJ. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018; 67(1):328–357. doi: 10.1002/hep.29367.
8.    Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, George J and Bugianesi E. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018; 15(1):11-20. doi: 10.1038/nrgastro.2017.109.
9.    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016; 64(1):73–84. doi: 10.1002/hep.28431.
10.    Mahady SE, George J. Predicting the future burden of NAFLD and NASH. J Hepatol. 2018; 69(4):774–5. doi: 10.1016/j.jhep.2018.06.025.
11.    Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005; 128(7):1898–906.
12.    Mahady SE, George J. Predicting the future burden of NAFLD and NASH. J Hepatol. 2018; 69(4):774–5. doi: 10.1053/j.gastro.2005.03.084.
13.    Veena J, Muragundla A, Sidgiddi S, Subramaniam S. Non-alcoholic fatty liver disease: need for a balanced nutritional source. Br J Nutr. 2014; 112(11):1858–72. doi: 10.1017/S0007114514002591.
14.    Choudhari S, Jothipriya A. Non-Alcoholic Fatty Liver Disease. Research J Pharm. and Tech. 2016; 9(10):1782-1785. doi: 10.5958/0974-360X.2016.00360.7
15.    Al-Ogaidi SO, Abdulsattar SA, Hameed M J A. The Impact of Serum Leptin, Leptin Receptor and Insulin on Maternal Obesity. Research J Pharm. and Tech. 2019; 12(7): 3569-3574. doi: 10.5958/0974-360X.2019.00609.7.
16.    Solís Herruzo JA, García Ruiz I, Pérez Carreras M, Munoz Yague MT. Non-alcoholic fatty liver disease. From insulin resistance to mitochondrial dysfunction. Rev Esp Enferm Dig. 2006; 98:844-74. doi: 10.4321/s1130-01082006001100006.
17.    Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs. 2005; 65: 2445-61. doi: 10.2165/00003495-200565170-00003.
18.    Majano PL, García-Monzón C, López-Cabrera M, Lara-Pezzi E, Fernández-Ruiz E, Garcia-Iglesias C, et al. Inducible nitric oxide synthase expression in chronic viral hepatitis. Evidence for a virus-induced gene upregulation. J Clin Invest. 1998; 101:1343-52. doi: 10.1172/JCI774.
19.    García-Monzón C, Majano PL, Zubia I, Sanz P, Apolinario A, Moreno-Otero R. Intrahepatic accumulation of nitrotyrosine in chronic viral hepatitis is associated with histological severity of liver disease. J Hepatol. 2000; 32: 331-8. doi: 10.1016/s0168-8278(00)80080-x.
20.    Carter-Kent C, Zein NN, Feldstein AE. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: Implications for treatment. Am J Gastroenterol. 2008; 103:1036-42. doi: 10.1111/j.1572-0241.2007.01709.x.
21.    Sanz-Cameno P, Medina J, García-Buey L, García-Sánchez A, Borque MJ, Martin-Vilchez S, et al. Enhanced intrahepatic inducible nitric oxide synthase expression and nitrotyrosine accumulation in primary biliary cirrhosis and autoimmune hepatitis. J Hepatol. 2002; 37:723-9. doi: 10.1016/s0168-8278(02)00266-0.
22.    Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis. 2010; 28:155-61. doi: 10.1159/000282080.
23.    Medina J, Fernández-Salazar LI, García-Buey L, Moreno-Otero R. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diab Car. 2004; 27(8):2057-66. doi: 10.2337/diacare.27.8.2057
24.    Romero FP. Will non-invasive testing replace liver biopsy in the diagnosis and follow-up of non-alcoholic steatohepatitis (NASH)? Rev Esp Enferm Dig. 2009; 101(8):521-7. doi: 10.4321/s1130-01082009000800001.
25.    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41:1313-21. doi: 10.1002/hep.20701.
26.    Jamali R, Arj A, Razavizade M, Aarabi MH. Prediction of nonalcoholic fatty liver disease via a novel panel of serum adipokines. Medicine. 2016; 95(5):e2630. doi: 10.1097/MD.0000000000002630.
27.    Sorbi D, Boynton J, Lindor KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating non-alcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999; 94:1018-22. doi: 10.1111/j.1572-0241.1999.01006.x.
28.    Mohammed A K, Mokif T A, Hadwan M S. The effect of Morbid Obesity on the Liver Function Enzymes. Research J Pharm and Tech. 2019; 12(5): 2241-2244. doi: 10.5958/0974-360X.2019.00373.1.
29.    Azeez FS, Saadi AM. Evaluation of Liver Function in Type 2 Diabetic Patients during Clinical Trials in Kirkuk City. Research J Pharm and Tech. 2019; 12(4):1659-1663. doi: 10.5958/0974-360X.2019.00278.6.
30.    Maher MM, Ibrahim WA, Saleh SA et al. Cytokeratin 18 as a non invasive marker in diagnosis of NASH and its usefulness in correlation with disease severity in Egyptian patients. Egypt J med hum Genet. 2014, 16:41–46. doi.org/10.1016/j.ejmhg.2014.11.003.
31.    Bechmann LP, Kocabayoglu P, Sowa JP et al. Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis. Hepatology. 2013; 57:1394–1406. doi: 10.1002/hep.26225.
32.    Tilg H, Moschen AR, Roden M. NAFLD and diabetes mellitus. Nat Rev Gastroenterol Hepatol. 2017; 14(1):32–42. doi: 10.1038/nrgastro.2016.147.
33.    Yoneda M, Uchiyama T, Kato S et al. Plasma pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol. 2008; 53(8):1-9. doi:10.1186/1471-230X-8-53.
34.    Ruscica M, Ferri N, Macchi C et al. Liver fat accumulation is associated with circulating PCSK9. Ann Med. 2016; 48(5): 384–91. doi: 10.1080/07853890.2016.1188328.
35.    Takahashi Y, Sugimoto K, Inui H, Fukusato T. Current pharmacological therapies for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Worl J Gastroenterol. 2015; 21(13): 3777-85. doi: 10.3748/wjg.v21.i13.3777
36.    Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis. Gastroenterology. 2008; 134: 1682-1698. doi: 10.1053/j.gastro.2008.
37.    Yusta B, Baggio LL, Koehler J, Holland D, Cao X, Pinnell LJ, et al. GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte GLP-1R. Diabetes. 2015; 64:2537-49. doi: 10.2337/db14-1577.
38.    Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling AS, Harrison SA. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med. 2021, 384, 1113–24. doi: 10.1056/NEJMoa2028395.
39.    Kaser S, Ebenbichler CF, Tilg H. Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease. Int J Clin Pract. 2010; 64: 968-83. doi: 10.1111/j.1742-1241.2009.02327.x.
40.    Cobo Martin M, Fernandez Gil P, Crespo J. Treatment of fatty liver disease. Gastroenterol Hepatol. 2008; 31:229-38. doi: 10.1157/13117902.
41.    Ratziu V, de Ledinghen V, Oberti F, Mathurin P, Wartelle-Bladou C, Renou C, et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol. 2011; 54(5):1011-9. doi: 10.1016/j.jhep.2010.08.030.
42.    Zein CO, Lopez R, Fu X, Kirwan JP, Yerian LM, McCullough AJ, et al. Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: New evidence on the potential therapeutic mechanism. Hepatology. 2013; 56(4):1291-9. doi: 10.1002/hep.25778.
43.    Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, GarcíaBuey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther. 2006; 23(11): 1643-1647. doi: 10.1111/j.1365-2036.2006.
44.    Harrison SA, Fecht W, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis: a randomized, prospective trial. Hepatology. 2009; 49(1):80–6. doi: 10.1002/hep.22575.
45.    Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, Shanahan WR, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011; 96(10): 3067–77. doi: 10.1210/jc.2011-1256.
46.    Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. Pharmacological management of obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015; 100(2):342–62. doi: 10.1210/jc.2014-3415.
47.    Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med .2015; 373(1):11–22. doi: 10.1056/NEJMoa1411892.
48.    Anstee QM, Concas D, Kudo H, Levene A, Pollard J, Charlton P, Thomas HC, Thursz MR, Goldin RD. Impact of pan-caspase inhibition in animal models of established steatosis and nonalcoholic steatohepatitis. J Hepatol. 2010; 53(3): 542-50. doi: 10.1016/j.jhep.2010.03.016.
49.    Witek RP, Stone WC, Karaca FG, Syn WK, Pereira TA, Agboola KM, Omenetti A, jung Y, Teaberry V, Choi SS, Guy CD, Pollard J, Charlton P, Diehl AM. Pan-caspase inhibitor VX-166 reduces fibrosis in an animal model of nonalcoholic steatohepatitis. Hepatology. 2009; 50(5): 1421-1430. doi:10.1002/hep.23167.
50.    Karnik S, Charlton M, Popov Y, Goodman ZD, Nash M, Sulfab M, Barry V, Huntzicker eG, French D, LI K, Decaris M, emson C, Turner S, Breckenridge D, Tumas D. Pharmacological inhibition of apoptosis signal-regulating kinase 1 (ASK1) in a murine model of NASH with pre-existing disease blocks fibrosis, steatosis, and insulin resistance. Hepatology. 2014; 60: 570A.
51.    Karnik S, Charlton MR, Li L, Nash M, Sulfab M, Newstrom D, Huntzicker eG, French D, Goodman ZD, Shafizadeh T, Watkins S, Breckenridge D, Tumas D. efficacy of an ASK1 Inhibitor to Reduce Fibrosis and Steatosis in a Murine Model of NASH is Associated with Normalization of Lipids and Hepatic Gene expression and a Reduction in Serum Biomarkers of Inflammation and Fibrosis. Hepatology. 2015; 62: 877A.
52.    Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, FiorasoCartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, Brenner DA. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012; 56: 2316-2327. doi: 10.1002/hep.25938.
53.    Fuchs M. Non-alcoholic Fatty liver disease: the bile Acid-activated farnesoid x receptor as an emerging treatment target. J Lipids. 2012; 2012: 934396. doi: 10.1155/2012/934396.
54.    Safadi R, Konikoff FM, Mahamid M, Zelber-Sagi S, Halpern M, Gilat T, Oren R; FLORA Group. The fatty acid-bile acid conjugate Aramchol reduces liver fat content in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2014; 12: 2085-2091. doi: 10.1016/j.cgh.2014.04.038.
55.    Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, Liepelt A, Lefebvre E, Luedde T, Hellerbrand C, Weiskirchen R., Longerich T, Costa IG, Anstee QM, Trautwein C, Tacke F. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018; 67 (4): 1270–1283. doi: 10.1002/hep.29544.
56.    Yu D, Cai SY, Mennone A, Vig P, Boyer JL. Cenicriviroc a cytokine receptor antagonist potentiates all-trans retinoic acid in reducing liver injury in cholestatic rodents. Liver Int. 2018: 38 (6): 1128–1138. doi: 10.1111/liv.13698.
57.    Kruger AJ, Fuchs BC, Masia R, Holmes JA, Salloum S, Sojoodi M, Ferreira DS, Rutledge SM, Caravan P, Alatrakchi N, Vig P, Lefebvre E, Chung RT. Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis. Hepatol Commun. 2018; 2 (5): 529–545. doi: 10.1002/hep4.1160.
58.    Thompson M, Saag M, DeJesus E, Gathe J, Lalezari J, Landay AL, Cade J, Enejosa J, Lefebvre E, Feinberg J. A 48-week randomized phase 2b study evaluating cenicriviroc versus efavirenz in treatment-naive HIV-infected adults with C-C chemokine receptor type 5-tropic virus. AIDS. 2016; 30 (6): 869–878. doi: 10.1097/QAD.0000000000000988.
59.    Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015; 149 (2): 389–397. doi: 10.1053/j.gastro.2015.04.043.
60.    Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med 2013; 56: 133-171. doi: 10.1016/j.freeradbiomed..
61.    Colak Y, Ozturk O, Senates E, Tuncer I, Yorulmaz E, Adali G, Doganay L, Enc FY. SIRT1 as a potential therapeutic target for treatment of nonalcoholic fatty liver disease. Med Sci Monit. 2011; 17(5): HY5-9. doi: 10.12659/msm.881749.
62.    Li L, Hai J, Li Z, Zhang Y, Peng H, Li K, Weng X. Resveratrol modulates autophagy and NF-κB activity in a murine model for treating non-alcoholic fatty liver disease. Food Chem Toxicol. 2014; 63: 166-173. doi: 10.1016/j.fct.2013.08.036.
63.    Shanmugasundaram P, Uma Maheshwari T N, Praveen D, Harini A. A Comprehensive Review on natural ways to Lose Weight. Research J Pharm and Tech. 2017; 10(11): 4030-4032. doi: 10.5958/0974-360X.2017.00730.2.
64.    Shilpa S, Naseeba P P, Princy P, Manoj G, Adheena P, Yusra K V, Kallada A B. Relationship between Physical activity and Obesity among female residents in a selected community. Int J Nur Edu Research. 2021; 9(1):45-53. doi: 10.5958/2454 2660.2021.00011.9.
65.    Bhargava Vyasa. Obesity in India – The Omnipresent Influence. Research J Pharmacology and Pharmacodynamics. 2013; 5(4): 220-226.
66.    Chandrakala M. Lifestyle Modification to Combat Adolescent Obesity. Asian J Nur Edu and Research 1(3): July-Sept. 2011; 82-84.
67.    Cobo Martin M, Fernandez Gil P, Crespo J. Treatment of fatty liver disease. Gastroenterol Hepatol. 2008; 31:229-38. doi: 10.1157/13117902.
68.    Simopoulos AP. Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients. 2013; 5: 2901-2923. doi: 10.3390/nu5082901.
69.    Kaser S, Ebenbichler CF, Tilg H. Pharmacological and non-pharmacological treatment of non-alcoholic fatty liver disease. Int J Clin Pract. 2010; 64:968-83. doi: 10.1111/j.1742-1241.2009.02327.x.
70.    Apthadevi A M, Roshni P R. Nutritional Deficiencies after Bariatric Surgery. Res J Pharmacology and Pharmacodynamics. 2019; 11(3):120-123. doi: 10.5958/2321-5836.2019.00021.1.
71.    Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH, Rosen CB, Batts KP. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transpl. 2001; 7: 608-614. doi: 10.1053/jlts.2001.25453.