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Hormones

Open Access 12-03-2024 | Liraglutide | Review Article

Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease

Authors: Chara Tsiampali, Ilias D. Vachliotis, Antonis Goulas, Stergios A. Polyzos

Published in: Hormones

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disease closely associated with the epidemics of obesity and type 2 diabetes mellitus (T2DM), but without licensed pharmacological treatment to date. As glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved anti-diabetic and anti-obesity medications, they were also considered a potential therapeutic option for NAFLD. Preclinical studies suggest that GLP-1RAs have a beneficial effect on major NAFLD histological outcomes, i.e., hepatic steatosis and inflammation, through multiple intrahepatic mechanisms, including increased fatty acid β-oxidation, activation of autophagy, suppression of inflammation, and oxidative stress. Data on hepatic fibrosis are limited or inconclusive, although some studies reported improvement in indices of fibrosis or prevention of fibrosis initiation or reduction of collagen deposition. Whether the positive impact of GLP-1RAs on hepatic histology is indirect, i.e., through their action on extrahepatic tissues, or whether their action is direct, i.e., through activating GLP-1R on the hepatocytes, is still a controversial issue. Alongside GLP-1RAs, newly emerging peptide polyagonists (i.e., synthetic molecules that combine the amino acid sequences of more than one peptide, thus having the ability to bind more than one receptor) are now being investigated in NAFLD with high expectations. This review summarizes the existing knowledge derived from animal studies on the effects of GLP-1RAs and GLP-1RA related peptide polyagonists on NAFLD in an attempt to illuminate areas of uncertainty and provide the groundwork for future animal and clinical research in the field.
Literature
1.
Henry L, Paik J, Younossi ZM (2022) Review article: the epidemiologic burden of non-alcoholic fatty liver disease across the world. Aliment Pharmacol Ther 56(6):942–956PubMedCrossRef
2.
Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, Arrese M, Bataller R, Beuers U, Boursier J, Bugianesi E, Byrne CD, Castro Narro GE, Chowdhury A, Cortez-Pinto H, Cryer DR, Cusi K, El-Kassas M, Klein S, Eskridge W, Fan J, Gawrieh S, Guy CD, Harrison SA, Kim SU, Koot BG, Korenjak M, Kowdley KV, Lacaille F, Loomba R, Mitchell-Thain R, Morgan TR, Powell EE, Roden M, Romero-Gómez M, Silva M, Singh SP, Sookoian SC, Spearman CW, Tiniakos D, Valenti L, Vos MB, Wong VW-S, Xanthakos S, Yilmaz Y, Younossi Z, Hobbs A, Villota-Rivas M, Newsome PN (2023) A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 79(6):1542–1556PubMedCrossRef
3.
Makri E, Goulas A, Polyzos SA (2021) Epidemiology, Pathogenesis, diagnosis and emerging treatment of nonalcoholic fatty liver disease. Arch Med Res 52(1):25–37PubMedCrossRef
4.
Vachliotis I, Goulas A, Papaioannidou P, Polyzos SA (2022) Nonalcoholic fatty liver disease: lifestyle and quality of life. Hormones (Athens) 21(1):41–49PubMedCrossRef
5.
Polyzos SA, Kang ES, Boutari C, Rhee E-J, Mantzoros CS (2020) Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metabolism 111S:154203PubMedCrossRef
6.
Tsiampali C, Papaioannidou P, Goulas A, Polyzos SA (2023) The role of glucagon-like peptide-1 receptor agonists in nonalcoholic fatty liver disease. Expert Rev Clin Pharmacol 16(11):1063–1072PubMedCrossRef
7.
Polyzos SA, Goulas A, Papaioannidou P (2023) Tirzepatide for diabetes and obesity: a new window to the treatment of non-alcoholic steatohepatitis. Curr Med Chem 30(22):2476–2479PubMedCrossRef
8.
Trevaskis JL, Griffin PS, Wittmer C, Neuschwander-Tetri BA, Brunt EM, Dolman CS, Erickson MR, Napora J, Parkes DG, Roth JD (2012) Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol 302(8):G762–G772PubMedCrossRef
9.
Fang X, Du Z, Duan C, Zhan S, Wang T, Zhu M, Shi J, Meng J, Zhang X, Yang M, Zuo Y (2021) Beinaglutide shows significantly beneficial effects in diabetes/obesity-induced nonalcoholic steatohepatitis in ob/ob mouse model. Life Sci 270:118966PubMedCrossRef
10.
Ao N, Yang J, Wang X, Du J (2016) Glucagon-like peptide-1 preserves non-alcoholic fatty liver disease through inhibition of the endoplasmic reticulum stress-associated pathway. Hepatol Res 46(4):343–353PubMedCrossRef
11.
He Q, Sha S, Sun L, Zhang J, Dong M (2016) GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem Biophys Res Commun 476(4):196–203PubMedCrossRef
12.
Tølbøl KS, Kristiansen MN, Hansen HH, Veidal SS, Rigbolt KT, Gillum MP, Jelsing J, Vrang N, Feigh M (2018) Metabolic and hepatic effects of liraglutide, obeticholic acid and elafibranor in diet-induced obese mouse models of biopsy-confirmed nonalcoholic steatohepatitis. World J Gastroenterol 24(2):179–194PubMedPubMedCentralCrossRef
13.
Zhu W, Feng P-P, He K, Li S-W, Gong J-P (2018) Liraglutide protects non-alcoholic fatty liver disease via inhibiting NLRP3 inflammasome activation in a mouse model induced by high-fat diet. Biochem Biophys Res Commun 505(2):523–529PubMedCrossRef
14.
Daniels SJ, Leeming DJ, Detlefsen S, Bruun MF, Hjuler ST, Henriksen K, Hein P, Karsdal MA, Brockbank S, Cruwys S (2019) Biochemical and histological characterisation of an experimental rodent model of non-alcoholic steatohepatitis - Effects of a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist and a glucagon-like peptide-1 analogue. Biomed Pharmacother 111:926–933PubMedCrossRef
15.
Duparc T, Briand F, Trenteseaux C, Merian J, Combes G, Najib S, Sulpice T, Martinez LO (2019) Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 317(4):G508–G517PubMedCrossRef
16.
Hao T, Chen H, Wu S, Tian H (2019) LRG ameliorates steatohepatitis by activating the AMPK/mTOR/SREBP1 signaling pathway in C57BL/6J mice fed a high-fat diet. Mol Med Rep 20(1):701–708PubMed
17.
Luo Y, Yang P, Li Z, Luo Y, Shen J, Li R, Zheng H, Liang Y, Xia N (2019) Liraglutide improves non-alcoholic fatty liver disease in diabetic mice by modulating inflammatory signaling pathways. Drug Des Devel Ther 13:4065–4074PubMedPubMedCentralCrossRef
18.
Ao N, Ma Z, Yang J, Jin S, Zhang K, Luo E, Du J (2020) Liraglutide ameliorates lipotoxicity-induced inflammation through the mTORC1 signalling pathway. Peptides 133:170375PubMedCrossRef
19.
Fang Y, Ji L, Zhu C, Xiao Y, Zhang J, Lu J, Yin J, Wei L (2020) Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway. Front Cell Dev Biol 8:602574PubMedPubMedCentralCrossRef
20.
Han X, Ding C, Zhang G, Pan R, Liu Y, Huang N, Hou N, Han F, Xu W, Sun X (2020) Liraglutide ameliorates obesity-related nonalcoholic fatty liver disease by regulating Sestrin2-mediated Nrf2/HO-1 pathway. Biochem Biophys Res Commun 525(4):895–901PubMedCrossRef
21.
Jin M, Niu X, Liu Y, Zhang D, Yuan D, Shen H (2020) Effect of glucagon-like peptide-1 receptor agonists on adipokine level of nonalcoholic fatty liver disease in rats fed high-fat diet. Open Med 15(1):689–696CrossRef
22.
Kojima M, Takahashi H, Kuwashiro T, Tanaka K, Mori H, Ozaki I, Kitajima Y, Matsuda Y, Ashida K, Eguchi Y, Anzai K (2020) Glucagon-like peptide-1 receptor agonist prevented the progression of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis. Int J Mol Sci 21(16):5722PubMedPubMedCentralCrossRef
23.
Liu Q, Cai B-Y, Zhu L-X, Xin X, Wang X, An Z-M, Li S, Hu Y-Y, Feng Q (2020) Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice. Life Sci 261:118457PubMedCrossRef
24.
Fang T, Huang S, Chen Y, Chen Z, Chen J, Hu W (2021) Glucagon like peptide-1 receptor agonists alter pancreatic and hepatic histology and regulation of endoplasmic reticulum stress in high-fat diet mouse model. Exp Clin Endocrinol Diabetes 129(9):625–633PubMedCrossRef
25.
Perakakis N, Stefanakis K, Feigh M, Veidal SS, Mantzoros CS (2021) Elafibranor and liraglutide improve differentially liver health and metabolism in a mouse model of non-alcoholic steatohepatitis. Liver Int 41(8):1853–1866PubMedCrossRef
26.
Somm E, Montandon SA, Loizides-Mangold U, Gaïa N, Lazarevic V, De Vito C, Perroud E, Bochaton-Piallat M-L, Dibner C, Schrenzel J, Jornayvaz FR (2021) The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res 227:75–88PubMedCrossRef
27.
Ji J, Feng M, Huang Y, Niu X (2022) Liraglutide inhibits receptor for advanced glycation end products (RAGE)/reduced form of nicotinamide-adenine dinucleotide phosphate (NAPDH) signaling to ameliorate non-alcoholic fatty liver disease (NAFLD) in vivo and vitro. Bioengineered 13(3):5091–5102PubMedPubMedCentralCrossRef
28.
Yu X, Bian X, Zhang H, Yang S, Cui D, Su Z (2023) Liraglutide ameliorates hepatic steatosis via retinoic acid receptor-related orphan receptor α-mediated autophagy pathway. IUBMB Life 75(10):856–867PubMedCrossRef
29.
Møllerhøj MB, Veidal SS, Thrane KT, Oró D, Overgaard A, Salinas CG, Madsen MR, Pfisterer L, Vyberg M, Simon E, Broermann A, Vrang N, Jelsing J, Feigh M, Hansen HH (2022) Hepatoprotective effects of semaglutide, lanifibranor and dietary intervention in the GAN diet-induced obese and biopsy-confirmed mouse model of NASH. Clin Transl Sci 15(5):1167–1186PubMedPubMedCentralCrossRef
30.
Pontes-da-Silva RM, de Souza MT, de Macedo Cardoso LE, Mandarim-de-Lacerda CA, Aguila MB (2022) Obese mice weight loss role on nonalcoholic fatty liver disease and endoplasmic reticulum stress treated by a GLP-1 receptor agonist. Int J Obes 46(1):21–29CrossRef
31.
Reis-Barbosa PH, Marcondes-de-Castro IA, de Marinho T, S, Aguila MB, Mandarim-de-Lacerda CA, (2022) The mTORC1/AMPK pathway plays a role in the beneficial effects of semaglutide (GLP-1 receptor agonist) on the liver of obese mice. Clin Res Hepatol Gastroenterol 46(6):101922PubMedCrossRef
32.
Niu S, Chen S, Chen X, Ren Q, Yue L, Pan X, Zhao H, Li Z, Chen X (2022) Semaglutide ameliorates metabolism and hepatic outcomes in an NAFLD mouse model. Front Endocrinol 13:1046130CrossRef
33.
Inia JA, Stokman G, Morrison MC, Worms N, Verschuren L, Caspers MPM, Menke AL, Petitjean L, Chen L, Petitjean M, Jukema JW, Princen HMG, van den Hoek AM (2023) Semaglutide Has Beneficial Effects on Non-Alcoholic Steatohepatitis in Ldlr-/-.Leiden Mice. Int J Mol Sci 24(10):8494PubMedPubMedCentralCrossRef
34.
35.
Park H-W, Lee JH (2014) Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies. Autophagy 10(12):2385–2386PubMedCrossRef
36.
Vachliotis ID, Polyzos SA (2023) The role of tumor necrosis factor-alpha in the pathogenesis and treatment of nonalcoholic fatty liver disease. Curr Obes Rep 12(3):191–206PubMedPubMedCentralCrossRef
37.
Polyzos SA, Kountouras J, Mantzoros CS (2016) Adipokines in nonalcoholic fatty liver disease. Metabolism 65(8):1062–1079PubMedCrossRef
38.
Moreira GV, Azevedo FF, Ribeiro LM, Santos A, Guadagnini D, Gama P, Liberti EA, Saad M, Carvalho C (2018) Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem 62:143–154PubMedCrossRef
39.
Zhang N, Tao J, Gao L, Bi Y, Li P, Wang H, Zhu D, Feng W (2020) Liraglutide attenuates nonalcoholic fatty liver disease by modulating gut microbiota in rats administered a high-fat diet. Biomed Res Int 2020:2947549PubMedPubMedCentral
40.
Jetten AM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7(1):e003PubMedPubMedCentralCrossRef
41.
Polyzos SA, Frühbeck G, Kiortsis DN (2023) Peptide polyagonists for the treatment of nonalcoholic fatty liver disease. Curr Pharm Des 29(41):3263–3265PubMedCrossRef
42.
43.
Valdecantos MP, Pardo V, Ruiz L, Castro-Sánchez L, Lanzón B, Fernández-Millán E, García-Monzón C, Arroba AI, González-Rodríguez Á, Escrivá F, Álvarez C, Rupérez FJ, Barbas C, Konkar A, Naylor J, Hornigold D, Santos AD, Bednarek M, Grimsby J, Rondinone CM, Valverde ÁM (2017) A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology 65(3):950–968PubMedCrossRef
44.
Patel V, Joharapurkar A, Kshirsagar S, Sutariya B, Patel M, Patel H, Pandey D, Patel D, Ranvir R, Kadam S, Bahekar R, Jain M (2018) Coagonist of GLP-1 and glucagon receptor ameliorates development of non-alcoholic fatty liver disease. Cardiovasc Hematol Agents Med Chem 16(1):35–43PubMedCrossRef
45.
Boland ML, Laker RC, Mather K, Nawrocki A, Oldham S, Boland BB, Lewis H, Conway J, Naylor J, Guionaud S, Feigh M, Veidal SS, Lantier L, McGuinness OP, Grimsby J, Rondinone CM, Jermutus L, Larsen MR, Trevaskis JL, Rhodes CJ (2020) Resolution of NASH and hepatic fibrosis by the GLP-1R/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat Metab 2(5):413–431PubMedPubMedCentralCrossRef
46.
Nestor JJ, Parkes D, Feigh M, Suschak JJ, Harris MS (2022) Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis. Sci Rep 12(1):6666ADSPubMedPubMedCentralCrossRef
47.
Liu C, Li C, Cai X, Zou Y, Mo J, Chen B, Cai Y, Han T, Huang W, Qian H, Zhang W (2021) Discovery of a novel GLP-1/GIP dual receptor agonist CY-5 as long-acting hypoglycemic, anti-obesity agent. Bioorg Chem 106:104492PubMedCrossRef
48.
Pan Q, Lin S, Li Y, Liu L, Li X, Gao X, Yan J, Gu B, Chen X, Li W, Tang X, Chen C, Guo L (2021) A novel GLP-1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis. EBioMedicine 63:103202PubMedPubMedCentralCrossRef
49.
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, Hazlehurst JM, Guo K, LEAN trial team, Abouda G, Aldersley MA, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG, Newsome PN, (2016) Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387(10019):679–690PubMedCrossRef
50.
Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, Sanyal AJ, Sejling A-S, Harrison SA (2021) A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 384(12):1113–1124PubMedCrossRef
51.
Polyzos SA, Kountouras J, Zavos C, Deretzi G (2012) Nonalcoholic fatty liver disease: multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol 46(4):272–284PubMedCrossRef
52.
Raptis DD, Mantzoros CS, Polyzos SA (2023) Fibroblast growth factor-21 as a potential therapeutic target of nonalcoholic fatty liver disease. Ther Clin Risk Manag 19:77–96PubMedPubMedCentralCrossRef
53.
54.
Gupta NA, Mells J, Dunham RM, Grakoui A, Handy J, Saxena NK, Anania FA (2010) Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 51(5):1584–1592PubMedCrossRef
55.
Panjwani N, Mulvihill EE, Longuet C, Yusta B, Campbell JE, Brown TJ, Streutker C, Holland D, Cao X, Baggio LL, Drucker DJ (2013) GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology 154(1):127–139PubMedCrossRef
56.
Tomas E, Stanojevic V, Habener JF (2011) GLP-1-derived nonapeptide GLP-1(28–36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. Regul Pept 167(2–3):177–184PubMedCrossRef
57.
Eslam M, Newsome PN, Sarin SK, Anstee QM, Targher G, Romero-Gomez M, Zelber-Sagi S, Wai-Sun Wong V, Dufour J-F, Schattenberg JM, Kawaguchi T, Arrese M, Valenti L, Shiha G, Tiribelli C, Yki-Järvinen H, Fan J-G, Grønbæk H, Yilmaz Y, Cortez-Pinto H, Oliveira CP, Bedossa P, Adams LA, Zheng M-H, Fouad Y, Chan W-K, Mendez-Sanchez N, Ahn SH, Castera L, Bugianesi E, Ratziu V, George J (2020) A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol 73(1):202–209PubMedCrossRef
58.
Polyzos SA, Kang ES, Tsochatzis EA, Kechagias S, Ekstedt M, Xanthakos S, Lonardo A, Mantovani A, Tilg H, Côté I, Grefhorst A, Greene MW, Araujo-Vilar D, Alisi A, Casanueva F, Mantzoros CS (2020) Commentary: Nonalcoholic or metabolic dysfunction-associated fatty liver disease? The epidemic of the 21st century in search of the most appropriate name. Metabolism 113(154413):154413PubMedCrossRef
Metadata
Title
Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease
Authors
Chara Tsiampali
Ilias D. Vachliotis
Antonis Goulas
Stergios A. Polyzos
Publication date
12-03-2024
Publisher
Springer International Publishing
Published in
Hormones
Print ISSN: 1109-3099
Electronic ISSN: 2520-8721
DOI
https://doi.org/10.1007/s42000-024-00541-2
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
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