Liraglutide (Synonyms: HAEGTFTSDVSSYL-{N6-[N-(1-oxohexadecyl)-L-γ-Etamyl]-Glu}-GQAAKEFIAWLVRGRG)

Liraglutide is a highly potent, long-acting GLP-1 receptor agonist (EC50 = 61 pM)and shares 97% of its amino acid sequence identity with human GLP-1 ^[6,7].

The number of viable cells in hepatocytes treated with PA/LPS was significantly reduced, and liraglutide reversed the decline in cell viability in a concentration-dependent manner. Liraglutide at 100 nM significantly increased cell viability compared with higher concentrations^[1].In H9c2 cardiomyoblasts,Pretreatment with 100 nM liraglutide could efficiently inhibit TNF-α and hypoxia-induced inflammasome activation. liraglutide reversed the level of SIRT1,Liraglutide diminished the levels of ROS generation and NOX4 expression^[2]. Liraglutide relieved steatosis by improving hepatic fat synthesis, transportation, storage, and use via PI3K and AMPK pathways ^[3].The cytoplasmic lipid droplet accumulation was visibly decreased in foam cells by treatment with liraglutide. The TG and cholesterol content in the liraglutide-treated foam cells was significantly decreased. Expression level of AMPKα1 and phosphorylated AMPKα1 was significantly increased while the expression level of SREBP1 and phosphorylated SREBP1 was significantly decreased in foam cells following treatment with liraglutide^[5].

In mice,The combination of HFD, Acrp30 knockdown and ApoE deficiency had additive effects on the development of insulin resistance (IR) and NAFLD. Administration of liraglutide prevented the development of HFD and hypoadiponectinaemia-induced IR and NAFLD in this model. Liraglutide also attenuated the expression of proinflammatory cytokines or transcription factor, including TNF-α and NF-κB(65) , and the expression of two lipogenesis-related genes, Acetyl-CoA Carboxylase (ACC) and fatty acid synthase (FAS)^[4].

References:
[1]: Yu X, Hao M, et,al. Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol. 2019 Dec 1;864:172715. doi: 10.1016/j.ejphar.2019.172715. Epub 2019 Oct 5. PMID: 31593687.
[2]: Chen A, Chen Z, et,al. Liraglutide attenuates NLRP3 inflammasome-dependent pyroptosis via regulating SIRT1/NOX4/ROS pathway in H9c2 cells. Biochem Biophys Res Commun. 2018 May 5;499(2):267-272. doi: 10.1016/j.bbrc.2018.03.142. Epub 2018 Mar 23. PMID: 29571736.
[3]: Liu J, Wang G, et,al. GLP-1 receptor agonists: effects on the progression of non-alcoholic fatty liver disease. Diabetes Metab Res Rev. 2015 May;31(4):329-35. doi: 10.1002/dmrr.2580. Epub 2014 Sep 14. PMID: 25066109.
[4]: Zhang L, Yang M, et,al. GLP-1 analogue prevents NAFLD in ApoE KO mice with diet and Acrp30 knockdown by inhibiting c-JNK. Liver Int. 2013 May;33(5):794-804. doi: 10.1111/liv.12120. Epub 2013 Feb 24. PMID: 23432843.
[5]: Wang YG, Yang TL. Liraglutide reduces oxidized LDL-induced oxidative stress and fatty degeneration in Raw 264.7 cells involving the AMPK/SREBP1 pathway. J Geriatr Cardiol. 2015 Jul;12(4):410-6. doi: 10.11909/j.issn.1671-5411.2015.04.013. PMID: 26346224; PMCID: PMC4554794.
[6]: Bode B. Liraglutide: a review of the first once-daily GLP-1 receptor agonist. Am J Manag Care. 2011 Mar;17(2 Suppl):S59-70. PMID: 21517658.
[7]: Knudsen LB, Nielsen PF, et,al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000 May 4;43(9):1664-9. doi: 10.1021/jm9909645. PMID: 10794683.