Background
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].
参考文献:
[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.
利拉鲁肽是一种高效、长效的 GLP-1 受体激动剂 (EC50 = 61 pM)，其氨基酸序列与人 GLP-1 有 97% 的同一性[6,7] .
用 PA/LPS 处理的肝细胞中的活细胞数量显着减少，利拉鲁肽以浓度依赖性方式逆转细胞活力的下降。与更高浓度相比，100 nM 利拉鲁肽可显着提高细胞活力[1]。在 H9c2 心肌细胞中，100 nM 利拉鲁肽预处理可有效抑制 TNF-α 和缺氧诱导的炎性体激活。 liraglutide 逆转 SIRT1 水平，Liraglutide 降低 ROS 生成和 NOX4 表达水平[2]。利拉鲁肽通过 PI3K 和 AMPK 通路改善肝脏脂肪的合成、运输、储存和使用，从而减轻脂肪变性[3]。利拉鲁肽处理后，泡沫细胞中的细胞质脂滴积累明显减少。利拉鲁肽处理的泡沫细胞中的甘油三酯和胆固醇含量显着降低。利拉鲁肽处理后泡沫细胞中AMPKα1和磷酸化AMPKα1的表达水平显着升高，而SREBP1和磷酸化SREBP1的表达水平显着降低[5]。
在小鼠中，HFD、Acrp30 敲低和 ApoE 缺陷的组合对胰岛素抵抗 (IR) 和 NAFLD 的发展具有累加效应。在该模型中，利拉鲁肽的给药阻止了 HFD 和低脂联素血症诱导的 IR 和 NAFLD 的发展。利拉鲁肽还减弱促炎细胞因子或转录因子的表达，包括 TNF-α 和 NF-κB(65)，以及两种脂肪生成相关基因乙酰辅酶 A 羧化酶 (ACC) 和脂肪酸合酶 (FAS) 的表达[4].
Protocol
| Kinase experiment [1]: |
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Preparation Method
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A cloned human GLP-1 receptor expressed in juvenile hamster kidney (BHK) cells was used, Study on functional assays of compounds( Liraglutide ) using SAR.
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Reaction Conditions
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10-14 -10-5 M liraglutide
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Applications
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Liraglutide is a highly potent, long-acting GLP-1 receptor agonistand and shares 97% of its amino acid sequence identity with human GLP-1 (EC50 = 61 pM).
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| Cell experiment [2]: |
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Cell experiment
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HepG2 cell line
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Preparation Method
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Cell viability assay ：HepG2 cells were seeded onto a 96-well plate, then treated with PA and LPS in the presence of liraglutide (0, 50, 100, 200, 500 nM) for 16 h. The number of viable cells was determined using Cell Counting Kit-8 (CCK-8)
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Reaction Conditions
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liraglutide (0, 50, 100, 200, 500 nM) for 16 h
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Applications
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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.
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| Animal experiment [3]: |
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Animal models
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Male ApoE KO mice on C57BL/6 background
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Preparation Method
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Liraglutide (1 mg/kg) or saline was given intraperitoneally twice daily for 8 weeks (from 9th to 16th week of HFD feeding)
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Dosage form
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Liraglutide (1 mg/kg) for 8 weeks
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Applications
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Liraglutide treatment improved insulin sensitivity and increased Acrp30 plasma levels and transcriptional activity, Liraglutide treatment reduces liver fat content, Liraglutide was sufficient to protect mice from the inflammatory consequences of HFD and Acrp30 knockdown.
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参考文献:
[1]. 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
[2]. 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.
[3]. 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.
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