Mechanism of Liraglutide Regulating the Expression of PI3K/AKT/NF-KB Pathway-related Proteins on Nonalcoholic Fatty Liver Disease

Yao Sang

doi:10.62051/0j03m472

Authors

Yao Sang

DOI:

https://doi.org/10.62051/0j03m472

Keywords:

NAFLD; Liraglutide; glucose and lipid metabolism; inflammation; PI3K/AKT/NF-κB signaling.

Abstract

Background and Objective: GLP-1RAs can effectively prevent hepatic steatosis. It was to investigate the mechanism by which the GLP-1RA Liraglutide ameliorates non-alcoholic fatty liver disease (NAFLD) and its impact on PI3K/AKT/NF-κB pathway. Materials and Methods: eight-week-old, clean-grade male C57BL/6J mice were assigned to Normal group (NG, fed standard chow), NAFLD group (high-calorie, high-cholesterol), and Liraglutide group (LG, high-calorie, high-cholesterol for 12 weeks + Liraglutide treatment at 1 mg/kg). Serum samples were collected from the mice to assess changes in glucose and lipid metabolism and liver function (LF) indicators. Histopathological changes in liver tissues (LTs) were visualized. Real-time quantitative PCR measured expression levels (ELs) of inflammatory genes in LTs. Western blotting was conducted to detect EL of proteins related to PI3K/AKT/NF-κB pathway in LTs. Results: NAFLD group exhibited markedly elevated levels of blood glucose (BG), blood lipids, and LF indicators relative to NG. Histopathological examination revealed increased scores for steatosis, lobular inflammation, and hepatocellular ballooning. The ELs of inflammatory genes IL-1β, TNF-α, and NF-κB p65 in LTs, were greatly elevated (P<0.05). In contrast, relative to NAFLD group, LG showed notably reduced levels of BG, blood lipids, and LF indicators, along with decreased histopathological scores. Furthermore, the ELs of inflammatory genes and protein ELs of p-PI3K, p-AKT, and p-NF-κBp65 in LTs were drastically lowered (P<0.05). Conclusion: Liraglutide ameliorates glucose and lipid metabolism disorders and suppresses inflammatory responses in liver by inhibiting PI3K/AKT/NF-κB signaling, thereby improving NAFLD in mice.

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References

[1] Duell PB, Welty FK, Miller M, Chait A, Hammond G, Ahmad Z, Cohen DE, Horton JD, Pressman GS, Toth PP; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022 Jun;42(6):e168-e185. doi: 10.1161/ATV.0000000000000153. Epub 2022 Apr 14. PMID: 35418240.

[2] Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021 May 13;184(10):2537-2564. doi: 10.1016/j.cell.2021.04.015. PMID: 33989548.

[3] Liu C, Liu T, Zhang Q, Jia P, Song M, Zhang Q, Ruan G, Ge Y, Lin S, Wang Z, Xie H, Shi J, Han R, Chen Y, Zheng X, Shen L, Deng L, Wu S, Shi H. New-Onset Age of Nonalcoholic Fatty Liver Disease and Cancer Risk. JAMA Netw Open. 2023 Sep 5;6(9):e2335511. doi: 10.1001/jamanetworkopen.2023.35511. PMID: 37747732; PMCID: PMC10520743.

[4] Muzica CM, Sfarti C, Trifan A, Zenovia S, Cuciureanu T, Nastasa R, Huiban L, Cojocariu C, Singeap AM, Girleanu I, Chiriac S, Stanciu C. Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: A Bidirectional Relationship. Can J Gastroenterol Hepatol. 2020 Dec 28;2020:6638306. doi: 10.1155/2020/6638306. PMID: 33425804; PMCID: PMC7781697.

[5] Stenlid R, Cerenius SY, Manell H, Küçükemre Aydin B, Mörwald K, Gomahr J, Höghammar Mitkas M, Eriksson I, Ciba I, Geiersberger S, Thivel D, Weghuber D, Bergsten P, Forslund A. Screening for Inflammatory Markers Identifies IL-18Rα as a Potential Link between Exenatide and Its Anti-Inflammatory Effect: New Results from the Combat-JUDO Randomized Controlled Trial. Ann Nutr Metab. 2023;79(6):522-527. doi: 10.1159/000534725. Epub 2023 Oct 26. PMID: 37883939.

[6] Yan J, Yao B, Kuang H, Yang X, Huang Q, Hong T, Li Y, Dou J, Yang W, Qin G, Yuan H, Xiao X, Luo S, Shan Z, Deng H, Tan Y, Xu F, Xu W, Zeng L, Kang Z, Weng J. Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Hepatology. 2019 Jun;69(6):2414-2426. doi: 10.1002/hep.30320. Epub 2019 Feb 22. PMID: 30341767; PMCID: PMC6594101.

[7] Lin X, Li Y, Zhang X, Wei Y, Wen S, Lu Z, Huang Q, Wei J. Tormentic acid inhibits hepatic stellate cells activation via blocking PI3K/Akt/mTOR and NF-κB signalling pathways. Cell Biochem Funct. 2021 Jan;39(1):77-87. doi: 10.1002/cbf.3564. Epub 2020 Jun 21. Retraction in: Cell Biochem Funct. 2021 Oct;39(7):921. doi: 10.1002/cbf.3666. PMID: 32564421.

[8] Huang X, Yao Y, Hou X, Wei L, Rao Y, Su Y, Zheng G, Ruan XZ, Li D, Chen Y. Macrophage SCAP Contributes to Metaflammation and Lean NAFLD by Activating STING-NF-κB Signaling Pathway. Cell Mol Gastroenterol Hepatol. 2022;14(1):1-26. doi: 10.1016/j.jcmgh.2022.03.006. Epub 2022 Mar 31. PMID: 35367665; PMCID: PMC9117819.

[9] Paternostro R, Trauner M. Current treatment of non-alcoholic fatty liver disease. J Intern Med. 2022 Aug;292(2):190-204. doi: 10.1111/joim.13531. Epub 2022 Jul 7. PMID: 35796150; PMCID: PMC9546342.

[10] Heeren J, Scheja L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Mol Metab. 2021 Aug;50:101238. doi: 10.1016/j.molmet.2021.101238. Epub 2021 Apr 20. PMID: 33892169; PMCID: PMC8324684.

[11] Rong L, Zou J, Ran W, Qi X, Chen Y, Cui H, Guo J. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD). Front Endocrinol (Lausanne). 2023 Jan 16;13:1087260. doi: 10.3389/fendo.2022.1087260. PMID: 36726464; PMCID: PMC9884828.

[12] Tanase DM, Gosav EM, Costea CF, Ciocoiu M, Lacatusu CM, Maranduca MA, Ouatu A, Floria M. The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD). J Diabetes Res. 2020 Jul 31;2020:3920196. doi: 10.1155/2020/3920196. PMID: 32832560; PMCID: PMC7424491.

[13] Watanabe M, Risi R, Camajani E, Contini S, Persichetti A, Tuccinardi D, Ernesti I, Mariani S, Lubrano C, Genco A, Spera G, Gnessi L, Basciani S. Baseline HOMA IR and Circulating FGF21 Levels Predict NAFLD Improvement in Patients Undergoing a Low Carbohydrate Dietary Intervention for Weight Loss: A Prospective Observational Pilot Study. Nutrients. 2020 Jul 18;12(7):2141. doi: 10.3390/nu12072141. PMID: 32708435; PMCID: PMC7400878.

[14] Xue Y, Xu J, Li M, Gao Y. Potential screening indicators for early diagnosis of NAFLD/MAFLD and liver fibrosis: Triglyceride glucose index-related parameters. Front Endocrinol (Lausanne). 2022 Sep 2;13:951689. doi: 10.3389/fendo.2022.951689. PMID: 36120429; PMCID: PMC9478620.

[15] Kelly AS, Auerbach P, Barrientos-Perez M, Gies I, Hale PM, Marcus C, Mastrandrea LD, Prabhu N, Arslanian S; NN8022-4180 Trial Investigators. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N Engl J Med. 2020 May 28;382(22):2117-2128. doi: 10.1056/NEJMoa1916038. Epub 2020 Mar 31. PMID: 32233338.

[16] Tan Y, Zhen Q, Ding X, Shen T, Liu F, Wang Y, Zhang Q, Lin R, Chen L, Peng Y, Fan N. Association between use of liraglutide and liver fibrosis in patients with type 2 diabetes. Front Endocrinol (Lausanne). 2022 Aug 10;13:935180. doi: 10.3389/fendo.2022.935180. PMID: 36034438; PMCID: PMC9399467.

[17] Somm E, Montandon SA, Loizides-Mangold U, Gaïa N, Lazarevic V, De Vito C, Perroud E, Bochaton-Piallat ML, Dibner C, Schrenzel J, Jornayvaz FR. The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res. 2021 Jan;227:75-88. doi: 10.1016/j.trsl.2020.07.008. Epub 2020 Jul 22. PMID: 32711187.

[18] Cuatrecasas G, Calbo M, Rossell O, Dachs L, Aguilar-Soler G, Coves MJ, Patrascioiu I, Benito CE, March S, Balfegó M, Cuatrecasas G, Di Gregorio S, Marina I, Garcia-Lorda P, Munoz-Marron E, De Cabo F. Effect of Liraglutide in Different Abdominal Fat Layers Measured by Ultrasound: The Importance of Perirenal Fat Reduction. Obes Facts. 2024 Apr 20:1-8. doi: 10.1159/000538996. Epub ahead of print. PMID: 38643760.

[19] An JR, Liu JT, Gao XM, Wang QF, Sun GY, Su JN, Zhang C, Yu JX, Yang YF, Shi Y. Effects of liraglutide on astrocyte polarization and neuroinflammation in db/db mice: focus on iron overload and oxidative stress. Front Cell Neurosci. 2023 Jun 1;17:1136070. doi: 10.3389/fncel.2023.1136070. PMID: 37323581; PMCID: PMC10267480.

[20] Guo T, Yan W, Cui X, Liu N, Wei X, Sun Y, Fan K, Liu J, Zhu Y, Wang Z, Zhang Y, Chen L. Liraglutide attenuates type 2 diabetes mellitus-associated non-alcoholic fatty liver disease by activating AMPK/ACC signaling and inhibiting ferroptosis. Mol Med. 2023 Sep 28;29(1):132. doi: 10.1186/s10020-023-00721-7. PMID: 37770820; PMCID: PMC10540362.

[21] Chen Z, Lin Z, Yu J, Zhong H, Zhuo X, Jia C, Wan Y. Mitofusin-2 Restrains Hepatic Stellate Cells’ Proliferation via PI3K/Akt Signaling Pathway and Inhibits Liver Fibrosis in Rats. J Healthc Eng. 2022 Jan 17;2022:6731335. doi: 10.1155/2022/6731335. PMID: 35083025; PMCID: PMC8786480.

[22] Zheng Y, Li Y, Ran X, Wang D, Zheng X, Zhang M, Yu B, Sun Y, Wu J. Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway. Cell Mol Life Sci. 2022 May 22;79(6):311. doi: 10.1007/s00018-022-04331-0. PMID: 35598196; PMCID: PMC9124663.

[23] Phusuntornsakul P, Jitpukdeebodintra S, Pavasant P, Leethanakul C. Vibration activates the actin/NF-κB axis and upregulates IL-6 and IL-8 expression in human periodontal ligament cells. Cell Biol Int. 2020 Feb;44(2):661-670. doi: 10.1002/cbin.11267. Epub 2019 Dec 4. PMID: 31769560.

[24] Li J, Wang T, Liu P, Yang F, Wang X, Zheng W, Sun W. Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD. Food Funct. 2021 May 11;12(9):3898-3918. doi: 10.1039/d0fo02736g. PMID: 33977953.

[25] Sommerhalder C, Cummins CB, Wang X, Ramdas D, Lopez ON, Gu Y, Zhou J, Radhakrishnan RS. HJC0416 Attenuates Fibrogenesis in Activated Hepatic Stellate Cells via STAT3 and NF-κB Pathways. J Surg Res. 2021 May;261:334-342. doi: 10.1016/j.jss.2020.12.045. Epub 2021 Jan 21. PMID: 33486415; PMCID: PMC8634552.

[26] Lee SM, Koh DH, Jun DW, Roh YJ, Kang HT, Oh JH, Kim HS. Auranofin attenuates hepatic steatosis and fibrosis in nonalcoholic fatty liver disease via NRF2 and NF- κB signaling pathways. Clin Mol Hepatol. 2022 Oct;28(4):827-840. doi: 10.3350/cmh.2022.0068. Epub 2022 Jun 22. PMID: 35730208; PMCID: PMC9597229.

[27] Zhang L, Tian J, Diao S, Zhang G, Xiao M, Chang D. GLP-1 receptor agonist liraglutide protects cardiomyocytes from IL-1β-induced metabolic disturbance and mitochondrial dysfunction. Chem Biol Interact. 2020 Dec 1;332:109252. doi: 10.1016/j.cbi.2020.109252. Epub 2020 Sep 6. PMID: 32898504.

[28] Zou Z, Wang Z. Liraglutide attenuates intestinal ischemia/reperfusion injury via NF-κB and PI3K/Akt pathways in mice. Life Sci. 2022 Nov 15;309:121045. doi: 10.1016/j.lfs.2022.121045. Epub 2022 Oct 4. PMID: 36206837.