The influence of phenformin on the extracellular matrix of the liver of rats under long-term administration of ethanol
A.O. Mykytenko, O.Y. Akimov, K.S. Neporada
Poltava State Medical University, Poltava, Ukraine
DOI: https://doi.org/10.15407/fz70.02.075
![](/images/cite.png)
Abstract
Experimental and clinical studies have revealed the influence of AMP-activated protein kinase (AMPK)
signaling on the development of non-alcoholic liver fibrosis. Currently, the results of experimental studies
demonstrate that inhibition of AMPK promotes fibrogenesis, while its activation prevents the development
of liver fibrosis. The purpose of this work is to establish the effect of activation of AMP-activated protein
kinase by the administration of phenformin on the content of glycosaminoglycans, oxyproline and sialic
acids in the liver of rats under the conditions of long-term administration of ethanol. The study was conducted on 24 male Wistar rats. The animals were randomly divided into 4 groups of 6 animals each, on
which we modeled ethanol-induced liver damage and administered phenformin hydrochloride at a dose of
10 mg/kg. The experiment lasted 63 days. In the liver of rats, the content of total glycosaminoglycans, the
concentration of heparin-heparan, keratan-dermatan and chondroitin fractions of glycosaminoglycans,
the content of free oxyproline and sialic acids were studied. Long-term alcoholization leads to a violation
of the extracellular matrix of the liver of rats, which is evidenced by a decrease in the concentration of
proteoglycans and a redistribution of their fractions in the direction of a decrease in anti-inflammatory
and regenerative fractions. Chronic intake of alcohol increases the processes of desialylation of glycoconjugates and the intensity of collagenolysis. Activation of AMP-activated protein kinase by administration
of phenformin under the conditions of simulating ethanol-induced liver damage leads to an increase in the
concentration of glycosaminoglycans due to the growth of heparin-heparan and chondroitin fractions and
reduces the intensity of desialylation of glycoconjugates and collagenolysis in the liver of rats.
Keywords:
liver; AMP-activated protein kinase; phenformin; extracellular matrix; ethanol; alcoholassociated liver disease; glycosaminoglycans; collagen; sialic acids; oxyproline.
References
- Yan Y, Zeng J, Xing L, Li C. Extra- and intra-cellular mechanisms of hepatic stellate cell activation. Biomedicines. 2021; 9(8): 1014.
CrossRef
PubMed PubMedCentral
- Subramaniyan V, Chakravarthi S, Jegasothy R, Seng WY, Fuloria NK, Fuloria S, Hazarika I, Das A. Alcoholassociated liver disease: A review on its pathophysiology, diagnosis and drug therapy. Toxicol Rep. 2021; 8: 376-85.
CrossRef
PubMed PubMedCentral
- Hynes RO, Naba A. Overview of the matrisome - an inventory of extracellular matrix constituents and functions. Cold Spring Harb Perspect Biol. 2012; 4(1): a004903.
CrossRef
PubMed PubMedCentral
- Novo E, Bocca C, Foglia B, Protopapa F, Maggiora M, Parola M, Cannito S. Liver fibrogenesis: un update on established and emerging basic concepts. Arch Biochem Biophys. 2020; 689: 108445.
CrossRef
PubMed
- Wang Y, Liu Y, Liu Y, Zhong J, Wang J, Sun L, Yu L, Wang Y, Li Q, Jin W, Yan Z. Remodeling liver microenvironment by L-arginine loaded hollow polydopamine nanoparticles for liver cirrhosis treatment. Biomaterials. 2023; 295: 122028.
CrossRef
PubMed
- Reszegi A, Tátrai P, Regős E, Kovalszky I, Baghy K. Syndecan-1 in liver pathophysiology. Am J Physiol Cell Physiol. 2022; 323(2): C289-94.
CrossRef
PubMed
- Arriazu E, Ruiz de Galarreta M, Cubero FJ, Varela-Rey M, Pérez de Obanos MP, Leung TM, et al. Extracellular matrix and liver disease. Antioxid Redox Signal. 2014; 21(7): 1078-97.
CrossRef
PubMed PubMedCentral
- Huang R, Guo F, Li Y, Liang Y, Li G, Fu P, Ma L. Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis. Phytomedicine. 2021; 92: 153739.
CrossRef
PubMed
- Tian J, Cai M, Jin S, Chen Q, Xu J, Guo Q, Yan Z, Han X, Lu H. JianPi-QingHua formula attenuates nonalcoholic fatty liver disease by regulating the AMPK/SIRT1/NF-κB pathway in high-fat-diet-fed C57BL/6 mice. Pharm Biol. 2023; 61(1): 647-56.
CrossRef
PubMed PubMedCentral
- Dong Z, Su L, Esmaili S, Iseli TJ, Ramezani-Moghadam M, Hu L, Xu A, George J, Wang J. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells. J Mol Med (Berl). 2015; 93(12): 1327-39.
CrossRef
PubMed
- Liang Z, Li T, Jiang S, Xu J, Di W, Yang Z, Hu W, Yang Y. AMPK: a novel target for treating hepatic fibrosis. Oncotarget. 2017; 8(37): 62780-92.
CrossRef
PubMed PubMedCentral
- Lu X, Xuan W, Li J, Yao H, Huang C, Li J. AMPK protects against alcohol-induced liver injury through UQCRC2 to up-regulate mitophagy. Autophagy. 2021; 17(11): 3622-43.
CrossRef
PubMed PubMedCentral
- Dilman VM, Berstein LM, Zabezhinski MA, Alexandrov VA, Bobrov JF, Pliss GB. Inhibition of DMBA-induced carcinogenesis by phenformin in the mammary gland of rats. Arch Geschwulstforsch. 1978; 48(1): 1-8.
- Mykytenko AO, Akimov OY, Shevchenko OM, Neporada KS. Role of sulfide anion in the development of chronic alcoholic hepatitis under the conditions of modulation of adenosine monophosphate kinase - a correlational study. Eur J Clin Exp Med. 2023; 21(3): 567-75.
CrossRef
- Akimov OY, Mykytenko AO, Mischenko AV, Kostenko VO. Influence of bacterial lipopolysaccharide on the degradation of the components of the extracellular matrix of rat biceps femoris muscle during high fructose dietinduced metabolic syndrome. Fiziol Zh. 2023; 69(3): 99-105.
CrossRef
- Mykytenko AО, Akimov OY, Yeroshenko GA, Neporada KS. Influence of doxorubicin on the extracellular matrix of the liver of rats under conditions of chronic alcoholic hepatitis. Regul Mech Biosyst. 2023; 14(2): 278-83.
CrossRef
- Sun X, Liu Z, Zhou L, Ma R, Zhang X, Wang T, Fu F, Wang Y. Escin avoids hemorrhagic transformation in ischemic stroke by protecting BBB through the AMPK/Cav-1/ MMP-9 pathway. Phytomedicine. 2023; 120: 155071.
CrossRef
PubMed
- Tsomidis I, Notas G, Xidakis C, Voumvouraki A, Samonakis DN, Koulentaki M, Kouroumalis E. Enzymes of fibrosis in chronic liver disease. Biomedicines. 2022; 10(12): 3179.
CrossRef
PubMed PubMedCentral
- Shrikanth CB, Jagannath S, Chilkunda ND. AMPK differentially alters sulphated glycosaminoglycans under normal and high glucose milieu in proximal tubular cells. J Biochem. 2021; 169(1): 75-86.
CrossRef
PubMed
- de Dios ST, Frontanilla KV, Nigro J, Ballinger ML, Ivey ME, Cawson EA, Little PJ. Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents. J Diabet Complicat. 2007; 21(2): 108-17.
CrossRef
PubMed
- Utami AR, Maksum IP, Deawati Y. Berberine and its study as an antidiabetic compound. Biology (Basel). 2023; 12(7): 973.
CrossRef
PubMed PubMedCentral
- Mykytenko AO, Akimov OY, Yeroshenko GA, Neporada KS. Extracellular matrix of rat liver under the conditions of combining systemic inflammatory response syndrome and chronic alcohol intoxication. World Med Biol. 2022; 1(79): 214-7.
CrossRef
- Dhounchak S, Popp SK, Brown DJ, Laybutt DR, Biden TJ, Bornstein SR, Parish CR, Simeonovic CJ. Heparan sulfate proteoglycans in beta cells provide a critical link between endoplasmic reticulum stress, oxidative stress and type 2 diabetes. PLoS One. 2021; 16(6): e0252607.
CrossRef
PubMed PubMedCentral
- Jin T, Zhang Y, Botchway BOA, Huang M, Lu Q, Liu X. Quercetin activates the Sestrin2/AMPK/SIRT1 axis to improve amyotrophic lateral sclerosis. Biomed Pharmacother. 2023; 161: 114515.
CrossRef
PubMed
- Zdanowicz K, Kowalczuk-Kryston M, Olanski W, Werpachowska I, Mielech W, Lebensztejn DM. Increase in serum MMP-9 and TIMP-1 concentrations during alcohol intoxication in adolescents-a preliminary study. Biomolecules. 2022; 12(5): 710.
CrossRef
PubMed PubMedCentral
- Yang C, Gong X, Ai Q, Ge P, Lin L, Zhang L. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside alleviated carbon tetrachloride-induced acute hepatitis in mice. Int Immunopharmacol. 2015; 25(2): 393-9.
CrossRef
PubMed
- Ding Y, Zhang Y, Wang Z, Zeng F, Zhen Q, Zhao H, Li J, Ma T, Huang C. Echinacoside from Cistanche tubulosa ameliorates alcohol-induced liver injury and oxidative stress by targeting Nrf2. FASEB J. 2023; 37(3): e22792.
CrossRef
PubMed
- Guo Z, Fan D, Liu FY, Ma SQ, An P, Yang D, Wang MY, Yang Z, Tang QZ. NEU1 Regulates mitochondrial energy metabolism and oxidative stress post-myocardial infarction in mice via the SIRT1/PGC-1 alpha axis. Front Cardiovascul Med. 2022; 9: 821317.
CrossRef
PubMed PubMedCentral
|