L-carnitine Attenuates Autophagic Flux, Apoptosis, and Necroptosis in Rats with Dexamethasone-induced Non-alcoholic Steatohepatitis

Overview

Journal BMC Pharmacol Toxicol

Publisher Biomed Central

Specialty Pharmacology

Date 2024 Dec 30

PMID 39736705

Authors

Ahmed E Amer

Hamdy A Ghoneim

Rania R Abdelaziz

George S G Shehatou

Ghada M Suddek

Affiliations

Soon will be listed here.

Abstract

Background: UpToDate, no drugs have been approved to treat nonalcoholic steatohepatitis, the advanced stage of the most prevalent liver disease, non-alcoholic fatty liver disease. The present study was conducted to explore the potential influences of L-carnitine on the pathomechanisms of hepatic injury that mediate progression to non-alcoholic steatohepatitis in dexamethasone-toxified rats.

Methods: Male Wistar rats were allocated as follows: dexamethasone group, rats received dexamethasone (8 mg/kg/day, intraperitoneally) for 6 days; DEXA-LCAR300, DEXA-LCAR500, and DEXA-MET groups, rats administered L-carnitine (300 or 500 mg/kg/day, IP) or metformin (500 mg/kg/day, orally) one week prior to dexamethasone injection (8 mg/kg/day, IP) and other six days alongside dexamethasone administration. Two groups of age-matched normal rats received either the drug vehicle (the control group) or the higher dose of L-carnitine (the drug-control group). At the end of the experiment, sets of biochemical, histological, and immunohistochemical examinations were performed.

Results: L-carnitine (mainly at the dose of 500 mg/kg/day) markedly abolished dexamethasone-induced alterations in glucose tolerance, hepatic histological features, and serum parameters of hepatic function and lipid profile. Moreover, it significantly ameliorated dexamethasone-induced elevations of hepatic oxidative stress, SREBP-1 and p-MLKL protein levels, and nuclear FOXO1, LC3, P62, and caspase-3 immunohistochemical expression. Furthermore, it markedly diminished dexamethasone-induced suppression of hepatic Akt phosphorylation and Bcl2 immunohistochemical expression. The effects of L-carnitine (500 mg/kg/day) were comparable to those of metformin in most assessments and better than its corresponding lower dose.

Conclusion: These findings introduce L-carnitine as a potential protective drug that may mitigate the rate of disease progression in non-alcoholic fatty liver disease patients with early stages or those at the highest risks.

References

Kim Y, Lee E, Shin K, Kim M, Pewzner-Jung Y, Lee Y . Hepatic triglyceride accumulation via endoplasmic reticulum stress-induced SREBP-1 activation is regulated by ceramide synthases. Exp Mol Med. 2019; 51(11):1-16. PMC: 6825147. DOI: 10.1038/s12276-019-0340-1. View

Wang L, Jiao X, Wu C, Li X, Sun H, Shen X . Trimetazidine attenuates dexamethasone-induced muscle atrophy via inhibiting NLRP3/GSDMD pathway-mediated pyroptosis. Cell Death Discov. 2021; 7(1):251. PMC: 8449784. DOI: 10.1038/s41420-021-00648-0. View

Yang M, Lin Y, Wang Y, Wang Y . High-glucose induces cardiac myocytes apoptosis through Foxo1 /GRK2 signaling pathway. Biochem Biophys Res Commun. 2019; 513(1):154-158. DOI: 10.1016/j.bbrc.2019.03.193. View

Xing Y, Li A, Yang Y, Li X, Zhang L, Guo H . The regulation of FOXO1 and its role in disease progression. Life Sci. 2017; 193:124-131. DOI: 10.1016/j.lfs.2017.11.030. View

Zhao Q, Lin X, Wang G . Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer. Front Oncol. 2022; 12:952371. PMC: 9330218. DOI: 10.3389/fonc.2022.952371. View

Yaribeygi H, Farrokhi F, Butler A, Sahebkar A . Insulin resistance: Review of the underlying molecular mechanisms. J Cell Physiol. 2018; 234(6):8152-8161. DOI: 10.1002/jcp.27603. View

Khatab L, Abdel-Raheem I, Ghoneim A . Protective effects of melatonin and L-carnitine against methotrexate-induced toxicity in isolated rat hepatocytes. Naunyn Schmiedebergs Arch Pharmacol. 2021; 395(1):87-97. DOI: 10.1007/s00210-021-02176-1. View

Islam M, Sooro M, Zhang P . Autophagic Regulation of p62 is Critical for Cancer Therapy. Int J Mol Sci. 2018; 19(5). PMC: 5983640. DOI: 10.3390/ijms19051405. View

Qian L, Ji J, Jiang Y, Guo J, Wu Y, Yang Z . Serpina3c deficiency induced necroptosis promotes non-alcoholic fatty liver disease through β-catenin/Foxo1/TLR4 signaling. FASEB J. 2022; 36(5):e22316. DOI: 10.1096/fj.202101345RRR. View

10.

Buist N . Historical Perspective on Clinical Trials of Carnitine in Children and Adults. Ann Nutr Metab. 2016; 68 Suppl 3:1-4. DOI: 10.1159/000448320. View

11.

Zhang D, Ma Y, Liu J, Deng Y, Zhou B, Wen Y . Metformin Alleviates Hepatic Steatosis and Insulin Resistance in a Mouse Model of High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease by Promoting Transcription Factor EB-Dependent Autophagy. Front Pharmacol. 2021; 12:689111. PMC: 8346235. DOI: 10.3389/fphar.2021.689111. View

12.

Schmoll D, Walker K, Alessi D, Grempler R, Burchell A, Guo S . Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. J Biol Chem. 2000; 275(46):36324-33. DOI: 10.1074/jbc.M003616200. View

13.

Vinodraj K, Nayak I, Rao J, Mathai P, Chandralekha N, Nitasha B . Comparison of the efficacy of liraglutide with pioglitazone on dexamethasone induced hepatic steatosis, dyslipidemia and hyperglycaemia in albino rats. Indian J Pharmacol. 2015; 47(2):181-4. PMC: 4386127. DOI: 10.4103/0253-7613.153426. View

14.

Biddinger S, Hernandez-Ono A, Rask-Madsen C, Haas J, Aleman J, Suzuki R . Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab. 2008; 7(2):125-34. PMC: 4251554. DOI: 10.1016/j.cmet.2007.11.013. View

15.

Deng S, Dai G, Chen S, Nie Z, Zhou J, Fang H . Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/GSK3β signaling pathway. Biomed Pharmacother. 2018; 110:602-608. DOI: 10.1016/j.biopha.2018.11.103. View

16.

Li R, Chen L, Zhao W, Zhao S, Huang X . Metformin ameliorates obesity-associated hypertriglyceridemia in mice partly through the apolipoprotein A5 pathway. Biochem Biophys Res Commun. 2016; 478(3):1173-8. DOI: 10.1016/j.bbrc.2016.08.087. View

17.

Rashad W, Saadawy S, Refaay N . Mitigating effect of L-carnitine against atrazine-induced hepatotoxicity: histopathological and biochemical analyses in albino rats. Environ Sci Pollut Res Int. 2022; 30(8):22034-22045. PMC: 9938065. DOI: 10.1007/s11356-022-23568-7. View

18.

Park J, Rah S, An H, Lee J, Roh G, Ryter S . Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis. Metabolism. 2023; 141:155516. DOI: 10.1016/j.metabol.2023.155516. View

19.

Wang X, Zhang X, Chu E, Chen X, Kang W, Wu F . Defective lysosomal clearance of autophagosomes and its clinical implications in nonalcoholic steatohepatitis. FASEB J. 2017; 32(1):37-51. DOI: 10.1096/fj.201601393R. View

20.

Rajasekar P, Anuradha C . Effect of L-carnitine on skeletal muscle lipids and oxidative stress in rats fed high-fructose diet. Exp Diabetes Res. 2007; 2007:72741. PMC: 1880866. DOI: 10.1155/2007/72741. View