Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Krüppel-like factor 15 ameliorates alcohol-induced liver injury in mice via regulation of the PFKFB3/AKT axis

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Alcohol-associated liver disease (ALD) remains a predominant cause of chronic hepatic pathology, and effective therapeutic strategies are needed. Krüppel-like factor 15 (KLF15) is a member of the KLF family of zinc-finger transcription factors and is ubiquitously expressed in metabolically active tissues, with a particularly high abundance in the liver. KLF15 has been implicated in various hepatic disorders. In this study, we investigated the pathophysiological role of KLF15 in ALD. We established a National Institute on Alcohol Abuse and Alcoholism (NIAAA) model in mice by feeding them an ethanol Lieber–DeCarli liquid diet containing 5% (vol/vol) ethanol for 10 days. EtOH-fed mice were administered binge ethanol gavage (5 g/kg, body weight) on D11. We observed that the expression levels of KLF15 were significantly decreased in the livers of ALD patients and model mice. Overexpression of KLF15 conferred substantial protective effects in EtOH-fed mice, as evidenced by attenuated hepatic injury, apoptosis, steatosis and inflammation. In ethanol-treated AML-12 cells, overexpression of KLF15 reduced apoptosis and steatosis, whereas KLF15 knockdown exacerbated these pathological features. By performing RNA-seq and bioinformatics analyses, we observed that KLF15 regulated the AKT pathway by directly binding to the PFKFB3 promoter (−128 to −121). The physical interaction between PFKFB3 and AKT1 was further verified by Co-IP and molecular docking. These results suggest that KLF15 is a pivotal regulator of ALD pathogenesis through modulation of the PFKFB3/AKT axis, highlighting its potential as a novel therapeutic target for ALD intervention.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Hepatic KLF15 expression is decreased in ALD patients and mouse models of ALD.
Fig. 2: KLF15 expression is regulated by the inflammatory response.
Fig. 3: KLF15 overexpression ameliorates ethanol-induced liver injury.
Fig. 4: Overexpression of KLF15 alleviates lipid deposition and apoptosis in ethanol-induced AML-12 cells.
Fig. 5: KLF15 knockdown exacerbates lipid deposition and apoptosis in ethanol-induced AML-12 cells.
Fig. 6: KLF15 mitigates ethanol-induced liver injury by regulating the PI3K/AKT pathway.
Fig. 7: KLF15 inhibits the transcription of PFKFB3 by binding to its promoter.
Fig. 8: PFKFB3 binds to AKT1 in AML-12 cells.

Similar content being viewed by others

References

  1. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Prim. 2018;4:16.

    Article  PubMed  Google Scholar 

  2. Bajaj JS. Alcohol, liver disease and the gut microbiota. Nat Rev Gastroenterol Hepatol. 2019;16:235–46.

    Article  PubMed  Google Scholar 

  3. Parker R, Kim SJ, Gao B. Alcohol, adipose tissue and liver disease: mechanistic links and clinical considerations. Nat Rev Gastroenterol Hepatol. 2018;15:50–9.

    Article  CAS  PubMed  Google Scholar 

  4. Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol. 2017;66:1300–12.

    Article  CAS  PubMed  Google Scholar 

  5. Liu K, Wang FS, Xu R. Neutrophils in liver diseases: pathogenesis and therapeutic targets. Cell Mol Immunol. 2021;18:38–44.

    Article  CAS  PubMed  Google Scholar 

  6. Rogal S, Youk A, Zhang H, Gellad WF, Fine MJ, Good CB, et al. Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis. Hepatology. 2020;71:2080–92.

    Article  CAS  PubMed  Google Scholar 

  7. Chen H, Li LL, Du Y. Kruppel-like factor 15 in liver diseases: insights into metabolic reprogramming. Front Pharmacol. 2023;14:1115226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Anzai K, Tsuruya K, Ida K, Kagawa T, Inagaki Y, Kamiya A. Kruppel-like factor 15 induces the development of mature hepatocyte-like cells from hepatoblasts. Sci Rep. 2021;11:18551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhou L, Li Q, Chen A, Liu N, Chen N, Chen X, et al. KLF15-activating Twist2 ameliorated hepatic steatosis by inhibiting inflammation and improving mitochondrial dysfunction via NF-kappaB-FGF21 or SREBP1c-FGF21 pathway. FASEB J. 2019;33:14254–69.

    Article  CAS  PubMed  Google Scholar 

  10. Wang G, Wu B, Cui Y, Zhang B, Jiang C, Wang H. Teneligliptin promotes bile acid synthesis and attenuates lipid accumulation in obese mice by targeting the KLF15-Fgf15 pathway. Chem Res Toxicol. 2020;33:2164–71.

    Article  CAS  PubMed  Google Scholar 

  11. Hou W, Huo KG, Guo X, Xu M, Yang Y, Shi Z, et al. KLF15-Cyp3a11 axis regulates rifampicin-induced liver injury. Drug Metab Dispos. 2024;52:606–13.

    Article  CAS  PubMed  Google Scholar 

  12. Bertola A, Mathews S, Ki SH, Wang H, Gao B. Mouse model of chronic and binge ethanol feeding (the NIAAA model). Nat Protoc. 2013;8:627–37.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Song Q, Chen Y, Wang J, Hao L, Huang C, Griffiths A, et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. J Hepatol. 2020;73:783–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sun LJ, Chen X, Zhu S, Xu JJ, Li XF, Diao SX, et al. Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2. Acta Pharmacol Sin. 2024;45:354–65.

    Article  CAS  PubMed  Google Scholar 

  15. Jung DY, Chalasani U, Pan N, Friedline RH, Prosdocimo DA, Nam M, et al. KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance. PLoS One. 2013;8:e77851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gao X, Huang L, Grosjean F, Esposito V, Wu J, Fu L, et al. Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats: a role for KLF15. Kidney Int. 2011;79:987–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang K, Qiu T, Zhou J, Gong X, Zhang X, Lan Y, et al. Blockage of glycolysis by targeting PFKFB3 suppresses the development of infantile hemangioma. J Transl Med. 2023;21:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shi WK, Zhu XD, Wang CH, Zhang YY, Cai H, Li XL, et al. PFKFB3 blockade inhibits hepatocellular carcinoma growth by impairing DNA repair through AKT. Cell Death Dis. 2018;9:428.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dou Q, Grant AK, Callahan C, Coutinho de Souza P, Mwin D, Booth AL, et al. PFKFB3-mediated pro-glycolytic shift in hepatocellular carcinoma proliferation. Cell Mol Gastroenterol Hepatol. 2023;15:61–75.

    Article  CAS  PubMed  Google Scholar 

  20. Mejias M, Gallego J, Naranjo-Suarez S, Ramirez M, Pell N, Manzano A, et al. CPEB4 increases expression of PFKFB3 to induce glycolysis and activate mouse and human hepatic stellate cells, promoting liver fibrosis. Gastroenterology. 2020;159:273–88.

    Article  CAS  PubMed  Google Scholar 

  21. Wang C, Chu X, Deng Y, Wang J, Qiu T, Zhu J, et al. PA and OA induce abnormal glucose metabolism by inhibiting KLF15 in adipocytes. Nutr Metab. 2021;18:100.

    Article  CAS  Google Scholar 

  22. Takeuchi Y, Murayama Y, Aita Y, Mehrazad Saber Z, Karkoutly S, Tao D, et al. GR-KLF15 pathway controls hepatic lipogenesis during fasting. FEBS J. 2024;291:259–71.

    Article  CAS  PubMed  Google Scholar 

  23. Fan L, Hsieh PN, Sweet DR, Jain MK. Kruppel-like factor 15: regulator of BCAA metabolism and circadian protein rhythmicity. Pharmacol Res. 2018;130:123–6.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang X, Tian X, Wang Y, Yan Y, Wang Y, Su M, et al. Application of lipopolysaccharide in establishing inflammatory models. Int J Biol Macromol. 2024;279:135371.

    Article  PubMed  Google Scholar 

  25. Prosdocimo DA, John JE, Zhang L, Efraim ES, Zhang R, Liao X, et al. KLF15 and PPARalpha cooperate to regulate cardiomyocyte lipid gene expression and oxidation. PPAR Res. 2015;2015:201625.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hu Y, Xu J, Gao R, Xu Y, Huangfu B, Asakiya C, et al. Diallyl trisulfide prevents adipogenesis and lipogenesis by regulating the transcriptional activation function of KLF15 on PPARgamma to ameliorate obesity. Mol Nutr Food Res. 2022;66:e2200173.

    Article  PubMed  Google Scholar 

  27. Xiao J, Xiang H, Xiang H, Sun Z, Xu J, Ren H, et al. GW9662 ameliorates nonalcoholic steatohepatitis by inhibiting the PPARgamma/CD36 pathway and altering the gut microbiota. Eur J Pharmocol. 2023;960:176113.

    Article  CAS  Google Scholar 

  28. Lin H, Wang L, Liu Z, Long K, Kong M, Ye D, et al. Hepatic MDM2 causes metabolic associated fatty liver disease by blocking triglyceride-VLDL secretion via ApoB degradation. Adv Sci. 2022;9:e2200742.

    Article  Google Scholar 

  29. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799–806.

    Article  CAS  PubMed  Google Scholar 

  30. Arab HH, Salama SA, Eid AH, Kabel AM, Shahin NN. Targeting MAPKs, NF-kappaB, and PI3K/AKT pathways by methyl palmitate ameliorates ethanol-induced gastric mucosal injury in rats. J Cell Physiol. 2019;234:22424–38.

    Article  CAS  PubMed  Google Scholar 

  31. Han S, Liang CP, Westerterp M, Senokuchi T, Welch CL, Wang Q, et al. Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice. J Clin Invest. 2009;119:1029–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Song L, Huang Y, Liu L, Chang X, Hu L, Wang G, et al. Meteorin-like alleviates hepatic steatosis by regulating hepatic triglyceride secretion and fatty acid oxidation. Cell Rep. 2025;44:115246.

    Article  CAS  PubMed  Google Scholar 

  33. Sun YY, Zhao YX, Li XF, Huang C, Meng XM, Li J. beta-Arrestin 2 promotes hepatocyte apoptosis by inhibiting Akt pathway in alcoholic liver disease. Front Pharmacol. 2018;9:1031.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zheng H, Ye W, Huang K, Chen Q, Yang J, Luo L. KLF15 alleviates oxidative stress and apoptosis of H/R-induced trophoblast cells to improve invasion and migration capacity via the activation of IGF1R. Tissue Cell. 2024;90:102485.

    Article  CAS  PubMed  Google Scholar 

  35. Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab. 2011;14:21–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bijl N, Sokolovic M, Vrins C, Langeveld M, Moerland PD, Ottenhoff R, et al. Modulation of glycosphingolipid metabolism significantly improves hepatic insulin sensitivity and reverses hepatic steatosis in mice. Hepatology. 2009;50:1431–41.

    Article  CAS  PubMed  Google Scholar 

  37. Song ZK, Zhao L, Liu DS, Zhao LN, Peng QB, Li ZY, et al. Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1. J Mol Cell Cardiol. 2024;186:57–70.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82400205), the Pharmaceutical Innovative Fund of Anhui Medical University (YXCX202210) and the Natural Science Projects for Colleges and Universities in Anhui Province (2022AH051163).

Author information

Author notes

  1. These authors contributed equally: Hao Chen, Lin Yang, Xiao-feng Li

Authors and Affiliations

  1. Department of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Hao Chen, Ling Fang & Yan Du

  2. The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230022, China

    Hao Chen, Ling Fang & Yan Du

  3. School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China

    Lin Yang, Xiao-feng Li, Si-yuan Han, Qi Zhao, Rong-cheng Xiao, Zi-yao Ou, Ling Fang & Yan Du

Authors
  1. Hao Chen
    View author publications

    Search author on:PubMed Google Scholar

  2. Lin Yang
    View author publications

    Search author on:PubMed Google Scholar

  3. Xiao-feng Li
    View author publications

    Search author on:PubMed Google Scholar

  4. Si-yuan Han
    View author publications

    Search author on:PubMed Google Scholar

  5. Qi Zhao
    View author publications

    Search author on:PubMed Google Scholar

  6. Rong-cheng Xiao
    View author publications

    Search author on:PubMed Google Scholar

  7. Zi-yao Ou
    View author publications

    Search author on:PubMed Google Scholar

  8. Ling Fang
    View author publications

    Search author on:PubMed Google Scholar

  9. Yan Du
    View author publications

    Search author on:PubMed Google Scholar

Contributions

HC, LY and XFL designed and performed this research, performed the experiments and wrote the manuscript; SYH, QZ and RCX participated in data processing; ZYO analysed the software data and methodology; LF and YD supervised the experiments. All the authors read and approved the manuscript.

Corresponding authors

Correspondence to Ling Fang or Yan Du.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, H., Yang, L., Li, Xf. et al. Krüppel-like factor 15 ameliorates alcohol-induced liver injury in mice via regulation of the PFKFB3/AKT axis. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01651-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-025-01651-2

Keywords

Search

Advanced search

Quick links