Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Licochalcone E Ameliorates Hepatic Steatosis in Obese Mice by Activating the Sirt1/AMPK Pathway and Reducing Hepatic Lipid Accumulation

  • Wen-Chung Huang (Graduate Institute of Health Industry Technology, Center for Drug Research and Development, Chang Gung University of Science and Technology) ;
  • Shu-Ju Wu (Department of Nutrition and Health Sciences, Center for Drug Research and Development, Chang Gung University of Science and Technology) ;
  • Xuan-Min Liu (Graduate Institute of Health Industry Technology, Center for Drug Research and Development, Chang Gung University of Science and Technology) ;
  • Shu-Chen Cheng (Graduate Institute of Health Industry Technology, Center for Drug Research and Development, Chang Gung University of Science and Technology) ;
  • Po-Ting Lin (Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University) ;
  • Chun-Ling Kuo (Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital) ;
  • Chian-Jiun Liou (Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital)
  • Received : 2025.08.22
  • Accepted : 2026.03.19
  • Published : 2026.05.01
Download PDF
⟨ Previous Next ⟩

Abstract

Licochalcone E is a chalcone isolated from Glycyrrhiza uralensis and G. inflata Batal. This study explored the effect of licochalcone E on improving hepatic steatosis in obese mice and evaluated the role of licochalcone E in regulating lipid accumulation in hepatocytes. In vitro, oleic acid-induced hepatocytes were treated with licochalcone E to investigate its effect on lipid metabolic pathways. In animal experiments, male C57BL/6 mice were fed with a high-fat diet (HFD) and treated with licochalcone E by intraperitoneal injection for 12 weeks to assess its effects on biochemical indexes and hepatic steatosis. Furthermore, mice were fed a methionine/choline-deficient (MCD) diet and administered licochalcone E, followed by evaluation of liver fibrosis. Licochalcone E effectively reduced body weight, epididymal and inguinal fat weight, and adipocyte size in HFD-induced obese mice. Licochalcone E treatment of obese mice also reduced hepatic lipid accumulation and improved hepatocyte steatosis. Licochalcone E regulated the expression of lipogenesis- and lipolysis-related genes in the livers of obese mice and increased AMPK phosphorylation and Sirt1 expression in the liver. Licochalcone E also attenuated hepatic inflammation and oxidative stress in obese mice. Furthermore, treatment of MCD-induced mice with licochalcone E reduced the number of lipid vacuoles and the extent of fibrosis and inhibited liver inflammation. In FL83B hepatocytes, licochalcone E could regulate lipogenesis and lipolysis, and increase the phosphorylation of AMPK and ACC. These findings provide new insights into the role of licochalcone E in regulating lipid metabolism and preventing hepatic steatosis.

Keywords

Acknowledgement

This study was supported in part by grants from Chang Gung Memorial Hospital (CMRPG3P0951, CMRP1N0071, CMRPF1N0051, CMRPF1N0081, and CMRPF1L0031), the Chang Gung University of Science and Technology (ZRRPF3N0091, ZRRPF3P0091, and ZRRPF3Q0091), and the Ministry of Science and Technology in Taiwan (112-2320-B-255-005-MY3, 112-2320-B-255-006-MY3, 112-2320-B-255-007-MY3).

References

  1. Alshawsh, M. A., Alsalahi, A., Alshehade, S. A., Saghir, S. A. M., Ahmeda, A. F., Al Zarzour, R. H. and Mahmoud, A. M. (2022) A comparison of the gene expression profiles of non-alcoholic fatty liver disease between animal models of a high-fat diet and methioninecholine-deficient diet. Molecules 27, 858.  https://doi.org/10.3390/molecules27030858
  2. Alves-Bezerra, M. and Cohen, D. E. (2017) Triglyceride metabolism in the liver. Compr. Physiol. 8, 1-8. https://doi.org/10.1002/cph4.v8.1
  3. Börgeson, E., Wallenius, V., Syed, G. H., Darshi, M., Lantero Rodriguez, J., Biörserud, C., Ragnmark Ek, M., Björklund, P., QuidingJärbrink, M., Fändriks, L., Godson, C. and Sharma, K. (2017) AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin. Diabetologia 60, 729-739. https://doi.org/10.1007/s00125-017-4211-9
  4. Cao, Y., Si, Y., Li, M., Fan, D., Cao, M., Cheon, S. H., Liang, J. and Lu, P. (2021) Licochalcone E improves insulin sensitivity in palmitic acid-treated HepG2 cells through inhibition of the NLRP3 signaling pathway. Int. Immunopharmacol. 99, 107923. https://doi.org/10.1016/j.intimp.2021.107923
  5. Carbó, N., López-Soriano, F. J. and Argilés, J. M. (1991) Glucose handling by hepatocytes from obese Zucker rats. Biosci. Rep. 11, 285-292. https://doi.org/10.1007/BF01127504
  6. Chan, W. K., Chuah, K. H., Rajaram, R. B., Lim, L. L., Ratnasingam, J. and Vethakkan, S. R. (2023) Metabolic dysfunction-associated steatotic liver disease (MASLD): a state-of-the-art review. J. Obes. Metab. Syndr. 32, 197-213. https://doi.org/10.7570/jomes23052
  7. Cheng, S. C., Liou, C. J., Wu, Y. X., Yeh, K. W., Chen, L. C. and Huang, W. C. (2024) Gypenoside XIII regulates lipid metabolism in HepG2 hepatocytes and ameliorates nonalcoholic steatohepatitis in mice. Kaohsiung J. Med. Sci. 40, 280-290. https://doi.org/10.1002/kjm2.v40.3
  8. Clare, K., Dillon, J. F. and Brennan, P. N. (2022) Reactive oxygen species and oxidative stress in the pathogenesis of MAFLD. J. Clin. Transl. Hepatol. 10, 939-946. https://doi.org/10.14218/JCTH.2022.00067
  9. Day, E. A., Ford, R. J. and Steinberg, G. R. (2017) AMPK as a therapeutic target for treating metabolic diseases. Trends Endocrinol. Metab. 28, 545-560. https://doi.org/10.1016/j.tem.2017.05.004
  10. Deng, N., Qiao, M., Li, Y., Liang, F., Li, J. and Liu, Y. (2023) Anticancer effects of licochalcones: a review of the mechanisms. Front. Pharmacol. 14, 1074506. https://doi.org/10.3389/fphar.2023.1074506
  11. Ding, L., Sun, W., Balaz, M., He, A., Klug, M., Wieland, S., Caiazzo, R., Raverdy, V., Pattou, F., Lefebvre, P., Lodhi, I. J., Staels, B., Heim, M. and Wolfrum, C. (2021) Peroxisomal -oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis. Nat. Metab. 3, 1648-1661.
  12. Engin, A. (2024) Adiponectin resistance in obesity: adiponectin leptin/insulin interaction. Adv. Exp. Med. Biol. 1460, 431-462. https://doi.org/10.1007/978-3-031-63657-8
  13. Fang, C., Pan, J., Qu, N., Lei, Y., Han, J., Zhang, J. and Han, D. (2022) The AMPK pathway in fatty liver disease. Front. Physiol. 13, 970292. https://doi.org/10.3389/fphys.2022.970292
  14. Fritzen, A. M., Lundsgaard, A. M. and Kiens, B. (2020) Tuning fatty acid oxidation in skeletal muscle with dietary fat and exercise. Nat. Rev. Endocrinol. 16, 683-696. https://doi.org/10.1038/s41574-020-0405-1
  15. Garcia, N., Mellergaard, M., Salomon, C., Sepulveda, P., Kristensen, P. and Handberg, A. (2025) CD36 and its role in obesity. Obes. Rev. e70039.
  16. Göransson, O., Kopietz, F. and Rider, M. H. (2023) Metabolic control by AMPK in white adipose tissue. Trends Endocrinol. Metab. 34, 704-717. https://doi.org/10.1016/j.tem.2023.08.011
  17. Grabner, G. F., Xie, H., Schweiger, M. and Zechner, R. (2021) Lipolysis: cellular mechanisms for lipid mobilization from fat stores. Nat. Metab. 3, 1445-1465. https://doi.org/10.1038/s42255-021-00493-6
  18. Han, J., Wang, D., Li, D., Chen, X., Wang, B., Wang, F., Liu, X., Shang, J. and Zheng, Q. (2017) Licochalcone E protects against carbon tetrachloride-induced liver toxicity by activating peroxisome proliferator-activated receptor gamma. Mol. Med. Rep. 16, 5269-5276. https://doi.org/10.3892/mmr.2017.7268
  19. Hellerstein, M. K., Christiansen, M., Kaempfer, S., Kletke, C., Wu, K., Reid, J. S., Mulligan, K., Hellerstein, N. S. and Shackleton, C. H. (1991) Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J. Clin. Invest. 87, 1841-1852. https://doi.org/10.1172/JCI115206
  20. Hughey, C. C., Puchalska, P. and Crawford, P. A. (2022) Integrating the contributions of mitochondrial oxidative metabolism to lipotoxicity and inflammation in NAFLD pathogenesis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1867, 159209.
  21. Huttasch, M., Roden, M. and Kahl, S. (2024) Obesity and MASLD: is weight loss the (only) key to treat metabolic liver disease? Metabolism 157, 155937. https://doi.org/10.1016/j.metabol.2024.155937
  22. Jeon, Y. G., Kim, Y. Y., Lee, G. and Kim, J. B. (2023) Physiological and pathological roles of lipogenesis. Nat. Metab. 5, 735-759. https://doi.org/10.1038/s42255-023-00786-y
  23. Kleiner, D. E., Brunt, E. M., Van Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y. C., Torbenson, M. S., Unalp-Arida, A., Yeh, M., McCullough, A. J. and Sanyal, A. J. (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313-1321. https://doi.org/10.1002/hep.20701
  24. Li, X., Ren, Y., Chang, K., Wu, W., Griffiths, H. R., Lu, S. and Gao, D. (2023) Adipose tissue macrophages as potential targets for obesity and metabolic diseases. Front. Immunol. 14, 1153915.
  25. Li, Y., Yang, P., Ye, J., Xu, Q., Wu, J. and Wang, Y. (2024) Updated mechanisms of MASLD pathogenesis. Lipids Health Dis. 23, 117. https://doi.org/10.1186/s12944-024-02108-x
  26. Liou, C. J., Dai, Y. W., Wang, C. L., Fang, L. W. and Huang, W. C. (2019) Maslinic acid protects against obesity-induced nonalcoholic fatty liver disease in mice through regulation of the Sirt1/AMPK signaling pathway. FASEB J. 33, 117910-111803. https://doi.org/10.1096/fsb2.v33.11
  27. Liou, C. J., Wu, S. J., Shen, S. C., Chen, L. C., Chen, Y. L. and Huang, W. C. (2020) Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice. Cell Biosci. 10, 114. https://doi.org/10.1186/s13578-020-00477-1
  28. Liou, C. J., Wu, S. J., Yang, H. C., Fang, L. W., Cheng, S. C. and Huang, W. C. (2024) Licochalcone D ameliorates lipid metabolism in hepatocytes by modulating lipogenesis and autophagy. Eur. J. Pharmacol. 975, 176644. https://doi.org/10.1016/j.ejphar.2024.176644
  29. Mateo-Marín, M. A. and Alves-Bezerra, M. (2024) Targeting acetylCoA carboxylases for the treatment of MASLD. J. Lipid Res. 65, 100676. https://doi.org/10.1016/j.jlr.2024.100676
  30. Palomer, X., Wang, J. R., Escalona, C., Wu, S., Wahli, W. and Vázquez-Carrera, M. (2025) Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD. Trends Pharmacol. Sci. 46, 551-566. https://doi.org/10.1016/j.tips.2025.03.008
  31. Plummer, A. M., Culbertson, A. T. and Liao, M. (2021) The ABCs of sterol transport. Annu. Rev. Physiol. 83, 153-181. https://doi.org/10.1146/physiol.2021.83.issue-1
  32. Samovski, D., Jacome-Sosa, M. and Abumrad, N. A. (2023) Fatty acid transport and signaling: mechanisms and physiological implications. Annu. Rev. Physiol. 85, 317-337. https://doi.org/10.1146/physiol.2023.85.issue-1
  33. Schwärzler, J., Grabherr, F., Grander, C., Adolph, T. E. and Tilg, H. (2024) The pathophysiology of MASLD: an immunometabolic perspective. Expert Rev. Clin. Immunol. 20, 375-386. https://doi.org/10.1080/1744666X.2023.2294046
  34. Smith, B. K., Marcinko, K., Desjardins, E. M., Lally, J. S., Ford, R. J. and Steinberg, G. R. (2016) Treatment of nonalcoholic fatty liver disease: role of AMPK. Am. J. Physiol. Endocrinol. Metab. 311, E730-E740. https://doi.org/10.1152/ajpendo.00225.2016
  35. Stefan, N., Yki-Järvinen, H. and Neuschwander-Tetri, B. A. (2025) Metabolic dysfunction-associated steatotic liver disease: heterogeneous pathomechanisms and effectiveness of metabolism-based treatment. Lancet Diabetes Endocrinol. 13, 134-148. https://doi.org/10.1016/S2213-8587(24)00318-8
  36. Sun, T., Chen, M., Shen, H., PingYin, Fan, L., Chen, X., Wu, J., Xu, Z. and Zhang, J. (2022) Predictive value of LDL/HDL ratio in coronary atherosclerotic heart disease. BMC Cardiovasc. Disord. 22, 273.
  37. Syed-Abdul, M. M. (2023) Lipid metabolism in metabolic-associated steatotic liver disease (MASLD). Metabolites 14, 12. https://doi.org/10.3390/metabo14010012
  38. Targher, G., Byrne, C. D. and Tilg, H. (2024) MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut 73, 691-702. https://doi.org/10.1136/gutjnl-2023-330595
  39. Tejada, S., Capó, X., Mascaró, C. M., Monserrat-Mesquida, M., Quetglas-Llabrés, M. M., Pons, A., Tur, J. A. and Sureda, A. (2021) Hepatoprotective effects of resveratrol in non-alcoholic fatty live disease. Curr. Pharm. Des. 27, 2558-2570. https://doi.org/10.2174/1381612826666200417165801
  40. Wang, F., Liu, Y., Yuan, J., Yang, W. and Mo, Z. (2019) Compound C protects mice from hfd-induced obesity and nonalcoholic fatty liver disease. Int. J. Endocrinol. 2019, 3206587.
  41. Wang, Y., Viscarra, J., Kim, S. J. and Sul, H. S. (2015) Transcriptional regulation of hepatic lipogenesis. Nat. Rev. Mol. Cell Biol. 16, 678-689. https://doi.org/10.1038/nrm4074
  42. Wu, S. J., Huang, W. C., Yu, M. C., Chen, Y. L., Shen, S. C., Yeh, K. W. and Liou, C. J. (2021) Tomatidine ameliorates obesity-induced nonalcoholic fatty liver disease in mice. J. Nutr. Biochem. 91, 108602.
  43. Yunna, C., Mengru, H., Lei, W. and Weidong, C. (2020) Macrophage M1/M2 polarization. Eur. J. Pharmacol. 877, 173090.
  44. Zhang, M., Dong, K., Du, Q., Xu, J., Bai, X., Chen, L. and Yang, J. (2024) Chemically synthesized osteocalcin alleviates NAFLD via the AMPK-FOXO1/BCL6-CD36 pathway. J. Transl. Med. 22, 782.
  45. Zhang, Q., Zhang, J., Liu, B. and Wei, J. (2022) Licochalcone E inhibits trxR1 expression, alters Nrf2/STAT6 signal, and induces antitumor effects in vitro against human SH-SY5Y and SK-N-BE(2) neuroblastoma cells. Environ. Toxicol. 37, 1173-1184. https://doi.org/10.1002/tox.v37.5
  46. Zhang, Y. and Chua, S., Jr. (2017) Leptin function and regulation. Compr. Physiol. 8, 351-369. https://doi.org/10.1002/cph4.v8.1