Advanced Search

Journal of Traditional Chinese Medicine >

2026 , Vol. 46 >Issue 4: 788 - 797

DOI: https://doi.org/10.19852/j.cnki.jtcm.2026.04.002

Original Articles

Berberine alleviates alcoholic liver disease via activating intestinal nuclear receptor subfamily 1 group D member 1

  • HUANG Yuwei ,
  • CAI Yuting ,
  • LI Zanjin ,
  • WU Zicong ,
  • GUO Lianxia ,
  • LIN Luomin ,
  • DONG Linlin ,
  • WU Baojian ,
  • DONG Dong
Expand
  • 1 Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine, Guangzhou 510000, China
    2 Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou 510632, China
    3 Hebei Geo-Environment Monitoring Institute, Shijiazhuang 050021, China
HUANG Yuwei and CAI Yuting are co-first authors and contributed equally to this work

Received date: 2025-04-25

  Accepted date: 2025-10-15

  Online published: 2026-08-08

Supported by

Project for Young Qihuang Scholars of the National Administration of Traditional Chinese Medicine;China Postdoctoral Science Foundation-Founded Project: Mechanism Study of Circadian Rhythm in Allergic Rhinitis(2024M760666);Scientific Research Platforms and Projects of Guangdong Higher Education Institutions-founded Project: Circadian Controlled Disease and Innovative Drug Investigation Team(2023KCXTD009)

Fold

Abstract

OBJECTIVES: To elucidate the hepatoprotective mechanism of berberine (BBR) against alcohol-induced liver injury.

METHODS: Chronic and acute alcohol-induced liver injury models in mice were established to mimic human alcoholic liver disease (ALD). The therapeutic effect of BBR was evaluated in both models. The severity of liver injury, lipid metabolism and circadian clock related factors were assessed using histopathology, biochemical assays, and Western blotting. Intestinal-specific nuclear receptor subfamily 1 group D member 1 (Rev-erbα) knockout mice were used to validate intestinal Rev-erbα as the key mediator.

RESULTS: BBR alleviated hepatic steatosis and inflammation in both chronic and acute ALD models. Mechanistically, BBR activated intestinal REV-ERBα, upregulating intestinal fatty acid desaturase 2 (FADS2) expression, suppressing hepatic sterol regulatory element binding protein-1 (SREBP-1c) and its downstream lipogenic genes. These effects were abolished in intestinal specific Rev-erba knockout mice. BBR was most effective against ALD when administered during the peak expression phase of REV-ERBα (Zeitgeber Time 6).

CONCLUSIONS: Intestinal REV-ERBα represents a promising therapeutic target for ALD, and chrono-modulated BBR administration may enhance treatment efficacy. This study underscores the role of gut-liver axis in ALD pathogenesis and provides a rationale for developing time-tailored therapies.

Key words： liver diseases, alcoholic; berberine; intestines; intestinal-specific nuclear receptor subfamily 1 group D member 1

Cite this article

HUANG Yuwei , CAI Yuting , LI Zanjin , WU Zicong , GUO Lianxia , LIN Luomin , DONG Linlin , WU Baojian , DONG Dong . Berberine alleviates alcoholic liver disease via activating intestinal nuclear receptor subfamily 1 group D member 1[J]. Journal of Traditional Chinese Medicine, 2026 , 46(4) : 788 -797 . DOI: 10.19852/j.cnki.jtcm.2026.04.002

References

1. Gilmore W, Chikritzhs T, Stockwell T, Jernigan D, Naimi T, Gilmore I. Alcohol: taking a population perspective. Nat Rev Gastroenterol Hepatol 2016; 13: 426-34.
2. Mandrekar P, Bataller R, Tsukamoto H, Gao B. Alcoholic hepatitis: translational approaches to develop targeted therapies. Hepatology 2016; 64: 1343-55.
3. Seitz HK, Bataller R, Cortez-Pinto H, et al. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4: 16.
4. Liangpunsakul S, Haber P, McCaughan GW. Alcoholic liver disease in Asia, Europe, and North America. Gastroenterology 2016; 150: 1786-97.
5. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013; 59: 160-8.
6. Taieb J, Mathurin P, Elbim C, et al. Blood neutrophil functions and cytokine release in severe alcoholic hepatitis: effect of corticosteroids. J Hepatol 2000; 32: 579-86.
7. Naveau S, Chollet-Martin S, Dharancy S, et al. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology 2004; 39: 1390-7.
8. Vonghia L, Leggio L, Ferrulli A, Bertini M, Gasbarrini G, Addolorato G. Acute alcohol intoxication. Eur J Intern Med 2008; 19: 561-7.
9. Mao YM, Zeng MD, Li YM, et al. Capsule metadoxine in the treatment of alcoholic liver disease: a randomized, double-blind, placebo-controlled, multicenter study. Zhong Hua Gan Zang Bing Za Zhi 2009; 17: 213-6.
10. Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004; 10: 1344-51.
11. Qin X, Guo BT, Wan B, et al. Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine. J Immunol 2010; 185: 1855-63.
12. Tang LQ, Wei W, Chen LM, Liu S. Effects of berberine on diabetes induced by alloxan and a high-fat/high-cholesterol diet in rats. J Ethnopharmacol 2006; 108: 109-15.
13. Li-Weber M. Targeting apoptosis pathways in cancer by Chinese medicine. Cancer Lett 2013; 332: 304-12.
14. Shuai H, Zhikang D, Zirui W, et al. Network pharmacology approach to unveiling the mechanism of berberine in the amelioration of morphine tolerance. J Tradit Chin Med 2025; 45: 376-384.
15. Zhou XQ, Zeng XN, Kong H, Sun XL. Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci Lett 2008; 447: 31-6.
16. Baska A, Leis K, Galazka P. Berberine in the treatment of diabetes mellitus: a review. Endocr Metab Immune Disord Drug Targets 2021; 21: 1379-86.
17. Pang B, Zhao LH, Zhou Q, et al. Application of berberine on treating type 2 diabetes mellitus. Int J Endocrinol 2015; 2015: 905749.
18. Li GS, Liu XH, Zhu H, et al. Berberine-improved visceral white adipose tissue insulin resistance associated with altered sterol regulatory element-binding proteins, liver X receptors, and peroxisome proliferator-activated receptors transcriptional programs in diabetic hamsters. Biol Pharm Bull 2011; 34: 644-54.
19. Xia X, Yan J, Shen Y, et al. Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011; 6: e16556.
20. Altman BJ, Hsieh AL, Gouw AM, Dang CV. Correspondence: oncogenic MYC persistently upregulates the molecular clock component REV-ERBα. Nat Commun 2017; 8: 14862.
21. Chu G, Zhou X, Hu Y, Shi S, Yang G. Rev-erbα inhibits proliferation and promotes apoptosis of preadipocytes through the agonist GSK4112. Int J Mol Sci 2019; 20: 4524.
22. Li T, Eheim AL, Klein S, et al. Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation: potential therapeutic target for liver injury. Hepatology 2014; 59: 2383-96.
23. Cho H, Zhao X, Hatori M, et al. Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 2012; 485: 123-7.
24. Zhangsun ZY, Xu XZ, Escames G, et al. Targeting NR1D1 in organ injury: challenges and prospects. Mil Med Res 2023; 10: 62.
25. Yang Z, Smalling RV, Huang Y, et al. The role of SHP/REV-ERBalpha/CYP4A axis in the pathogenesis of alcohol-associated liver disease. Jci Insight 2021; 6: e140687.
26. Yu F, Wang Z, Zhang T, et al. Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding. Nat Commun 2021; 12: 5323.
27. Chen M, Lin Y, Dang Y, et al. Reprogramming of rhythmic liver metabolism by intestinal clock. J Hepatol 2023; 79: 741-57.
28. Zhou Z, Lin Y, Gao L, Yang Z, Wang S, Wu B. Circadian pharmacological effects of berberine on chronic colitis in mice: role of the clock component Rev-erbalpha. Biochem Pharmacol 2020; 172: 113773.
29. 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.
30. Lachenmeier DW, Monakhova YB, Rehm J. Influence of unrecorded alcohol consumption on liver cirrhosis mortality. World J Gastroenterol 2014; 20: 7217-22.
31. Sozio MS, Liangpunsakul S, Crabb D. The role of lipid metabolism in the pathogenesis of alcoholic and nonalcoholic hepatic steatosis. Semin Liver Dis 2010; 30: 378-90.
32. You M, Arteel GE. Effect of ethanol on lipid metabolism. J Hepatol 2019; 70: 237-48.
33. Tomita K, Azuma T, Kitamura N, et al. Pioglitazone prevents alcohol-induced fatty liver in rats through up-regulation of c-Met. Gastroenterology 2004; 126: 873-85.
34. Zhou R, Lin J, Wu D. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis. Biochim Biophys Acta 2014; 1840: 209-18.
35. Zhang P, Ma D, Wang Y, et al. Berberine protects liver from ethanol-induced oxidative stress and steatosis in mice. Food Chem Toxicol 2014; 74: 225-32.
36. Yi J, Wu S, Tan S, et al. Berberine alleviates liver fibrosis through inducing ferrous redox to activate ROS-mediated hepatic stellate cells ferroptosis. Cell Death Discov 2021; 7: 374.
37. Yue SJ, Liu J, Wang WX, et al. Berberine treatment-emergent mild diarrhea associated with gut microbiota dysbiosis. Biomed Pharmacother 2019; 116: 109002.
38. Kim YH, Marhon SA, Zhang Y, Steger DJ, Won KJ, Lazar MA. Rev-erbalpha dynamically modulates chromatin looping to control circadian gene transcription. Science 2018; 359: 1274-7.
39. Liu Q, Xu L, Wu M, et al. Rev-erbalpha exacerbates hepatic steatosis in alcoholic liver diseases through regulating autophagy. Cell Biosci 2021; 11: 129.
40. Luo ZC, Li ZH, Liang Z, et al. Berberine increases stromal production of Wnt molecules and activates Lgr5+ stem cells to promote epithelial restitution in experimental colitis. BMC Biol 2022; 20: 287.
41. Xiong W, Sang W, Linghu KG, et al. Dual-functional Brij-S20-modified nanocrystal formulation enhances the intestinal transport and oral bioavailability of berberine. Int J Nanomedicine 2018; 13: 3781-93.
42. Nakakuki M, Kawano H, Notsu T, Imada K, Mizuguchi K, Shimano H. A novel processing system of sterol regulatory element-binding protein-1c regulated by polyunsaturated fatty acid. J Biochem 2014; 155: 301-13.
43. Kesharwani D, Kumar A, Rizvi A, Datta M. miR-539-5p regulates Srebf1 transcription in the skeletal muscle of diabetic mice by targeting DNA methyltransferase 3b. Mol Ther Nucleic Acids 2022; 29: 718-732.
44. Solt LA, Wang Y, Banerjee S, et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 2012; 485: 62-8.
45. Grant D, Yin L, Collins JL, et al. GSK4112, a small molecule chemical probe for the cell biology of the nuclear heme receptor Rev-erbalpha. Acs Chem Biol 2010; 5: 925-32.
46. Cheng J, Yan G, Tan W, et al. Berberine alleviates fructose-induced hepatic injury via ADK/AMPK/Nrf 2 pathway: a novel insight. Biomed Pharmacother 2024; 179: 117361.
47. Delezie J, Dumont S, Dardente H, et al. The nuclear receptor REV-ERBalpha is required for the daily balance of carbohydrate and lipid metabolism. Faseb J 2012; 26: 3321-35.
48. Yang Z, Tsuchiya H, Zhang Y, et al. REV-ERBα activates C/EBP homologous protein to control small heterodimer partner-mediated oscillation of alcoholic fatty liver. Am J Pathol 2016; 186: 2909-20.
Options
Outlines

/

〈 〉