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Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins

Nature Medicine volume 10, pages 1344–1351 (2004)Cite this article

Abstract

We identify berberine (BBR), a compound isolated from a Chinese herb, as a new cholesterol-lowering drug. Oral administration of BBR in 32 hypercholesterolemic patients for 3 months reduced serum cholesterol by 29%, triglycerides by 35% and LDL-cholesterol by 25%. Treatment of hyperlipidemic hamsters with BBR reduced serum cholesterol by 40% and LDL-cholesterol by 42%, with a 3.5-fold increase in hepatic LDLR mRNA and a 2.6-fold increase in hepatic LDLR protein. Using human hepatoma cells, we show that BBR upregulates LDLR expression independent of sterol regulatory element binding proteins, but dependent on ERK activation. BBR elevates LDLR expression through a post-transcriptional mechanism that stabilizes the mRNA. Using a heterologous system with luciferase as a reporter, we further identify the 5′ proximal section of the LDLR mRNA 3′ untranslated region responsible for the regulatory effect of BBR. These findings show BBR as a new hypolipidemic drug with a mechanism of action different from that of statin drugs.

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Figure 1: Upregulation of LDLR expression by BBR in human hepatoma cell lines.
Figure 2: BBR increases LDLR expression by stabilizing LDLR mRNA through the 5′ proximal section of the LDLR mRNA 3′UTR.
Figure 3: Blocking ERK activation abolished the regulatory effect of BBR on LDLR.
Figure 4: BBR reduces plasma LDL-c and increases liver LDLR expression in hamsters.

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Acknowledgements

We thank F. B. Kraemer for his review of the manuscript and S. M. Prescott for providing the pLuc plasmid. This study was supported by the National Natural Sciences Foundation of China (39925037, 39870889 & 39930190; J.-D.J.), by the Department of Veterans Affairs (Office of Research and Development, Medical Research Service; J. Liu) and by grant (1RO1CA83648-01; J.L.) from United States National Institute of Health.

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  1. Weijia Kong, Jing Wei and Parveen Abidi: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100050, China

    Weijia Kong, Shuyi Si, Zhuorong Li & Jian-Dong Jiang

  2. Division of Endocrinology and Laboratory of Molecular Medicine, First Hospital of Nanjing City, Nanjing Medical University, Nanjing, 210006, China

    Jing Wei, Zizheng Wang, Huaining Pan, Shukui Wang & Jingdan Wu

  3. Department of Veterans Affairs Palo Alto Health Care System, Research Service, Palo Alto, 94304, CA, USA

    Parveen Abidi, Meihong Lin, Satoru Inaba, Cong Li & Jingwen Liu

  4. Department of Medicine, Mount Sinai School of Medicine, New York, 10029, NY, USA

    Yanling Wang, Yue Wang & Jian-Dong Jiang

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  1. Weijia Kong
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Correspondence to Jingwen Liu or Jian-Dong Jiang.

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Supplementary information

Supplementary Table 1

Effects of BBR in the entire hypercholesterolemic patient cohort (PDF 25 kb)

Supplementary Table 2

Characterization of the subgroup of hypercholesterolemic patients who were not taking other medication before or during BBR treatment (PDF 16 kb)

Supplementary Table 3

Lipid-lowering effect of BBR in hypercholesterolemia Type IIa & IIb (PDF 12 kb)

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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 10, 1344–1351 (2004). https://doi.org/10.1038/nm1135

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