Skip to main content
SpringerLink
Log in

Berberine Inhibits Inflammatory Response and Ameliorates Insulin Resistance in Hepatocytes

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Berberine, a major isoquinoline alkaloid present in Chinese herb Rhizoma coptidis, is a potent inhibitor of inflammation and has anti-diabetic activity. This study aims to investigate effects of berberine on ameliorating insulin resistance and molecular mechanisms involved in HepG2 cells. Inflammatory responses and insulin resistance were induced by palmitate (PA) stimulation for 24 h. Treatment of berberine enhanced insulin-mediated glycogen synthesis and restored insulin inhibition of triglyceride secretion. Stimulation of PA resulted in IL-6 and TNF-α production in HepG2 cells, and antibody-neutralizing assay further confirmed that IL-6 and TNF-α were involved in the development of insulin resistance. Berberine effectively inhibited IL-6 and TNF-α production in a concentration-dependent manner, demonstrating its anti-inflammatory activity in hepatocytes. Meanwhile, PA-evoked inflammation impaired insulin signaling cascade and berberine improved insulin signaling cascade by modification of Ser/Thr phosphorylation of insulin receptor substrate-1(IRS-1) and downstream Akt (T308). Above results suggest that berberine improved insulin sensitivity in PA-stimulated hepatocytes and this regulation might relative with its anti-inflammatory activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

REFERENCES

  1. Mokdad, A.H., E.S. Ford, B.A. Bowman, W.H. Dietz, F. Vinicor, V.S. Bales, and J.S. Marks. 2003. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. Journal of the American Medical Association 289: 76–79.

    Article  PubMed  Google Scholar 

  2. Hotamisligil, G.S., N.S. Shargill, and B.M. Spiegelman. 1993. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259: 87–91.

    Article  PubMed  CAS  Google Scholar 

  3. Feinstein, R., H. Kanety, M.Z. Papa, B. Lunenfeld, and A. Karasik. 1993. Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. Journal of Biological Chemistry 268: 26055–26058.

    PubMed  CAS  Google Scholar 

  4. Hotamisligil, G.S. 2003. Inflammatory pathways and insulin action. International Journal of Obesity and related Metabolic Disorders 27(Suppl 3): S53–S55.

    Article  PubMed  CAS  Google Scholar 

  5. Moller, D.E. 2000. Potential role of TNF-alpha in the pathogenesis of insulin resistance and type 2 diabetes. Trends in Endocrinology and Metabolism 11: 212–217.

    Article  PubMed  CAS  Google Scholar 

  6. Yuan, M., N. Konstantopoulos, J. Lee, L. Hansen, Z.W. Li, M. Karin, and S.E. Shoelson. 2001. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293: 1673–1677.

    Article  PubMed  CAS  Google Scholar 

  7. Hundal, R.S., K.F. Petersen, A.B. Mayerson, P.S. Randhawa, S. Inzucchi, S.E. Shoelson, and G.I. Shulman. 2002. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. Journal of Clinical Investigation 109: 1321–1326.

    PubMed  CAS  Google Scholar 

  8. Kuhlmann, J., C. Neumann-Haefelin, U. Belz, J. Kalisch, H.P. Juretschke, M. Stein, E. Kleinschmidt, W. Kramer, and A.W. Herling. 2003. Intramyocellular lipid and insulin resistance: a longitudinal in vivo 1 H-spectroscopic study in Zucker diabetic fatty rats. Diabetes 52: 138–144.

    Article  PubMed  CAS  Google Scholar 

  9. Dresner, A., D. Laurent, M. Marcucci, M.E. Griffin, S. Dufour, G.W. Cline, L.A. Slezak, D.K. Andersen, R.S. Hundal, D.L. Rothman, K.F. Petersen, and G.I. Shulman. 1999. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. Journal of Clinical Investigation 103: 253–259.

    Article  PubMed  CAS  Google Scholar 

  10. Cai, D., M. Yuan, D.F. Frantz, P.A. Melendez, L. Hansen, J. Lee, and S.E. Shoelson. 2005. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nature Medicine 11(2): 183–190.

    Article  PubMed  CAS  Google Scholar 

  11. Seppälä-Lindroos, A., S. Vehkavaara, A.M. Häkkinen, T. Goto, J. Westerbacka, A. Sovijärvi, J. Halavaara, and H. Yki-Järvinen. 2002. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. Journal of Clinical Endocrinology and Metabolism 87: 3023–3028.

    Article  PubMed  Google Scholar 

  12. Ryysy, L., A.M. Häkkinen, T. Goto, S. Vehkavaara, J. Westerbacka, J. Halavaara, and H. Yki-Järvinen. 2000. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes 49: 749–758.

    Article  PubMed  CAS  Google Scholar 

  13. Lau, C.W., X.Q. Yao, Z.Y. Chen, W.H. Ko, and Y. Huang. 2001. Cardiovascular actions of berberine. Cardiovascular Drug Reviews 19: 234–244.

    Article  PubMed  CAS  Google Scholar 

  14. Zhang, Y., X. Li, D. Zou, W. Liu, J. Yang, N. Zhu, L. Huo, M. Wang, J. Hong, P. Wu, G. Ren, and G. Ning. 2008. Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. Journal of Clinical Endocrinology and Metablism 93: 2559–2565.

    Article  CAS  Google Scholar 

  15. Lee, Y.S., W.S. Kim, K.H. Kim, M.J. Yoon, H.J. Cho, Y. Shen, J.M. Ye, C.H. Lee, W.K. Oh, C.T. Kim, C. Hohnen-Behrens, A. Gosby, E.W. Kraegen, D.E. James, and J.B. Kim. 2006. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55: 2256–2264.

    Article  PubMed  CAS  Google Scholar 

  16. Yin, J., R. Hu, M. Chen, J. Tang, F. Li, Y. Yang, and J. Chen. 2002. Effects of berberine on glucose metabolism in vitro. Metabolism 51: 1439–1443.

    Article  PubMed  CAS  Google Scholar 

  17. Leng, S.H., F.E. Lu, and L.J. Xu. 2004. Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacological Sinica 25: 496–502.

    CAS  Google Scholar 

  18. Ko, B.S., S.B. Choi, S.K. Park, J.S. Jang, Y.E. Kim, and S. Park. 2005. Insulin sensitizing and insulinotropic action of berberine from Coptidis Rhizoma. Biological and Pharmaceutical Bulletin 28: 1431–1437.

    Article  PubMed  CAS  Google Scholar 

  19. Jeong, H.W., K.C. Hsu, J.W. Lee, M. Ham, J.Y. Huh, H.J. Shin, W.S. Kim, and J.B. Kim. 2009. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. American Journal of Physiology-Endocrinology and Metabolism 296: 955–964.

    Article  Google Scholar 

  20. Choi, B.H., I.S. Ahn, Y.H. Kim, J.W. Park, S.Y. Lee, C.K. Hyun, and M.S. Do. 2006. Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3T3–L1 adipocyte. Experimental and Molecular Medicine 38: 599–605.

    PubMed  CAS  Google Scholar 

  21. Baldeweg, S.E., A. Golay, A. Natali, B. Balkau, S. Del Prato, and S.W. Coppack. 2000. Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR). European Journal of Clinical Investigation 30: 45–52.

    Article  PubMed  CAS  Google Scholar 

  22. Bradford, M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72: 248–254.

    Article  PubMed  CAS  Google Scholar 

  23. Bolinder, J., D.A. Kerckhoffs, E. Moberg, E. Hagstrom-Toft, and P. Arner. 2000. Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects. Diabetes 49: 797–802.

    Article  PubMed  CAS  Google Scholar 

  24. Boden, G. 1997. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46: 3–10.

    Article  PubMed  CAS  Google Scholar 

  25. Kelley, D.E., and L.J. Mandarino. 2000. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes 49: 677–683.

    Article  PubMed  CAS  Google Scholar 

  26. Lewis, G.F., A. Carpentier, K. Adeli, and A. Giacca. 2002. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocrine Reviews 23: 201–229.

    Article  PubMed  CAS  Google Scholar 

  27. Kelley, D.E., T.M. McKolanis, R.A. Hegazi, L.H. Kuller, and S.C. Kalhan. 2003. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. American Journal of Physiology 285: 906–916.

    Google Scholar 

  28. Shi, H., M.V. Kokoeva, K. Inouye, I. Tzameli, H. Yin, and J.S. Flier. 2006. TLR4 links innate immunity and fatty acid-induced insulin resistance. Journal of Clinical Investigation 116: 3015–3025.

    Article  PubMed  CAS  Google Scholar 

  29. Jeong, H.W., K.C. Hsu, J.W. Lee, M. Ham, J.Y. Huh, H.J. Shin, W.S. Kim, and J.B. Kim. 2009. Berberine suppresses pro-inflammatory responses through AMPK activation in macrophages. American Journal of Physiology-Endocrinology and Metabolism 296: E955–E964.

    Article  PubMed  CAS  Google Scholar 

  30. Senn, J.J., P.J. Klover, I.A. Nowak, and A. Robert. 2002. Mooney Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes. Diabetes 51: 3391–3399.

    Article  PubMed  CAS  Google Scholar 

  31. Hotamisligil, G.S., P. Peraldi, A. Budavari, R. Ellis, M.F. White, and B.M. Spiegelman. 1996. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α and obesity-induced insulin resistance. Science 1996(271): 665–668.

    Article  Google Scholar 

  32. Uysal, K.T., S.M. Wiesbrock, M.W. Marino, and G.S. Hotamisligil. 1997. Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389: 610–614.

    Article  PubMed  CAS  Google Scholar 

  33. Hotamisligil, G.S., A. Budavari, D. Murray, and B.M. Spiegelman. 1994. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes central role of tumor necrosis factor-α. Journal of Clinical Investigation 94: 1543–1549.

    Article  PubMed  CAS  Google Scholar 

  34. Cheung, A.T., D. Ree, J.K. Kolls, J. Fuselier, D.H. Coy, and M. Bryer-Ash. 1998. An in vivo model for elucidation of the mechanism of tumor necrosis factor—(TNF-α)-induced insulin resistance: evidence for differential regulation of insulin signaling by TNF-α. Endocrinology 139: 4928–4935.

    Article  PubMed  CAS  Google Scholar 

  35. Cheung, A.T., J. Wang, D. Ree, J.K. Kolls, and M. Bryer-Ash. 2000. Tumor necrosis factor-induces hepatic insulin resistance in obese Zucker (fa/fa) rats via interaction of leukocyte antigen-related tyrosine phosphatase with focal adhesion kinase. Diabetes 49: 810–819.

    Article  PubMed  CAS  Google Scholar 

  36. Yamada, Y., E.M. Webber, I. Kirillova, J.J. Peschon, and N. Fausto. 1998. Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. Hepatology 28: 959–970.

    Article  PubMed  CAS  Google Scholar 

  37. Campbell, J.S., L. Prichard, F. Schaper, J. Schmitz, A. Stephenson-Famy, M.E. Rosenfeld, G.M. Argast, P.C. Heinrich, and N. Fausto. 2001. Expression of suppressors of cytokine signaling during liver regeneration. Journal of Clinical Investigation 107: 1285–1292.

    Article  PubMed  CAS  Google Scholar 

  38. Senn, J.J., P.J. Klover, I.A. Nowak, and R.A. Mooney. 2002. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes 12: 3391–3399.

    Article  Google Scholar 

  39. Liu, Y.F., A. Herschkovitz, H.S. Boura, D. Ronen, K. Paz, D. Leroith, and Y. Zick. 2004. Serine phosphorylation proximal to its phosphotyrosine binding domain inhibits insulin receptor substrate 1 function and promotes insulin resistance. Molecular and Cellular Biology 24: 9668–9681.

    Article  PubMed  CAS  Google Scholar 

  40. Liu, Y.F., K. Paz, A. Herschkovitz, A. Alt, T. Tennenbaum, S.R. Sampson, M. Ohba, T. Kuroki, D. LeRoith, and Y. Zick. 2001. Insulin stimulates PKCzeta-mediated phosphorylation of insulin receptor substrate-1 (IRS-1). A self-attenuated mechanism to negatively regulate the function of IRS proteins. Journal of Biological Chemistry 276: 14459–14465.

    PubMed  CAS  Google Scholar 

  41. Park, E., V. Wong, X. Guan, A.I. Oprescu, and A. Giacca. 2007. Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo. Journal of Endocrinology 2: 323–331.

    Article  Google Scholar 

  42. Shi, Shu, Liu Xiaomei, Song Lina, Zhou Jinfang, Song Jumin. 2009. Effect of berberine on the gene expression of IRS-1/-2, p85 in 2-type diabetic rats. Zhejiang Journal of Traditional Chinese Medicine 44: 254–257.

    Google Scholar 

  43. Toker, A., and A.C. Newton. 2000. Akt/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site. Journal of Biological Chemistry 12: 8271–8274.

    Article  Google Scholar 

  44. Kim, S.H., E.J. Shin, E.D. Kim, T. Bayaraa, S.C. Frost, and C.K. Hyun. 2007. Berberine activates GLUT1-mediated glucose uptake in 3 T3-L1 adipocytes. Biological & Pharmaceutical Bulletin 30: 2120–2105.

    Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

This work is supported by grant of Medical Development Program from Nanjing Science and Technology Bureau (2KZ08031).

Author information

Authors and Affiliations

  1. Department of Gerontology, Hospital of Traditional Chinese Medicine of Nanjing, 1 Jinglin Road, Nanjing, 210001, People’s Republic of China

    Tianjiong Lou, Zhongai Zhang & Zhilei Xi

  2. Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People’s Republic of China

    Kang Liu, Lin Li, Baolin Liu & Fang Huang

Authors
  1. Tianjiong Lou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhongai Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhilei Xi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Baolin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fang Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lou, T., Zhang, Z., Xi, Z. et al. Berberine Inhibits Inflammatory Response and Ameliorates Insulin Resistance in Hepatocytes. Inflammation 34, 659–667 (2011). https://doi.org/10.1007/s10753-010-9276-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-010-9276-2

KEY WORDS

Search

Navigation