Home Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function
Article
Licensed
Unlicensed Requires Authentication

Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function

  • Laili Ding , Shufeng Li , Fan Wang , Jian Xu , Shaojun Li , Bo Wang , Junjie Kou , Yongshun Wang and Wei Cao ORCID logo EMAIL logo
Published/Copyright: May 5, 2021
Biological Chemistry
From the journal Biological Chemistry Volume 402 Issue 7

Abstract

Multiple studies have showed that berberine protects against heart diseases, including obesity-associated cardiomyopathy. However, it is not fully disclosed the potential molecular mechanisms of berberine on controlling cardiac remodeling. Kruppel-like factor (KLF) 4, identified as a critical transcriptional factor, participates in multiple cardiac injuries. The present study was to explore whether KLF4 determined the cardioprotective benefits of berberine in dietary-induced obese mice. High fat diet-induced obese mice were treated with berberine with or without lentivirus encoding Klf4 siRNA, and cardiac parameters were analyzed by multiple biological approaches. In dietary-induced obese mouse model, administration of berberine obviously increased cardiac level of KLF4, which closely correlated with improvement of cardiac functional parameters. Co-treatment of lentivirus encoding Klf4 siRNA abolished cardioprotective benefits of berberine, including induction of cardiac hypertrophy, fibrosis, functional disorders, inflammatory response and oxidative stress. Mechanistically, we found berberine improved cardiac mitochondrial biogenesis and activities, whereas silencing Klf4 decreased berberine-upregulated mitochondrial quality, ATP production and oxygen consumption. Our present study demonstrated that berberine protected against dietary-induced cardiac structural disorders and mitochondrial dysfunction dependent on cardiac KLF4 signaling. Cardiac KLF4 was one of potential therapeutic targets for obesity-induced cardiac injuries.

Keywords: berberine; cardiomyopathy; Kruppel-like factor 4; mitochondria; obesity
Corresponding author: Wei Cao, Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin150001, Heilongjiang Province, China; and The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin150086, Heilongjiang Province, China, E-mail:
Laili Ding and Shufeng Li contributed equally to this work.

Funding source: Young and middle-aged innovation science foundation from Second Affiliated Hospital of Harbin Medical University

Award Identifier / Grant number: KYCX2018-24

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: 81800269 81800362

Funding source: Harbin Medical University

Acknowledgments

This work was supported through grants from National Natural Science Foundation of China (81800269 and 81800362) and young and middle-aged innovation science foundation from Second Affiliated Hospital of Harbin Medical University (KYCX2018-24).

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

Bayeva, M., Gheorghiade, M., and Ardehali, H. (2013). Mitochondria as a therapeutic target in heart failure. J. Am. Coll. Cardiol. 61: 599–610, https://doi.org/10.1016/j.jacc.2012.08.1021.Search in Google Scholar PubMed PubMed Central

Brustovetsky, N., Brustovetsky, T., Purl, K.J., Capano, M., Crompton, M., and Dubinsky, J.M. (2003). Increased susceptibility of striatal mitochondria to calcium-induced permeability transition. J. Neurosci. 23: 4858–4867, https://doi.org/10.1523/jneurosci.23-12-04858.2003.Search in Google Scholar

Chang, W., Chen, L., and Hatch, G.M. (2015a). Berberine as a therapy for type 2 diabetes and its complications: from mechanism of action to clinical studies. Biochem. Cell. Biol. 93: 479–486, https://doi.org/10.1139/bcb-2014-0107.Search in Google Scholar PubMed

Chang, W., Zhang, M., Chen, L., and Hatch, G.M. (2017). Berberine inhibits oxygen consumption rate independent of alteration in cardiolipin levels in H9c2 cells. Lipids 52: 961–967, https://doi.org/10.1007/s11745-017-4300-z.Search in Google Scholar PubMed

Chang, W., Zhang, M., Meng, Z., Yu, Y., Yao, F., Hatch, G.M., and Chen, L. (2015b). Berberine treatment prevents cardiac dysfunction and remodeling through activation of 5’-adenosine monophosphate-activated protein kinase in type 2 diabetic rats and in palmitate-induced hypertrophic H9c2 cells. Eur. J. Pharmacol. 769: 55–63, https://doi.org/10.1016/j.ejphar.2015.10.043.Search in Google Scholar PubMed

Chen, Y., Chen, C., Dong, B., Xing, F., Huang, H., Yao, F., Ma, Y., He, J., and Dong, Y. (2017). AMPK attenuates ventricular remodeling and dysfunction following aortic banding in mice via the Sirt3/Oxidative stress pathway. Eur. J. Pharmacol. 814: 335–342, https://doi.org/10.1016/j.ejphar.2017.08.042.Search in Google Scholar PubMed

Chen, K., Li, G., Geng, F., Zhang, Z., Li, J., Yang, M., Dong, L., and Gao, F. (2014). Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K-Akt signaling in diabetic rats. Apoptosis 19: 946–957, https://doi.org/10.1007/s10495-014-0977-0.Search in Google Scholar PubMed

Cheng, Z., Pang, T., Gu, M., Gao, A.H., Xie, C.M., Li, J.Y., Nan, F.J., and Li, J. (2006). Berberine-stimulated glucose uptake in L6 myotubes involves both AMPK and p38 MAPK. Biochim. Biophys. Acta 1760: 1682–1689, https://doi.org/10.1016/j.bbagen.2006.09.007.Search in Google Scholar PubMed

Daskalopoulos, E.P., Dufeys, C., Bertrand, L., Beauloye, C., and Horman, S. (2016). AMPK in cardiac fibrosis and repair: actions beyond metabolic regulation. J. Mol. Cell. Cardiol. 91: 188–200, https://doi.org/10.1016/j.yjmcc.2016.01.001.Search in Google Scholar PubMed

Di Pierro, F., Bellone, I., Rapacioli, G., and Putignano, P. (2015). Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins. Diabetes Metab. Syndrome Obes. Targets Ther. 8: 89–96, https://doi.org/10.2147/dmso.s78877.Search in Google Scholar

Edgley, A.J., Krum, H., and Kelly, D.J. (2012). Targeting fibrosis for the treatment of heart failure: a role for transforming growth factor-β. Cardiovasc. Ther. 30: e30–e40. https://doi.org/10.1111/j.1755-5922.2010.00228.x.Search in Google Scholar PubMed

Fisch, S., Gray, S., Heymans, S., Haldar, S.M., Wang, B., Pfister, O., Cui, L., Kumar, A., Lin, Z., Sen-Banerjee, S., et al. (2007). Kruppel-like factor 15 is a regulator of cardiomyocyte hypertrophy. Proc. Natl. Acad. Sci. U. S. A. 104: 7074–7079, https://doi.org/10.1073/pnas.0701981104.Search in Google Scholar PubMed PubMed Central

Fukushima, A. and Lopaschuk, G.D. (2016). Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes. Biochim. Biophys. Acta 1861: 1525–1534, https://doi.org/10.1016/j.bbalip.2016.03.020.Search in Google Scholar PubMed

Ghaleb, A.M., Laroui, H., Merlin, D., and Yang, V.W. (2014). Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate-induced colitis by modulating the NF-κB pathway inflammatory response. Inflamm. Bowel Dis. 20: 811–820, https://doi.org/10.1097/mib.0000000000000022.Search in Google Scholar PubMed PubMed Central

Goldberg, I.J., Reue, K., Abumrad, N.A., Bickel, P.E., Cohen, S., Fisher, E.A., Galis, Z.S., Granneman, J.G., Lewandowski, E.D., Murphy, R., et al. (2018). Deciphering the role of lipid droplets in cardiovascular disease: a report from the 2017 National heart, Lung, and Blood institute Workshop. Circulation 138: 305–315, https://doi.org/10.1161/circulationaha.118.033704.Search in Google Scholar PubMed PubMed Central

Gomes, A.P., Duarte, F.V., Nunes, P., Hubbard, B.P., Teodoro, J.S., Varela, A.T., Jones, J.G., Sinclair, D.A., Palmeira, C.M., and Rolo, A.P. (2012). Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim. Biophys. Acta 1822: 185–195, https://doi.org/10.1016/j.bbadis.2011.10.008.Search in Google Scholar PubMed PubMed Central

Ha, H., Hajek, P., Bedwell, D.M., and Burrows, P.D. (1993). A mitochondrial porin cDNA predicts the existence of multiple human porins. J. Biol. Chem. 268: 12143–12149, https://doi.org/10.1016/s0021-9258(19)50319-2.Search in Google Scholar

Hartmann, P., Zhou, Z., Natarelli, L., Wei, Y., Nazari-Jahantigh, M., Zhu, M., Grommes, J., Steffens, S., Weber, C., and Schober, A. (2016). Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4. Nat. Commun. 7: 10521, https://doi.org/10.1038/ncomms10521.Search in Google Scholar PubMed PubMed Central

Horie, T., Ono, K., Nagao, K., Nishi, H., Kinoshita, M., Kawamura, T., Wada, H., Shimatsu, A., Kita, T., and Hasegawa, K. (2008). Oxidative stress induces GLUT4 translocation by activation of PI3-K/Akt and dual AMPK kinase in cardiac myocytes. J. Cell. Physiol. 215: 733–742, https://doi.org/10.1002/jcp.21353.Search in Google Scholar PubMed

Jin, L., Ye, H., Pan, M., Chen, Y., Ye, B., Zheng, Y., Huang, W., Pan, S., Shi, Z., and Zhang, J. (2019). Kruppel-like factor 4 improves obesity-related nephropathy through increasing mitochondrial biogenesis and activities. J. Cell Mol. Med. 24: 1200–1207, https://doi.org/10.1111/jcmm.14628.Search in Google Scholar PubMed PubMed Central

Jouven, X., Charles, M.A., Desnos, M., and Ducimetiere, P. (2001). Circulating nonesterified fatty acid level as a predictive risk factor for sudden death in the population. Circulation 104: 756–761, https://doi.org/10.1161/hc3201.094151.Search in Google Scholar PubMed

Kee, H.J., and Kook, H. (2009). Kruppel-like factor 4 mediates histone deacetylase inhibitor-induced prevention of cardiac hypertrophy. J. Mol. Cell. Cardiol. 47: 770–780, https://doi.org/10.1016/j.yjmcc.2009.08.022.Search in Google Scholar PubMed

Kim, W.S., Lee, Y.S., Cha, S.H., Jeong, H.W., Choe, S.S., Lee, M.R., Oh, G.T., Park, H.S., Lee, K.U., Lane, M.D., et al. (2009). Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am. J. Physiol. Endocrinol. Metab. 296: E812–819, https://doi.org/10.1152/ajpendo.90710.2008.Search in Google Scholar PubMed

Lavallee, G., Andelfinger, G., Nadeau, M., Lefebvre, C., Nemer, G., Horb, M.E., and Nemer, M. (2006). The Kruppel-like transcription factor KLF13 is a novel regulator of heart development. EMBO J. 25: 5201–5213, https://doi.org/10.1038/sj.emboj.7601379.Search in Google Scholar PubMed PubMed Central

Li, M.H., Zhang, Y.J., Yu, Y.H., Yang, S.H., Iqbal, J., Mi, Q.Y., Li, B., Wang, Z.M., Mao, W.X., Xie, H.G., et al. (2014). Berberine improves pressure overload-induced cardiac hypertrophy and dysfunction through enhanced autophagy. Eur. J. Pharmacol. 728: 67–76, https://doi.org/10.1016/j.ejphar.2014.01.061.Search in Google Scholar PubMed

Liao, X., Haldar, S.M., Lu, Y., Jeyaraj, D., Paruchuri, K., Nahori, M., Cui, Y., Kaestner, K.H., and Jain, M.K. (2010). Kruppel-like factor 4 regulates pressure-induced cardiac hypertrophy. J. Mol. Cell. Cardiol. 49: 334–338, https://doi.org/10.1016/j.yjmcc.2010.04.008.Search in Google Scholar PubMed PubMed Central

Liao, X., Zhang, R., Lu, Y., Prosdocimo, D.A., Sangwung, P., Zhang, L., Zhou, G., Anand, P., Lai, L., Leone, T.C., et al. (2015). Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis. J. Clin. Invest. 125: 3461–3476, https://doi.org/10.1172/jci79964.Search in Google Scholar

Mann, J.I. (2002). Diet and risk of coronary heart disease and type 2 diabetes. Lancet 360: 783–789, https://doi.org/10.1016/s0140-6736(02)09901-4.Search in Google Scholar PubMed

Marin-Neto, J.A., Maciel, B.C., Secches, A.L., and Gallo Junior, L. (1988). Cardiovascular effects of berberine in patients with severe congestive heart failure. Clin. Cardiol. 11: 253–260, https://doi.org/10.1002/clc.4960110411.Search in Google Scholar PubMed

Nie, H., Pan, Y., and Zhou, Y. (2018). Exosomal microRNA-194 causes cardiac injury and mitochondrial dysfunction in obese mice. Biochem. Biophys. Res. Commun. 503: 3174–3179, https://doi.org/10.1016/j.bbrc.2018.08.113.Search in Google Scholar PubMed

Pan, Y., Hui, X., Hoo, R.L.C., Ye, D., Chan, C.Y.C., Feng, T., Wang, Y., Lam, K.S.L., and Xu, A. (2019). Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J. Clin. Invest. 129: 834–849. https://doi.org/10.1172/jci123069.Search in Google Scholar

Pan, Y., Wang, Y., Zhao, Y., Peng, K., Li, W., Wang, Y., Zhang, J., Zhou, S., Liu, Q., Li, X., et al. (2014). Inhibition of JNK phosphorylation by a novel curcumin analog prevents high glucose-induced inflammation and apoptosis in cardiomyocytes and the development of diabetic cardiomyopathy. Diabetes 63: 3497–3511, https://doi.org/10.2337/db13-1577.Search in Google Scholar PubMed

Pan, Y., Zhu, G., Wang, Y., Cai, L., Cai, Y., Hu, J., Li, Y., Yan, Y., Wang, Z., Li, X., Wei, T., and Liang, G. (2013). Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart. J. Nutr. Biochem. 24: 146–155, https://doi.org/10.1016/j.jnutbio.2012.03.012.Search in Google Scholar PubMed

Pearson, R., Fleetwood, J., Eaton, S., Crossley, M., and Bao, S. (2008). Kruppel-like transcription factors: a functional family. Int. J. Biochem. Cell Biol. 40: 1996–2001, https://doi.org/10.1016/j.biocel.2007.07.018.Search in Google Scholar PubMed

Qin, S., Liu, M., Niu, W., and Zhang, C.L. (2011). Dysregulation of Kruppel-like factor 4 during brain development leads to hydrocephalus in mice. Proc. Natl. Acad. Sci. U. S. A. 108: 21117–21121, https://doi.org/10.1073/pnas.1112351109.Search in Google Scholar PubMed PubMed Central

Segura, A.M., Frazier, O.H., and Buja, L.M. (2014). Fibrosis and heart failure. Heart Fail. Rev. 19: 173–185, https://doi.org/10.1007/s10741-012-9365-4.Search in Google Scholar PubMed

Tsui, H., Zi, M., Wang, S., Chowdhury, S.K., Prehar, S., Liang, Q., Cartwright, E.J., Lei, M., Liu, W., and Wang, X. (2015). Smad3 couples Pak1 with the antihypertrophic pathway through the E3 ubiquitin ligase, Fbxo32. Hypertension 66: 1176–1183, https://doi.org/10.1161/hypertensionaha.115.06068.Search in Google Scholar PubMed

Van Gaal, L.F., Mertens, I.L., and De Block, C.E. (2006). Mechanisms linking obesity with cardiovascular disease. Nature 444: 875–880, https://doi.org/10.1038/nature05487.Search in Google Scholar PubMed

Wild, S., Roglic, G., Green, A., Sicree, R., and King, H. (2004). Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053, https://doi.org/10.2337/diacare.27.5.1047.Search in Google Scholar PubMed

Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R.C., et al. (1999). Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98: 115–124, https://doi.org/10.1016/s0092-8674(00)80611-x.Search in Google Scholar PubMed

Zhou, Q., Hong, Y., Zhan, Q., Shen, Y., and Liu, Z. (2009). Role for Kruppel-like factor 4 in determining the outcome of p53 response to DNA damage. Cancer Res. 69: 8284–8292. https://doi.org/10.1158/0008-5472.can-09-1345.Search in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0267).

Received: 2020-07-30
Accepted: 2021-01-06
Published Online: 2021-05-05
Published in Print: 2021-06-25

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Research Articles/Short Communications
  3. Protein Structure and Function
  4. Structural and kinetic characterization of Porphyromonas gingivalis glutaminyl cyclase
  5. Molecular Medicine
  6. Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies
  7. Carotenoids in Sporidiobolus pararoseus ameliorate diabetic nephropathy in mice through attenuating oxidative stress
  8. Cell Biology and Signaling
  9. Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function
  10. Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway
  11. JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells
  12. Modulation of recombinant human alpha 1 glycine receptor by flavonoids and gingerols
  13. IL-24 inhibits the malignancy of human glioblastoma cells via destabilization of Zeb1
  14. Glycation of benign meningioma cells leads to increased invasion
  15. Proteolysis
  16. Marked difference in efficiency of the digestive enzymes pepsin, trypsin, chymotrypsin, and pancreatic elastase to cleave tightly folded proteins
https://doi.org/10.1515/hsz-2020-0267
Keywords for this article
berberine; cardiomyopathy; Kruppel-like factor 4; mitochondria; obesity

Articles in the same Issue

  1. Frontmatter
  2. Research Articles/Short Communications
  3. Protein Structure and Function
  4. Structural and kinetic characterization of Porphyromonas gingivalis glutaminyl cyclase
  5. Molecular Medicine
  6. Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies
  7. Carotenoids in Sporidiobolus pararoseus ameliorate diabetic nephropathy in mice through attenuating oxidative stress
  8. Cell Biology and Signaling
  9. Berberine improves dietary-induced cardiac remodeling by upregulating Kruppel-like factor 4-dependent mitochondrial function
  10. Decreased level of miR-1301 promotes colorectal cancer progression via activation of STAT3 pathway
  11. JMJD3-regulated expression of IL-6 is involved in the proliferation and chemosensitivity of acute myeloid leukemia cells
  12. Modulation of recombinant human alpha 1 glycine receptor by flavonoids and gingerols
  13. IL-24 inhibits the malignancy of human glioblastoma cells via destabilization of Zeb1
  14. Glycation of benign meningioma cells leads to increased invasion
  15. Proteolysis
  16. Marked difference in efficiency of the digestive enzymes pepsin, trypsin, chymotrypsin, and pancreatic elastase to cleave tightly folded proteins
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 24.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2020-0267/html
Scroll to top button