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[1]Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 68(2), 213-217 (2012)
[2]Singh J, Kakkar P. Antihyperglycemic and antioxidant effect of Berberis aristata root extract and its role in regulating carbohydrate metabolism in diabetic rats. J Ethnopharmacol 123(1), 22-26 (2009)
[3]Ko BS, Choi SB, Park SK, Jang JS, Kim YE, Park S. Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol Pharm Bull 28(8), 1431-1437 (2005)
[4]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 108(1), 109-115 (2005)
[5]Ding LB, Lu FE, Ye AL, Xu L, Wang K. (Effects of huanglian jiedu decoction on leptin and resistin in insulin resistive rats). Zhongguo Zhong Xi Yi Jie He Za Zhi 26(3), 232-235 (2006)
[6]Zhang J, Tang H, Deng R, Wang N, Zhang Y, Wang Y, Liu Y, Li F, Wang X, Zhou L. Berberine suppresses adipocyte differentiation via decreasing CREB transcriptional activity. PLoS One 10(4), eo125667 (2015)
[7]Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, Issandou M. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 47(6), 1281-1288 (2006)
[8]Xu M, Xiao Y, Yin J, Hou W, Yu X, Shen L, Liu F, Wei L, Jia W. Berberine promote glucose comsumption independently of AMP-activated protein kinase activation. PLoS One 9(7), e103702 (2014)
[9]Briand F, Thieblemont Q, Muzotte E, Sulpice T. Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters. Arterioscler Thromb Vasc Biol 33(1), 13-23 (2013)
[10]Lee S, Lim HJ, Park JH, Lee KS, Jang Y, Park HY. Berberine-induced LDLR up-regulation involves JNK pathway. Biochem Biophys Res Commun 362(4), 853-857 (2007)
[11]Ni WJ, Ding HH, Tang LQ. Berberine as a promising anti-diabetic nephropathy drug: An analysis of its effects and mechansms. Eur J Pharmacol 760, 103-112 (2015)
[12]Moghaddam HK, Baluchineiadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, Mahboobi F. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol Neurobiol 49(2), 820-826 (2014)
[13]Pierpaoli E, Damiani E, Orlando F, Lucarini G, Bartozzi B, Lombardi P, Salvatore C, Geroni C, Donati A, Provinciali M. Antiangiogenic and antitumor activity of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis 36(10), 1169-1179 (2015)
[14]Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 405 (6785), 421-424 (2000)
[15]Seedorf U, Assmann G. The role of PPAR alpha in obesity. Nutr Metab Cardiovasc Dis 11(3), 189-194 (2001)
[16]Sadana P, Zhang Y, Song S, Cook GA, Elam MB, Park EA. Regulation of carnitine palmitoyltransferase I (CPT-Ialpha) gene expression by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) isoforms. Mol Cell Endocrinol 267(1-2), 6-16 (2007)
[17]Askari B, Kanter JE, Sherrid AM, Golej DL, Bender AT, Liu J, Hsueh WA, Beavo JA, Coleman RA, Bornfeldt KE. Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes 56(4), 1143-1152 (2007)
[18]Liu PC, Huber R, Stow MD, Schlingmann KL, Collier P, Liao B, Link J, Burn TC, Hollis G, Young P R, Mukherjee R. Induction of endogenous genes by peroxisome proliferator activated receptor alpha ligands in a human kidney cell line and in vivo. J Steroid Biochem Mol Biol 85(1), 71-79 (2003)
[19]Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 273(10), 5678-5684 (1998)
[20]Oliver WR, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A 98(9), 5306-5311 (2001)
[21]Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest 97(11), 2408-2416 (1996)
[22]Murakami K, Tobe K, Ide T, Mochizuki T, Ohashi M, Akanuma Y, Yazaki Y, Kadowaki T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 47(12), 1841-1847 (1998)
[23]Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 15(19), 5336-5348 (1996)
[24]Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358 (6389), 771-774 (1992)
[25]Li C, Tian M, Yuan Y, Zhou Q. Expression of human peroxisome proliferator-activated receptors ligand binding domain-maltose binding protein fusion protein in Escherichia coli: a convenient and reliable method for preparing receptor for screening ligands. Assay Drug Dev Technol 6(6), 803-810 (2008)
[26]Kehrer JP, Biswal SS, La E, Thuillier P, Datta K, Fischer SM, Vanden Heuvel JP. Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886. Biochem J 356(Pt 3), 899-906 (2001)
[27]Ikram M. A review on the chemical and pharmacological aspects of genus Berberis. Planta Med 28(4), 353-358 (1975)
[28]Jung DW, Yoo GS, Choi JK. Detection of DNA in agarose gels using berberine and Mordant Yellow 3R. Anal Biochem 272(2), 254-256 (1999)
[29]Molero ML, Stockert JC. Fluorescence reaction of chromatin and basophilic cytoplasm by berberine sulfate. Cell Mol Biol Incl Cyto Enzymol 27(5), 523-525 (1981)
[30]Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, Staels B. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22(5), 717-726 (2002)
[31]Lavarias S, Pasquevich MY, Dreon MS, Heras H. Partial characterization of a malonyl-CoA-sensitive carnitine O-palmitoyltransferase I from Macrobrachium borellii (Crustacea: Palaemonidae). Comp Biochem Physiol B Biochem Mol Biol 152(4), 364-369 (2009)
[32]Mascaro C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem 273(15), 8560-8563 (1998)
[33]Pariente A, Avillach P, Salvo F, Thiessard F, Miremont-Salame G, Fourrier-Reqlate A, Haramburu F, Beqaud B, Moore N. Effect for competition bias in safety signal generation: analysis of a research database of spontaneous reports in France. Drug Saf 35(10), 855-864 (2012)
[34]Douros A, Bronder E, Andersohn F, Klimpel A, Thomae E, Ockenga J, Kreutz R,Garbe E. Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases. Aliment Pharmacol Ther 38(7), 825-834 (2013)
[35]Sqro C,Escousse A. (Side effects of fibtrats (except liver and muscle)). Therapie 46(5), 351-354 (1991)
[36]Lavarennne J, Poinas-Caillaud H. (Muscular involvement and fibrates. Analysis of databanks of the Frabce System of pharmacovigilance). Therapie 46(5), 347-349 (1991)
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Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.
1 Department of Pharmacology, Chongqing Medical University, Chongqing, China
2 Research Center of Neuroscience, Chongqing Medical University, Chongqing, China
Abstract
Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia.
Keywords
- Berberine
- hPPARalpha
- Agonist
- CPT-Ialpha
- Fenofibrate
References
- [1] Guo Y, Chen Y, Tan ZR, Klaassen CD, Zhou HH. Repeated administration of berberine inhibits cytochromes P450 in humans. Eur J Clin Pharmacol 68(2), 213-217 (2012)
- [2] Singh J, Kakkar P. Antihyperglycemic and antioxidant effect of Berberis aristata root extract and its role in regulating carbohydrate metabolism in diabetic rats. J Ethnopharmacol 123(1), 22-26 (2009)
- [3] Ko BS, Choi SB, Park SK, Jang JS, Kim YE, Park S. Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol Pharm Bull 28(8), 1431-1437 (2005)
- [4] 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 108(1), 109-115 (2005)
- [5] Ding LB, Lu FE, Ye AL, Xu L, Wang K. (Effects of huanglian jiedu decoction on leptin and resistin in insulin resistive rats). Zhongguo Zhong Xi Yi Jie He Za Zhi 26(3), 232-235 (2006)
- [6] Zhang J, Tang H, Deng R, Wang N, Zhang Y, Wang Y, Liu Y, Li F, Wang X, Zhou L. Berberine suppresses adipocyte differentiation via decreasing CREB transcriptional activity. PLoS One 10(4), eo125667 (2015)
- [7] Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, Issandou M. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 47(6), 1281-1288 (2006)
- [8] Xu M, Xiao Y, Yin J, Hou W, Yu X, Shen L, Liu F, Wei L, Jia W. Berberine promote glucose comsumption independently of AMP-activated protein kinase activation. PLoS One 9(7), e103702 (2014)
- [9] Briand F, Thieblemont Q, Muzotte E, Sulpice T. Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters. Arterioscler Thromb Vasc Biol 33(1), 13-23 (2013)
- [10] Lee S, Lim HJ, Park JH, Lee KS, Jang Y, Park HY. Berberine-induced LDLR up-regulation involves JNK pathway. Biochem Biophys Res Commun 362(4), 853-857 (2007)
- [11] Ni WJ, Ding HH, Tang LQ. Berberine as a promising anti-diabetic nephropathy drug: An analysis of its effects and mechansms. Eur J Pharmacol 760, 103-112 (2015)
- [12] Moghaddam HK, Baluchineiadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, Mahboobi F. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ-induced diabetic rats. Mol Neurobiol 49(2), 820-826 (2014)
- [13] Pierpaoli E, Damiani E, Orlando F, Lucarini G, Bartozzi B, Lombardi P, Salvatore C, Geroni C, Donati A, Provinciali M. Antiangiogenic and antitumor activity of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis 36(10), 1169-1179 (2015)
- [14] Kersten S, Desvergne B, Wahli W. Roles of PPARs in health and disease. Nature 405 (6785), 421-424 (2000)
- [15] Seedorf U, Assmann G. The role of PPAR alpha in obesity. Nutr Metab Cardiovasc Dis 11(3), 189-194 (2001)
- [16] Sadana P, Zhang Y, Song S, Cook GA, Elam MB, Park EA. Regulation of carnitine palmitoyltransferase I (CPT-Ialpha) gene expression by the peroxisome proliferator activated receptor gamma coactivator (PGC-1) isoforms. Mol Cell Endocrinol 267(1-2), 6-16 (2007)
- [17] Askari B, Kanter JE, Sherrid AM, Golej DL, Bender AT, Liu J, Hsueh WA, Beavo JA, Coleman RA, Bornfeldt KE. Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a peroxisome proliferator-activated receptor-gamma-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes 56(4), 1143-1152 (2007)
- [18] Liu PC, Huber R, Stow MD, Schlingmann KL, Collier P, Liao B, Link J, Burn TC, Hollis G, Young P R, Mukherjee R. Induction of endogenous genes by peroxisome proliferator activated receptor alpha ligands in a human kidney cell line and in vivo. J Steroid Biochem Mol Biol 85(1), 71-79 (2003)
- [19] Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 273(10), 5678-5684 (1998)
- [20] Oliver WR, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, Xu HE, Sternbach DD, Kliewer SA, Hansen BC, Willson TM. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A 98(9), 5306-5311 (2001)
- [21] Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest 97(11), 2408-2416 (1996)
- [22] Murakami K, Tobe K, Ide T, Mochizuki T, Ohashi M, Akanuma Y, Yazaki Y, Kadowaki T. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 47(12), 1841-1847 (1998)
- [23] Schoonjans K, Peinado-Onsurbe J, Lefebvre AM, Heyman RA, Briggs M, Deeb S, Staels B, Auwerx J. PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J 15(19), 5336-5348 (1996)
- [24] Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358 (6389), 771-774 (1992)
- [25] Li C, Tian M, Yuan Y, Zhou Q. Expression of human peroxisome proliferator-activated receptors ligand binding domain-maltose binding protein fusion protein in Escherichia coli: a convenient and reliable method for preparing receptor for screening ligands. Assay Drug Dev Technol 6(6), 803-810 (2008)
- [26] Kehrer JP, Biswal SS, La E, Thuillier P, Datta K, Fischer SM, Vanden Heuvel JP. Inhibition of peroxisome-proliferator-activated receptor (PPAR)alpha by MK886. Biochem J 356(Pt 3), 899-906 (2001)
- [27] Ikram M. A review on the chemical and pharmacological aspects of genus Berberis. Planta Med 28(4), 353-358 (1975)
- [28] Jung DW, Yoo GS, Choi JK. Detection of DNA in agarose gels using berberine and Mordant Yellow 3R. Anal Biochem 272(2), 254-256 (1999)
- [29] Molero ML, Stockert JC. Fluorescence reaction of chromatin and basophilic cytoplasm by berberine sulfate. Cell Mol Biol Incl Cyto Enzymol 27(5), 523-525 (1981)
- [30] Barbier O, Torra IP, Duguay Y, Blanquart C, Fruchart JC, Glineur C, Staels B. Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 22(5), 717-726 (2002)
- [31] Lavarias S, Pasquevich MY, Dreon MS, Heras H. Partial characterization of a malonyl-CoA-sensitive carnitine O-palmitoyltransferase I from Macrobrachium borellii (Crustacea: Palaemonidae). Comp Biochem Physiol B Biochem Mol Biol 152(4), 364-369 (2009)
- [32] Mascaro C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem 273(15), 8560-8563 (1998)
- [33] Pariente A, Avillach P, Salvo F, Thiessard F, Miremont-Salame G, Fourrier-Reqlate A, Haramburu F, Beqaud B, Moore N. Effect for competition bias in safety signal generation: analysis of a research database of spontaneous reports in France. Drug Saf 35(10), 855-864 (2012)
- [34] Douros A, Bronder E, Andersohn F, Klimpel A, Thomae E, Ockenga J, Kreutz R,Garbe E. Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases. Aliment Pharmacol Ther 38(7), 825-834 (2013)
- [35] Sqro C,Escousse A. (Side effects of fibtrats (except liver and muscle)). Therapie 46(5), 351-354 (1991)
- [36] Lavarennne J, Poinas-Caillaud H. (Muscular involvement and fibrates. Analysis of databanks of the Frabce System of pharmacovigilance). Therapie 46(5), 347-349 (1991)