Enhanced circulating PCSK9 concentration by berberine through SREBP-2 pathway in high fat diet-fed rats

Journal of Translational Medicine

Jian-Jun Li¹  Yue Tang¹  Jing Sun¹  Rui-Xa Xu¹  Yan-Jun Jia¹ 

[1] Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China

关键词: High fat diet-fed rats;    Low density lipoprotein receptor;    Proprotein convertase subtilisin/kexin type 9;    Simvastatin;    Berberine;   

Others  :  814967
DOI  :  10.1186/1479-5876-12-103

 received in 2014-01-28, accepted in 2014-04-14,  发布年份 2014

【 摘 要 】

Background

Berberine (BBR), a natural plant extract, has been shown to improve lipid metabolism. However, its effects on PCSK9, a key factor involving in the lipid metabolism, have not yet been evaluated in vivo. The aim of the present study was to investigate the effect of BBR on PCSK9 expression in high fat diet-fed (HFD) rats.

Methods

Thirty-two male Sprague Dawley (SD) rats were randomized into the four groups (n = 8): normal diet (Control), HFD, HFD + simvastatin (Sim, 2 mg/kg/d) and HDF + BBR (400 mg/kg/d) for 6 weeks. The following parameters were determined: 1) body weight; 2) serum lipid profile; 3) serum PCSK9 measured by enzyme-linked immuno sorbent assay (ELISA) ; 4) hepatic expressions of low-density lipoprotein receptor (LDLR), sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor 1 (HNF1) were examined by real time quantitative polymerase chain reaction (RT-PCR) and western blotting analysis.

Results

Compared with HFD rats, Sim and BBR significantly reduced body weight gain and improved lipid profile (P < 0.05 respectively). In addition, either of drug treatment for 6 weeks could increase serum concentration of PCSK9 in HFD rats (P < 0.05). This enhanced PCSK9 expression was demonstrated to be associated with the up-regulation of hepatic expression of LDLR and SREBP-2 and the down-regulation of hepatic expression of HNF1 (P < 0.05 respectively).

Conclusions

The data provided the first line of the evidence that BBR, similar to the Sim, could increase the expression of PCSK9 levels in HFD rats through SREBP-2 activation, suggesting that impacts of BBR on lipid profile may also be linked to SREBP-2 pathway.

【 授权许可】

   
2014 Jia et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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【 参考文献 】

• [1]Liao FH, Shieh MJ, Yang SC, Lin SH, Chien YW: Effectiveness of a soy-based compared with a traditional low-calorie diet on weight loss and lipid levels in overweight adults. Nutrition 2007, 23:551-556.
• [2]Eckel RH, Grundy SM, Zimmet PZ: The metabolic syndrome. Lancet 2005, 365:1415-1428.
• [3]Brown MS, Goldstein JL: Receptor-mediated endocytosis: insights from the lipoprotein receptor system. Proc Natl Acad Sci U S A 1979, 76:3330-3337.
• [4]Cariou B, Le May C, Costet P: Clinical aspects of PCSK9. Atherosclerosis 2011, 216:258-265.
• [5]Kingsley DM, Krieger M: Receptor-mediated endocytosis of low density lipoprotein: somatic cell mutants define multiple genes required for expression of surface-receptor activity. Proc Natl Acad Sci U S A 1984, 81:5454-5458.
• [6]Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, Cohen JC, Hobbs HH: Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007, 282:18602-18612.
• [7]McNutt MC, Kwon HJ, Chen C, Chen JR, Horton JD, Lagace TA: Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J Biol Chem 2009, 284:10561-10570.
• [8]Li J, Tumanut C, Gavigan JA, Huang WJ, Hampton EN, Tumanut R, Suen KF, Trauger JW, Spraggon G, Lesley SA, Liau G, Yowe D, Harris JL: Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity. Biochem J 2007, 406:203-207.
• [9]Brown MS, Goldstein JL: The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997, 89:331-340.
• [10]Brown MS, Goldstein JL: A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci U S A 1999, 96:11041-11048.
• [11]Horton JD, Goldstein JL, Brown MS: SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002, 109:1125-1131.
• [12]Attie AD, Seidah NG: Dual regulation of the LDL receptor–some clarity and new questions. Cell Metab 2005, 1:290-292.
• [13]Stancu C, Sima A: Statins: mechanism of action and effects. J Cell Mol Med 2001, 5:378-387.
• [14]Guo YL, Liu J, Xu RX, Zhu CG, Wu NQ, Jiang LX, Li JJ: Short-term impact of low-dose atorvastatin on serum proprotein convertase subtilisin/kexin type 9. Clin Drug Investig 2013, 33:877-883.
• [15]Liu J, Guo YL, Xu RX, Li JJ: Rapid effects of different lipid-lowering drugs on PCSK9 in humans. Clin Lipidol 2013, 8:519-524.
• [16]Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A: Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004, 24:1454-1459.
• [17]Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao GQ, Konrad RJ: Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res 2008, 49:394-398.
• [18]Goldstein JL, Brown MS, Anderson RG, Russell DW, Schneider WJ: Receptor-mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1985, 1:1-39.
• [19]Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW: Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res 2008, 49:399-409.
• [20]Choi BH, Ahn IS, Kim YH, Park JW, Lee SY, Hyun CK, Do MS: Berberine reduces the expression of adipogenic enzymes and inflammatory molecules of 3 T3-L1 adipocyte. Exp Mol Med 2006, 38:599-605.
• [21]Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Wang Y, Li Z, Liu J, Jiang JD: Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004, 10:1344-1351.
• [22]Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, Hohnen-Behrens C, Gosby A, Kraegen EW, James DE, Kim JB: Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 2006, 55:2256-2264.
• [23]Hu Y, Davies GE: Berberine inhibits adipogenesis in high-fat diet-induced obesity mice. Fitoterapia 2010, 81:358-366.
• [24]Cabioglu MT, Ergene N: Electroacupuncture therapy for weight loss reduces serum total cholesterol, triglycerides, and LDL cholesterol levels in obese women. Am J Chin Med 2005, 33:525-533.
• [25]Wang Y, Huang Y, Hobbs HH, Cohen JC: Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR. J Lipid Res 2012, 53:1932-1943.
• [26]Alborn WE, Cao G, Careskey HE, Qian YW, Subramaniam DR, Davies J, Conner EM, Konrad RJ: Serum proprotein convertase subtilisin kexin type 9 is correlated with serum LDL cholesterol. Clin Chem 2007, 53:1814-1819.
• [27]Briggs MR, Yokoyama C, Wang X, Brown MS, Goldstein JL: Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence. J Biol Chem 1993, 268:14490-14496.
• [28]Misawa K, Horiba T, Arimura N, Hirano Y, Inoue J, Emoto N, Shimano H, Shimizu M, Sato R: Sterol regulatory element-binding protein-2 interacts with hepatocyte nuclear factor-4 to enhance sterol isomerase gene expression in hepatocytes. J Biol Chem 2003, 278:36176-36182.
• [29]Dong B, Wu M, Li H, Kraemer FB, Adeli K, Seidah NG, Park SW, Liu J: Strong induction of PCSK9 gene expression through HNF1alpha and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters. J Lipid Res 2010, 51:1486-1495.
• [30]Welder G, Zineh I, Pacanowski MA, Troutt JS, Cao G, Konrad RJ: High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res 2010, 51:2714-2721.
• [31]Li H, Chen W, Zhou Y, Abidi P, Sharpe O, Robinson WH, Kraemer FB, Liu J: Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements. J Lipid Res 2009, 50:820-831.
• [32]Cameron J, Ranheim T, Kulseth MA, Leren TP, Berge KE: Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 2008, 201:266-273.
• [33]Zhou Y, Cao S, Wang Y, Xu P, Yan J, Bin W, Qiu F, Kang N: Berberine metabolites could induce low density lipoprotein receptor up-regulation to exert lipid-lowering effects in human hepatoma cells. Fitoterapia 2014, 92:230-237.
• [34]Li H, Dong B, Park SW, Lee HS, Chen W, Liu J: Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem 2009, 284:28885-28895.