Hyperlipidemias: Jiang JD

Kong WJ, Liu J, Jiang JD. · Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China. · J Mol Med. · Pubmed #16292665 No free full text.

Abstract: The low-density lipoprotein (LDL) receptor is a transmembrane glycoprotein that mediates the binding and endocytosis of lipoproteins containing apolipoprotein B and E, especially the cholesterol-rich LDL. Mutations in the LDL receptor gene can produce dysfunctional LDL receptors and cause familial hypercholesterolemia. The expression of the LDL receptor gene is under an intriguing regulation by sterol and nonsterol mediators either at the transcriptional level or at the posttranscriptional level, both of which are linked to cell signaling pathways. Upregulation of liver LDL receptor expression is effective in treating hypercholesterolemia. In this review, we focus on the latest progress on the mechanisms and regulation of the LDL receptor gene expression.

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. · Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100050, China. · Nat Med. · Pubmed #15531889 No free full text.

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.

Li YH, Yang P, Kong WJ, Wang YX, Hu CQ, Zuo ZY, Wang YM, Gao H, Gao LM, Feng YC, Du NN, Liu Y, Song DQ, Jiang JD. · Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. · J Med Chem. · Pubmed #19090767 No free full text.

Abstract: Twenty-nine derivatives of berberine (1) or pseudoberberine (2) were designed, semisynthesized, and evaluated for their up-regulatory activity on the low-density-lipoprotein receptor (LDLR) expression. SAR analysis revealed that (i) the methylenedioxy group at the 2- and 3-position is an essential element to keep the activity, (ii) the 7-position quaternary ammonium and planar structure of the compound are activity-required, and (iii) addition of electron-donating groups at the 7- or 13-position reduced the activity. Of the compound 1 analogues, compound 2 exhibited an increased activity on LDLR expression compared to 1. In the hyperlipidemic rats, compound 2 (100 (mg/kg)/day) reduced blood CHO and LDL-c by 42.6% and 49.4%, respectively, more efficient than 1 did (p < 0.01 for both). The results were confirmed in the hyperlipidemic mice. LD(50) of 2 in mice was over 5000 mg/kg (oral). We consider compound 2 a promising cholesterol-lowering drug candidate.

Yang P, Song DQ, Li YH, Kong WJ, Wang YX, Gao LM, Liu SY, Cao RQ, Jiang JD. · Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. · Bioorg Med Chem Lett. · Pubmed #18644725 No free full text.

Abstract: Berberine (BBR, 1) is a novel cholesterol-lowering agent that up-regulates low-density-lipoprotein receptor (LDLR) expression through a mechanism different from that of statins. Because of the unique mode of action and good safety record, BBR provoked our interest to do structure modification at different domains for its cholesterol-lowering activity. Nineteen BBR analogues with substituents on the benzene ring D were synthesized in the present study. The analysis of structure-activity relationship (SAR) indicated that the two methoxyl groups in an ortho-distribution on this benzene ring afforded a good activity. Among the 19 analogues, compound 8j bearing a methoxyl at both 10- and 11-position showed an increased LDLR up-regulatory activity in respect to BBR, and therefore has been selected as a promising cholesterol-lowering drug candidate for further evaluation.

Kong WJ, Wei J, Zuo ZY, Wang YM, Song DQ, You XF, Zhao LX, Pan HN, Jiang JD. · Department of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. · Metabolism. · Pubmed #18640378 No free full text.

Abstract: We have identified berberine (BBR) as a novel cholesterol-lowering drug acting through stabilization of the low-density lipoprotein receptor (LDLR) messenger RNA. Because the mechanism differs from that of statins, it is of great interest to examine the lipid-lowering activity of BBR in combination with statins. Our results showed that combination of BBR with simvastatin (SIMVA) increased the LDLR gene expression to a level significantly higher than that in monotherapies. In the treatment of food-induced hyperlipidemic rats, combination of BBR (90 mg/[kg d], oral) with SIMVA (6 mg/[kg d], oral) reduced serum LDL cholesterol by 46.2%, which was more effective than that of the SIMVA (28.3%) or BBR (26.8%) monotherapy (P < .01 for both) and similar to that of SIMVA at 12 mg/(kg d) (43.4%). More effective reduction of serum triglyceride was also achieved with the combination as compared with either monotherapy. Combination of BBR with SIMVA up-regulated the LDLR messenger RNA in rat livers to a level about 1.6-fold higher than the monotherapies did. Significant reduction of liver fat storage and improved liver histology were found after the combination therapy. The therapeutic efficacy of the combination was then evaluated in 63 hypercholesterolemic patients. As compared with monotherapies, the combination showed an improved lipid-lowering effect with 31.8% reduction of serum LDL cholesterol (P < .05 vs BBR alone, P < .01 vs SIMVA alone). Similar efficacies were observed in the reduction of total cholesterol as well as triglyceride in the patients. Our results display the rationale, effectiveness, and safety of the combination therapy for hyperlipidemia using BBR and SIMVA. It could be a new regimen for hypercholesterolemia.

Abidi P, Zhou Y, Jiang JD, Liu J. · VA Palo Alto Health Care System, Palo Alto, CA 94304, USA. · Arterioscler Thromb Vasc Biol. · Pubmed #16100034 links to  free full text

Abstract: OBJECTIVE: Our recent studies identified berberine (BBR) as a novel cholesterol-lowering drug that upregulates low-density lipoprotein (LDL) receptor expression through mRNA stabilization. Here, we investigated mechanisms underlying regulatory effects of BBR on LDL receptor (LDLR) messenger. METHODS AND RESULTS: We show that the extracellular signal-regulated kinase (ERK) signaling pathway is used primarily by BBR to attenuate the decay of LDLR mRNA in HepG2 cells. Using different reporter constructs, we demonstrate that BBR affects LDLR mRNA stability entirely through 3' untranslated region (UTR) in an ERK-dependent manner, and this stabilizing effect is more prominent in liver-derived cells than nonhepatic cell lines. In contrast to BBR, the mRNA stabilizing effect of bile acid chenodeoxycholic acid is mediated through the LDLR coding sequence, whereas the 5'UTR, 3'UTR, and the coding sequence of LDLR mRNA are all implicated in the action of phorbol 12-myristate 13-acetate. By performing UV cross-linking and SDS-PAGE, we identify 2 cytoplasmic proteins of 52 and 42 kDa that specifically bind to the LDLR 3'UTR in BBR-inducible and ERK-dependent manners. CONCLUSIONS: These new findings demonstrate that the BBR-induced stabilization of LDLR mRNA is mediated by the ERK signaling pathway through interactions of cis-regulatory sequences of 3'UTR and mRNA binding proteins that are downstream effectors of this signaling cascade.

Zhao W, Xue R, Zhou ZX, Kong WJ, Jiang JD. · No affiliation provided · Biomed Pharmacother. · Pubmed #18337056 No free full text.

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