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我国学者在nature medicine 发表黄连素降胆固醇药理
Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins
Weijia Kong1, 5, Jing Wei2, 5, Parveen Abidi3, 5, Meihong Lin3, Satoru Inaba3, Cong Li3, Yanling Wang4, Zizheng Wang2, Shuyi Si1, Huaining Pan2, Shukui Wang2, Jingdan Wu2, Yue Wang4, Zhuorong Li1, Jingwen Liu3 & Jian-Dong Jiang1, 4
1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100050, China.
2 Division of Endocrinology and Laboratory of Molecular Medicine, First Hospital of Nanjing City, Nanjing Medical University, Nanjing, 210006, China.
3 Research Service, Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
4 Department of Medicine, Mount Sinai School of Medicine, New York, NY, 10029, USA.
5 These authors contributed equally to this work.
Correspondence should be addressed to Jingwen Liu jingwen.liu@med.va.gov or Jian-Dong Jiang jiandong.jiang@mssm.edu
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.
The expression of liver low-density lipoprotein receptor (LDLR) regulates human plasma LDL cholesterol (LDL-c) homeostasis1, 2. Increased hepatic LDLR expression results in improved clearance of plasma LDL-c through receptor-mediated endocytosis, which has been strongly associated with a decreased risk of developing cardiovascular disease in humans3, 4. LDLR expression is predominantly regulated at the transcriptional level through a negative feedback mechanism by the intracellular cholesterol pool. This regulation is controlled through specific interactions of sterol-regulatory element (SRE-1) of the LDLR promoter5, 6 and SRE binding proteins (SREBPs)7, 8, 9. In the inactive state, SREBP resides in the endoplasmic reticulum (ER) and associates with another transmembrane protein, SREBP-cleavage activating protein (SCAP) which provides conditional chaperone activity to the SREBP10, 11, 12. SCAP contains a cholesterol-sensing domain, which responds to the depletion of sterol with activation of the SCAP-SREBP transporting activity13, 14, 15. Under cholesterol-depleted conditions, SCAP transports SREBP to the Golgi apparatus, where the N-terminal transcription activation domain of the SREBP is released from the precursor protein through specific cleavages11. The active form of the SREBP translocates to the nucleus, binds to its cognate SRE-1 site and activates transcription of the LDLR gene. In contrast, under cholesterol-replete conditions, the SCAP-SREBP complex remains in an inactive form in the ER through active repression by sterols and LDLR gene transcription is maintained at a minimal constitutive level.
Clinically, statins have been the most widely prescribed drugs for hypercholesterolemia3, 4. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Inhibition of cholesterol biosynthesis leads to a depletion of intracellular cholesterol and an activation of the SCAP-SREBP transporting activity, thereby resulting in upregulation of the LDLR and subsequent lowering of the LDL-c in blood. Statins effectively lower the plasma concentration of LDL-c and reduce mortality and morbidity from coronary artery disease16, 17. Recent studies showed additional benefits of statin beyond its cholesterol-lowering effects18. But despite the success of treatment with statins, there is a need for new therapies to reduce LDL-c. Some patients do not tolerate statins well, and more importantly, many patients under statin treatment alone do not achieve the LDL-c goal suggested by the US National Institutes of Health guidelines19. Therefore, for the treatment of hypercholesterolemia, it is desirable to develop other therapeutic interventions that increase hepatic LDLR expression by mechanisms distinct from the current statin therapy.
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作者:admin@医学,生命科学 2010-11-05 17:11
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