胆固醇吸收靶点NPC1L1研究进展
Research Progress of Niemann-Pick-C1-Like 1, a Key Target Related to Cholesterol Absorption

作者: 方沐潮 , 曹乐 , 贝伟剑 :广东药学院中医药研究院,广州;

关键词: 胆固醇吸收NPC1L1中药依泽麦布Cholesterol Absorption Niemann-Pick-C1-Like 1 Traditional Chinese Medicine Ezetimibe

摘要:
NPC1L1是近年发现对胆固醇的吸收有调控作用的新靶点。在小肠内NPC1L1蛋白与胆固醇吸收直接相关。NPC1L1蛋白与相关胆固醇转运蛋白Flotillin-1和Flotillin-2相互作用,将胆固醇和其他甾醇转运通过肠上皮细胞刷状缘、运送到肠上皮细胞内。降胆固醇药物Ezetimibe正是阻断了NPC1L1和Flotillin-1和Flotillin-2的相互作用,从而抑制胆固醇吸收。NPC1L1的表达受到多个核因子如PPARs,LXRα,SREBP2,HNF4α的调控;另一方面,NPC1L1又能够通过调节细胞胆固醇水平,进而调控胆固醇代谢相关的SREBP1c、FAS和ABCA1等基因,进一步维持体内胆固醇的动态平衡。多种中药对胆固醇吸收有抑制作用,但是目前尚未发现中药直接作用于NPC1L1而抑制胆固醇吸收的报道。

Abstract:
NPC1L1 is a new found target protein in the regulation of cholesterol absorption. NPC1L1 is directly related to cholesterol absorption in the intestine. By interacting with cholesterol transport protein Flotillin-1 and Flotillin-2, NPC1L1 protein transports the cholesterol and other sterols across the intestinal epithelial brush border membrane into the intestinal epithelial cells. The cholesterol transporter function of NPC1L1 was specifically inhibited by cholesterol- lowering agent Ezetimibe via blocking the interaction. NPC1L1 expression is highly modulated by a variety of nuclear regulators such as PPARs, LXRα, SREBP2, HNF4α. NPC1L1 could otherwise regulate the related downstream genes to maintain cholesterol homeostasis via regulating cholesterol level in the related cells. A variety of traditional Chinese medicine have inhibitory effect on cholesterol absorption. It has not yet reported that Traditional Chinese Medicine could regulate cholesterol absorption by inhibiting NPC1L1.

文章引用: 方沐潮 , 曹乐 , 贝伟剑 (2013) 胆固醇吸收靶点NPC1L1研究进展。 药物资讯, 2, 19-26. doi: 10.12677/PI.2013.22005

参考文献

[1] J. D. Mulligan, M. T. Flowers, A. Tebon, et al. ABCA1 is essential for efficient basolateral cholesterol efflux during the absorption of dietary cholesterol in chickens. The Journal of Biological Chemistry, 2003, 278(15): 13356-13366.

[2] H. J. Davis, L. J. Zhu, L. M. Hoos, et al. Niemann-Pick C1-Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. The Journal of Biological Chemistry, 2004, 279(32): 33586-33592.

[3] A. T. Sane, D. Sinnett, E. Delvin, et al. Localization and role of NPC1L1 in cholesterol absorption in human intestine. The Journal of Lipid Research, 2006, 47(10): 2112-2120.

[4] L. P. Duan, H. H. Wang, A. Ohashi, et al. Role of intestinal sterol transporters Abcg5, Abcg8, and Npc1l1 in cholesterol absorption in mice: gender and age effects. Journal of Physiology-Gastro- intestinal and Liver Physiology, 2006, 290(2): G269-G276.

[5] 魏长林, 李红霞, 满永等. 肝脏表达Niemann-Pick C1-Like 1调节肝X受体诱导的小鼠胆固醇分泌[J]. 心肺血管病杂志, 2012, 5: 616-619.

[6] D. Konopka-Postupolska, G. Clark and A. Hofmann. Structure, function and membrane interactions of plant annexins: An update. Plant Science, 2011, 181(3): 230-241.

[7] V. Gerke, S. E. Moss. Annexins: From structure to function. Physiological Reviews, 2002, 82(2): 331-371.

[8] J. Benz, A. Hofmann. Annexins: From structure to function. The Journal of Biological Chemistry, 1997, 378(3-4): 177-183.

[9] A. Aqul, B. Liu, C. M. Ramirez, et al. Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegen- eration and is prevented by driving cholesterol export from this compartment. The Journal of Neuroscience, 2011, 31(25): 9404- 9413.

[10] W. S. Garver, C. Xie, J. J. Repa, et al. Niemann-Pick C1 expression is not regulated by the amount of cholesterol flowing through cells in the mouse. The Journal of Lipid Research, 2005, 46(8): 1745-1754.

[11] J. J. Repa, J. M. Dietschy and S. D. Turley. Inhibition of cholesterol absorption by SCH 58053 in the mouse is not mediated via changes in the expression of mRNA for ABCA1, ABCG5, or ABCG8 in the enterocyte. The Journal of Lipid Research, 2002, 43(11): 1864-1874.

[12] K. K. Buhman, M. Accad, S. Novak, et al. Resistance to diet- induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nature Medicine, 2000, 6(12): 1341- 1347.

[13] M. J. Latasa, M. J. Griffin, Y. S. Moon, et al. Occupancy and function of the −150 sterol regulatory element and −65 E-box in nutritional regulation of the fatty acid synthase gene in living animals. Molecular and Cellular Biology, 2003, 23(16): 5896- 5907.

[14] Y. S. Moon, M. J. Latasa, M. J. Griffin, et al. Suppression of fatty acid synthase promoter by polyunsaturated fatty acids. The Journal of Lipid Research, 2002, 43(5): 691-698.

[15] J. P. Davies, B. Levy and Y. A. Ioannou. Evidence for a Niemann-pick C (NPC) gene family: Identification and characterization of NPC1L1. Genomics, 2000, 65(2): 137-145.

[16] J. D. Horton, J. L. Goldstein and M. S. Brown. SREBPs: Transcriptional mediators of lipid homeostasis. Cold Spring Harbor Symposia on Quantitative Biology, 2002, 67: 491-498.

[17] J. D. Horton, J. L. Goldstein and M. S. Brown. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation, 2002, 109(9): 1125-1131.

[18] 曹晓钢, 于刚, 叶小利等. 中药提取物抑制胆固醇吸收的研究[J]. 中成药, 2009, 4: 616-618.

[19] 陈继承, 何国庆. 醋粉对大鼠脂质代谢调节及体外脂肪酶抑制作用研究[A]. 北京: 中国食品科学技术学会第七届年会, 2010.

[20] 王玉斌, 张惠斌, 钱海等. 单环β-内酰胺类衍生物的合成及其胆固醇吸收抑制活性[J]. 中国药科大学学报, 2011, 3: 213- 219.

[21] 赵锐, 黄文龙, 张惠斌等. 新型单环β-内酰胺类降脂药物的合成及其活性[J]. 中国药科大学学报, 2006, 6: 483-486.

[22] 冯丹, 凌文华. 姜黄素抑制Caco-2细胞胆固醇吸收的作用及机制研究[J]. 营养学报, 2011, 5: 488-491.

[23] 廖安妮, 向一, 钱振宇等. 开口箭皂苷对高脂血症小鼠动脉粥样硬化的治疗作用[J]. 中国医院药学杂志, 2009, 13: 1077- 1080.

[24] 林建维, 钟进义. 魔芋多糖对小鼠肠道吸收功能的抑制作用与机制[J]. 营养学报, 2009, 2: 164-166.

[25] 马海英, 赵志涛, 王丽娟等. 薯蓣皂苷元和黄山药总皂苷抗高脂血症作用比较[J]. 中国中药杂志, 2002, 7: 51-54.

[26] 彭罡, 覃冬云. 岩豇豆脂肪酸对高脂血症小鼠动脉粥样硬化的治疗作用[J]. 中国现代医药杂志, 2009, 10: 13-16.

[27] 粟时颖. 山(金)银花有效成分的分析和提取以及抑制巨噬细胞胆固醇蓄积作用的研究[D]. 南华大学, 2011.

[28] S. W. Altmann, H. J. Davis, L. J. Zhu, et al. Niemann-Pick C1- Like 1 protein is critical for intestinal cholesterol absorption. Science, 2004, 303(5661): 1201-1204.

[29] M. Yoshida. Novel role of NPC1L1 in the regulation of hepatic metabolism: Potential contribution of ezetimibe in NAFLD/ NASH treatment. Current Vascular Pharmacology, 2011, 9(1): 121-123.

[30] B. Klop, J. W. Elte and M. C. Cabezas. Choles-terol homeostasis and enterohepatic connection: New insights in cho-lesterol absorption. Nederlands Tijdschrift voor Geneeskunde, 2011, 155: A2503.

[31] L. Jia, J. L. Betters and L. Yu. Niemann-Pick C1-Like 1 (NPC1L1) protein in intestinal and hepatic cholesterol transport. Annual Review of Physiology, 2011, 73: 239-259.

[32] J. L. Betters, L. Yu. Transporters as drug targets: Discovery and develop-ment of NPC1L1 inhibitors. Clinical Pharmacology & Therapeutics, 2010, 87(1): 117-121.

[33] H. J. Davis, S. W. Altmann. Niemann-Pick C1-Like 1 (NPC1L1) an intestinal sterol transporter. Biochimica et Biophysica Acta, 2009, 1791(7): 679-683.

[34] M. Garcia-Calvo, J. Lisnock, H. G. Bull, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proceedings of the National Academy of Sci-ences, 2005, 102(23): 8132- 8137.

[35] S. W Altmann, H. J. Davis, X. Yao, et al. The identification of intestinal scavenger receptor class B, type I (SR-BI) by expression cloning and its role in cholesterol absorp-tion. Biochimica et Biophysica Acta, 2002, 1580(1): 77-93.

[36] A. T. Sane, D. Sinnett, E. Delvin, et al. Localization and role of NPC1L1 in cholesterol absorption in human intestine. The Journal of Lipid Re-search, 2006, 47(10): 2112-2120.

[37] H. J. Davis, F. Basso, L. M. Hoos, et al. Cholesterol homeostasis by the intestine: Lessons from Niemann-Pick C1-Like 1 [NPC1L1]. Atherosclerosis Supplements, 2008, 9(2): 77-81.

[38] H. J. Davis, L. M. Hoos, G. Tetzloff, et al. Deficiency of Niemann-Pick C1 Like 1 prevents atherosclerosis in ApoE-/-mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 2007, 27(4): 841-849.

[39] H. J. Davis, L. J. Zhu, L. M. Hoos, et al. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. The Journal of Biological Chemistry, 2004, 279(32): 33586-33592.

[40] B. E. Hawes, K. A. O’Neill, X. Yao, et al. In vivo responsiveness to ezetimibe correlates with Niemann-Pick C1-Like-1 (NPC1L1) binding affinity: Comparison of multiple species NPC1L1 orthologs. Molecular Pharmacology, 2007, 71(1): 19-29.

[41] R. E. Temel, W. Tang, Y. Ma, et al. Hepatic Niemann-Pick C1-Like 1 regu-lates biliary cholesterol concentration and is a target of ezetimibe. Journal of Clinical Investigation, 2007, 117(7): 1968-1978.

[42] Y. Yamanashi, T. Takada and H. Suzuki. Niemann-Pick C1-Like 1 over-expression facilitates ezetimibe-sensitive cholesterol and beta-sitosterol uptake in Caco-2 cells. Journal of Pharmacology and Experimental Therapeutics, 2007, 320(2): 559-564.

[43] M. T. Chhabria, B. M. Mahajan. Update on patented cholesterol absorption inhibitors. Expert Opinion on Therapeutic Patents, 2009, 19(8): 1083-1107.

[44] A. Garg, V. Simha. Update on dyslipidemia. The Journal of Clinical Endocri-nology & Metabolism, 2007, 92(5): 1581-1589.

[45] D. Q. Wang. New concepts of mechanisms of intestinal cholesterol absorption. Annals of Hepatology, 2003, 2(3): 113-121.

[46] S. D. Turley, J. M. Dietschy. Sterol absorption by the small intestine. Current Opinion in Lipidology, 2003, 14(3): 233-240.

[47] Z. Z. Li, L. Y. Wang and Z. Q. Yu. Cholesterol absorption, synthesis markers and coronary heart dis-ease. Zhonghua Xin Xue Guan Bing Za Zhi, 2009, 37(9): 857-859.

[48] H. Drexel. Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: Which drugs for which patients? Fundamental & Clinical Pharmacol-ogy, 2009, 23(6): 687-692.

[49] A. K. Soutar, R. P. Naoumova. Mechanisms of disease: Genetic causes of familial hypercholes-terolemia. Nature Clinical Practice Cardiovascular Medicine, 2007, 4(4): 214-225.

[50] J. H. Zhang, L. Ge, W. Qi, et al. The N-terminal domain of NPC1L1 protein binds cholesterol and plays essential roles in cholesterol uptake. The Journal of Biological Chemistry, 2011, 286(28): 25088-25097.

[51] B. B. Chu, L. Ge, C. Xie, et al. Require-ment of myosin Vb.Rab11a.Rab11-FIP2 complex in choles-terol-regulated translocation of NPC1L1 to the cell surface. The Journal of Biological Chemistry, 2009, 284(33): 22481-22490.

[52] L. Ge, J. Wang, W. Qi, et al. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metabolism, 2008, 7(6): 508-519.

[53] L. J. Wang, B. L. Song. Niemann-Pick C1-Like 1 and cholesterol uptake. Biochimica et Biophysica Acta, 2012, 1821(7): 964-974.

[54] F. Wang, B. L. Song, B. Yang. Therapy with Chinese medicine in Waldenstrom’s macroglobu-linemia-associated retinal detachment. Chinese Journal of Integrative Medicine, 2012, 18(1): 46- 47.

[55] E. J. Smart, R. A. De Rose and S. A. Farber. Annexin 2-caveolin 1 complex is a target of ezetimibe and regulates intestinal cholesterol transport. Proceedings of the National Academy of Sciences, 2004, 101(10): 3450-3455.

[56] H. E. Li, J. Z. Qiu, Z. Q. Yang, et al. Glycyrrhetinic acid protects mice from Staphy-lococcus aureus pneumonia. Fitoterapia, 2012, 83(1): 241-248.

[57] C. Xie, N. Li, Z. J. Chen, et al. The small GTPase Cdc42 interacts with Niemann-Pick C1-Like 1 (NPC1L1) and controls its movement from endocytic recycling compartment to plasma membrane in a choles-terol-dependent manner. The Journal of Biological Chemistry, 2011, 286(41): 35933-35942.

[58] W. J. Oliver, J. L. Shenk, M. R. Snaith, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proceedings of the National Academy of Sciences, 2001, 98(9): 5306-5311.

[59] J. N. van der Veen, J. K. Kruit, R. Havinga, et al. Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expres-sion of NPC1L1[J]. The Journal of Lipid Research, 2005, 46(3): 526-534.

[60] M. Naples, C. Baker, M. Lino, et al. Ezetimibe amelio-rates intestinal chylomicron overproduction and improves glucose tolerance in a diet-induced hamster model of insulin resistance. Journal of Physiology-Gastrointestinal and Liver Physiology, 2012, 302(9): G1043-G1052.

[61] Z. Ravid, M. Bendayan, E. Delvin, et al. Modulation of intestinal cholesterol absorption by high glucose levels: Impact on cholesterol transporters, regulatory enzymes, and transcription factors. Journal of Physiology-Gastrointestinal and Liver Physiology, 2008, 295(5): G873-G885.

[62] M. A. Valasek, S. L. Clarke and J. J. Repa. Fenofibrate reduces intestinal cholesterol absorption via PPARalpha-dependent mo- dulation of NPC1L1 expression in mouse. The Journal of Lipid Research, 2007, 48(12): 2725-2735.

[63] J. J. Repa, K. K. Buhman, R. J. Farese, et al. ACAT2 deficiency limits cholesterol absorption in the cholesterol-fed mouse: Impact on hepatic cholesterol homeostasis. Hepatology, 2004, 40(5): 1088-1097.

[64] C. Duval, V. Touche, A. Tailleux, et al. Niemann-Pick C1-Like 1 gene expression is down-regulated by LXR activators in the intestine. Biochemical and Biophysical Research Communications, 2006, 340(4): 1259-1263.

[65] J. J. Repa, D. J. Mangelsdorf. The liver X receptor gene team: Potential new players in atherosclerosis. Nature Medicine, 2002, 8(11): 1243-1248.

[66] W. Tang, L. Jia, Y. Ma, et al. Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver. Biochimica et Biophysica Acta, 2011, 1811(9): 549-555.

[67] W. Tang, Y. Ma, L. Jia, et al. Niemann-Pick C1-Like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 2008, 28(3): 448-454.

[68] J. D. Horton, J. L. Goldstein and M. S. Brown. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. Journal of Clinical Investigation, 2002, 109(9): 1125-1131.

[69] C. Pramfalk, Z. Y. Jiang and P. Parini. Hepatic Niemann-Pick C1-Like 1. Current Opinion in Lipidology, 2011, 22(3): 225- 230.

[70] C. Pramfalk, Z. Y. Jiang, Q. Cai, et al. HNF1 alpha and SREBP2 are important regulators of NPC1L1 in human liver. The Journal of Lipid Research, 2010, 51(6): 1354-1362.

[71] J. L. Goldstein, M. S. Brown. Regulation of the mevalonate pathway. Nature, 1990, 343(6257): 425-430.

[72] Y. Iwayanagi, T. Takada and H. Suzuki. HNF4 alpha is a crucial modulator of the cholesterol-dependent regulation of NPC1L1. Pharmaceutical Research, 2008, 25(5): 1134-1141.

[73] Z. Y. Jiang, C. Y. Jiang, L. Wang, et al. Increased NPC1L1 and ACAT2 expression in the jejunal mucosa from Chinese gallstone patients. Biochemical and Biophysical Research Communications, 2009, 379(1): 49-54.

[74] L. Yu, S. Bharadwaj, J. M. Brown, et al. Cholesterol-regulated translocation of NPC1L1 to the cell surface facilitates free cholesterol uptake. The Journal of Biological Chemistry, 2006, 281(10): 6616-6624.

[75] M. Halleck, H. R. Davis, P. Kirschmeier, et al. An assessment of the carcinogenic potential of ezetimibe using nonclinical data in a weight-of-evidence approach. Toxicology, 2009, 258(2-3): 116-130.

[76] 王春艳. 普洱茶抑制膳食脂肪吸收功效的研究[D]. 吉林大学, 2011.

[77] 夏晓凯, 童希琼, 张庭廷等. 柚肉黄酮降脂作用研究[J]. 中国中医药现代远程教育, 2008, 10: 1164-1165.

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