PCSK9:从生物学到临床应用
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摘要
前蛋白转化酶枯草杆菌蛋白酶9型(PCSK9)是控制低密度脂蛋白胆固醇(LDL-C)循环水平的关键蛋白,它在LDL受体(LDLR)的降解中起到关键作用。在过去的15年中,体外和体内的研究揭示了PCSK9的结构与功能,从而促进了用于临床的PCSK9抑制剂的开发。本文综述了PCSK9的结构与功能,并探讨了PCSK9/PCSK9抑制剂在临床中的应用。
The pro-protein convertase subtilisin type 9( PCSK9) is a key protein controlling the circulating level of low-density lipoprotein cholesterol( LDL-C),which plays a key role in the degradation of LDL receptors( LDLR).Over the past 15 years,in vitro and in vivo studies have revealed the structure and function of PCSK9,thereby facilitating the development of clinically used PCSK9 inhibitors. In this report,we review the structure and function of PCSK9 and explore the clinical application of PCSK9/PCSK9 inhibitors.
The pro-protein convertase subtilisin type 9( PCSK9) is a key protein controlling the circulating level of low-density lipoprotein cholesterol( LDL-C),which plays a key role in the degradation of LDL receptors( LDLR).Over the past 15 years,in vitro and in vivo studies have revealed the structure and function of PCSK9,thereby facilitating the development of clinically used PCSK9 inhibitors. In this report,we review the structure and function of PCSK9 and explore the clinical application of PCSK9/PCSK9 inhibitors.
引文
[1] Hobbs HH,Brown MS,Goldstein JL.Molecular genetics of the LDL receptor gene in familial hypercholesterolemia[J]. Hum Mutat,1992,1(6):445-466.
[2] Soutar AK,Naoumova RP.Mechanisms of disease:genetic causes of familial hypercholesterolemia[J]. Nat Clin Pract Cardiovasc Med,2007,4(4):214-225.
[3] Innerarity TL,Mahley RW,Weisgraber KH,et al.Familial defective apolipoprotein B-100:a mutation of apolipoprotein B that causes hypercholesterolemia[J].J Lipid Res,1990,31(8):1337-1349.
[4] Abifadel M,Varret M,Rabès J-P,et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia[J]. Nat Genet,2003,34(2):154-156.
[5] Timms KM,Wagner S,Samuels ME,et al. A mutation in PCSK9causing autosomal-dominant hypercholesterolemia in a Utah pedigree[J].Hum Genet,2004,114(4):349-353.
[6] Leren TP.Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia[J].Clin Genet,2004,65(5):419-422.
[7] Naoumova RP,Tosi I,Patel D,et al.Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene:long-term follow-up and treatment response[J]. Arterioscler Thromb Vasc Biol,2005,25(12):2654-2660.
[8] Humphries SE,Whittall RA,Hubbart CS,et al.Genetic causes of familial hypercholesterolaemia in patients in the UK:relation to plasma lipid levels and coronary heart disease risk[J]. J Med Genet,2006,43(12):943-949.
[9] Cohen J,Pertsemlidis A,Kotowski IK,et al.Low LDL cholesterol in individuals of African descent resulting from frequent nonsense muta-tions in PCSK9[J].Nat Genet,2005,37(2):161-165.
[10] Cohen JC,Boerwinkle E,Mosley TH,et al.Sequence variations in PCSK9,low LDL,and protection against coronary heart disease[J].N Engl J Med,2006,354(12):1264-1272.
[11] Seidah NG,Mayer G,Zaid A,et al.The activation and physiological functions of the proprotein convertases[J]. Int J Biochem Cell Biol,2008,40(6-7):1111-1125.
[12] Seidah NG,Prat A.Precursor convertases in the secretory pathway,cytosol and extracellular milieu[J].Essays Biochem,2002,38:79-94.
[13] Lambert G,Charlton F,Rye KA,et al.Molecular basis of PCSK9function[J].Atherosclerosis,2009,203(1):1-7.
[14] Cunningham D,Danley DE,Geoghegan KF,et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia[J]. Nat Struct Mol Biol,2007,14(5):413-419.
[15] Piper DE,Jackson S,Liu Q,et al.The crystal structure of PCSK9:a regulator of plasma LDL-cholesterol[J]. Structure,2007,15(5):545-552.
[16] Seidah NG,Prat A.The proprotein convertases are potential targets in the treatment of dyslipidemia[J].J Mol Med,2007,85(7):685-696.
[17] Hampton EN,Knuth MW,Li J,et al.The self-inhibited structure of full-length PCSK9 at 1. 9 A reveals structural homology with resistin within the C-terminal domain[J]. Proc Natl Acad Sci USA,2007,104(37):14604-14609.
[18] Kwon HJ,Lagace TA,Mc Nutt MC,et al.Molecular basis for LDL receptor recognition by PCSK9[J].Proc Natl Acad Sci USA,2008,105(6):1820-1825.
[19] Lagace TA,Curtis DE,Garuti G,et al.Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice[J].J Clin Invest,2006,Vol.116(11):2995-3005.
[20] Leigh SE,Foster AH,Whittall RA,et al.Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database[J]. Ann Hum Genet,2008,72(4):485-498.
[21] Jeong HJ,Lee HS,Kim KS,et al.Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterolregulatory element binding protein-2[J]. J Lipid Res,2008,49(2):399-409.
[22] Horton JD,Goldstein JL,Brown MS. SREBPs:activators of the complete program of cholesterol and fatty acid synthesis in the liver[J].J Clin Invest,2002,109(9):1125-1131.
[23] Brown MS,Goldstein JL. The SREBP pathway:regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor[J].Cell,1997,89(3):331-340.
[24] Wu CY,Tang ZH,Jiang L,et al.PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3pathway[J].Mol Cell Biochem,2012,359(1-2):347-358.
[25] Wu Q,Tang ZH,Peng J,et al.The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer's disease progression(review)[J].Biomed Rep,2014,2(2):167-171.
[26] Poupon V,Girard M,Legendre-Guillemin V,et al. Clathrin light chains function in mannose phosphate receptor trafficking via regulation of actin assembly[J]. Proc Natl Acad Sci USA,2008,105(1):168-173.
[27] Poirier S,Mayer G,Poupon V,et al.Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation:evidence for an intracellular route[J]. J Biol Chem,2009,284(42):28856-28864.
[28] Wang Y,Huang Y,Hobbs HH,et al.Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR[J].J Lipid Res,2012,53(9):1932-1943.
[29] Essalmani R,Susan-Resiga D,Chamberland A,et al. In vivo evidence that furin from hepatocytes inactivates PCSK9[J]. J Biol Chem,2006,286(6):4257-4263.
[30] Han B, Eacho PI, Knierman MD, et al. Isolation and characterization of the circulating truncated form of PCSK9[J]. J Lipid Res,2014,55(7):1505-1514.
[31] Fan D,Yance PG,Qiu S,et al.Self-association of human PCSK9correlates with its LDLR-degrading activity[J]. Biochemistry,2008,47(6):1631-1639.
[32] Cannon CP,Blazing MA,Giugliano RP,et al.Ezetimibe added to statin therapy after acute coronary syndromes[J]. N Engl J Med,2015,372(25):2387-2397.
[33] Khera AV,Natarajan P,Kathiresan S. The future of low-density lipoprotein cholesterol lowering therapy:an end to statin exceptionalism?[J]. Eur JPrev Cardiol,2016,23(10):1062-1064.
[2] Soutar AK,Naoumova RP.Mechanisms of disease:genetic causes of familial hypercholesterolemia[J]. Nat Clin Pract Cardiovasc Med,2007,4(4):214-225.
[3] Innerarity TL,Mahley RW,Weisgraber KH,et al.Familial defective apolipoprotein B-100:a mutation of apolipoprotein B that causes hypercholesterolemia[J].J Lipid Res,1990,31(8):1337-1349.
[4] Abifadel M,Varret M,Rabès J-P,et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia[J]. Nat Genet,2003,34(2):154-156.
[5] Timms KM,Wagner S,Samuels ME,et al. A mutation in PCSK9causing autosomal-dominant hypercholesterolemia in a Utah pedigree[J].Hum Genet,2004,114(4):349-353.
[6] Leren TP.Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia[J].Clin Genet,2004,65(5):419-422.
[7] Naoumova RP,Tosi I,Patel D,et al.Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene:long-term follow-up and treatment response[J]. Arterioscler Thromb Vasc Biol,2005,25(12):2654-2660.
[8] Humphries SE,Whittall RA,Hubbart CS,et al.Genetic causes of familial hypercholesterolaemia in patients in the UK:relation to plasma lipid levels and coronary heart disease risk[J]. J Med Genet,2006,43(12):943-949.
[9] Cohen J,Pertsemlidis A,Kotowski IK,et al.Low LDL cholesterol in individuals of African descent resulting from frequent nonsense muta-tions in PCSK9[J].Nat Genet,2005,37(2):161-165.
[10] Cohen JC,Boerwinkle E,Mosley TH,et al.Sequence variations in PCSK9,low LDL,and protection against coronary heart disease[J].N Engl J Med,2006,354(12):1264-1272.
[11] Seidah NG,Mayer G,Zaid A,et al.The activation and physiological functions of the proprotein convertases[J]. Int J Biochem Cell Biol,2008,40(6-7):1111-1125.
[12] Seidah NG,Prat A.Precursor convertases in the secretory pathway,cytosol and extracellular milieu[J].Essays Biochem,2002,38:79-94.
[13] Lambert G,Charlton F,Rye KA,et al.Molecular basis of PCSK9function[J].Atherosclerosis,2009,203(1):1-7.
[14] Cunningham D,Danley DE,Geoghegan KF,et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia[J]. Nat Struct Mol Biol,2007,14(5):413-419.
[15] Piper DE,Jackson S,Liu Q,et al.The crystal structure of PCSK9:a regulator of plasma LDL-cholesterol[J]. Structure,2007,15(5):545-552.
[16] Seidah NG,Prat A.The proprotein convertases are potential targets in the treatment of dyslipidemia[J].J Mol Med,2007,85(7):685-696.
[17] Hampton EN,Knuth MW,Li J,et al.The self-inhibited structure of full-length PCSK9 at 1. 9 A reveals structural homology with resistin within the C-terminal domain[J]. Proc Natl Acad Sci USA,2007,104(37):14604-14609.
[18] Kwon HJ,Lagace TA,Mc Nutt MC,et al.Molecular basis for LDL receptor recognition by PCSK9[J].Proc Natl Acad Sci USA,2008,105(6):1820-1825.
[19] Lagace TA,Curtis DE,Garuti G,et al.Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice[J].J Clin Invest,2006,Vol.116(11):2995-3005.
[20] Leigh SE,Foster AH,Whittall RA,et al.Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database[J]. Ann Hum Genet,2008,72(4):485-498.
[21] Jeong HJ,Lee HS,Kim KS,et al.Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterolregulatory element binding protein-2[J]. J Lipid Res,2008,49(2):399-409.
[22] Horton JD,Goldstein JL,Brown MS. SREBPs:activators of the complete program of cholesterol and fatty acid synthesis in the liver[J].J Clin Invest,2002,109(9):1125-1131.
[23] Brown MS,Goldstein JL. The SREBP pathway:regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor[J].Cell,1997,89(3):331-340.
[24] Wu CY,Tang ZH,Jiang L,et al.PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3pathway[J].Mol Cell Biochem,2012,359(1-2):347-358.
[25] Wu Q,Tang ZH,Peng J,et al.The dual behavior of PCSK9 in the regulation of apoptosis is crucial in Alzheimer's disease progression(review)[J].Biomed Rep,2014,2(2):167-171.
[26] Poupon V,Girard M,Legendre-Guillemin V,et al. Clathrin light chains function in mannose phosphate receptor trafficking via regulation of actin assembly[J]. Proc Natl Acad Sci USA,2008,105(1):168-173.
[27] Poirier S,Mayer G,Poupon V,et al.Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation:evidence for an intracellular route[J]. J Biol Chem,2009,284(42):28856-28864.
[28] Wang Y,Huang Y,Hobbs HH,et al.Molecular characterization of proprotein convertase subtilisin/kexin type 9-mediated degradation of the LDLR[J].J Lipid Res,2012,53(9):1932-1943.
[29] Essalmani R,Susan-Resiga D,Chamberland A,et al. In vivo evidence that furin from hepatocytes inactivates PCSK9[J]. J Biol Chem,2006,286(6):4257-4263.
[30] Han B, Eacho PI, Knierman MD, et al. Isolation and characterization of the circulating truncated form of PCSK9[J]. J Lipid Res,2014,55(7):1505-1514.
[31] Fan D,Yance PG,Qiu S,et al.Self-association of human PCSK9correlates with its LDLR-degrading activity[J]. Biochemistry,2008,47(6):1631-1639.
[32] Cannon CP,Blazing MA,Giugliano RP,et al.Ezetimibe added to statin therapy after acute coronary syndromes[J]. N Engl J Med,2015,372(25):2387-2397.
[33] Khera AV,Natarajan P,Kathiresan S. The future of low-density lipoprotein cholesterol lowering therapy:an end to statin exceptionalism?[J]. Eur JPrev Cardiol,2016,23(10):1062-1064.