674
Views
13
CrossRef citations to date
0
Altmetric
Review Article

Molecular pathology of familial hypercholesterolemia, related dyslipidemias and therapies beyond the statins

, &
Pages 1-17 | Received 04 Nov 2011, Accepted 02 Dec 2011, Published online: 04 Jan 2012

References

  • Kwiterovich PO. Clinical implications of the molecular basis of familial hypercholesterolemia and other inherited dyslipidemias. Circulation 2011;123:1153–1155.
  • Taylor F, Ward K, Moore T, Burke M, Davey Smith G, Casas J., et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systemic Rev 2011. Available from: http://www.update-software.com/BCP/WileyPDF/EN/CD004816.pdf. Accessed on 21 November 2011..
  • Visiongain. Statins: World Market Outlook 2011–2021. New York, EC1V 2QY, United Kingdom 2011. Available from: http://www.visiongain.com/Report/581/Statins-World-Market-Outlook-2011–2021. Accessed on 21 November 2011.
  • Huijgen R, Kindt I, Verhoeven SBJ, Sijbrands EJG, Vissers MN, Kastelein JJP, et al. Two years after molecular diagnosis of familial hypercholesterolemia: majority on cholesterol-lowering treatment but a minority reaches treatment goal. PloS One 2010;5:e9220.
  • Sawicki P. Statins and diabetes – the lipid hypothesis revisited. European Association for the Study of Diabetes 47th Annual Meeting, 08 October 2011; Lisbon Portugal; 2011. Available from: http://www.incirculation.net/3430_119403.aspx?parentaid = 119273. Accessed on 21 November 2011.
  • Goldstein JL, Brown MS. Binding and degradation of low density lipoproteins by cultured human fibroblasts. J Biol Chem 1974;249:5153–5162.
  • Sudhof TC, Goldstein JL, Brown MS, Russell DW. The LDL receptor gene: a mosaic of exons shared with different proteins. Science 1985;228:815–822.
  • Yamamoto T, Davis CG, Brown MS, Schneider WJ, Casey ML, Goldstein JL, et al. The human LDL receptor: a cysteine-rich protein with multiple Alu sequences in its mRNA. Cell 1984;39:27–38.
  • Black DL. Mechanisms of alternative pre-messenger splicing Annu Rev Biochem 2003;72:291–336.
  • Staley JP, Guthrie C. Mechanical devices of the spliceosome: review motors, clocks, springs, and things. Cell 1998;92:315–326.
  • Soutar AK. Regulation of the LDL receptor in familial hypercholesterolemia. Clin Lipidol 2009;4:755–765.
  • Rudenko G, Henry L, Henderson K, Ichtchenko K, Brown MS, Goldstein JL, et al. Structure of the LDL receptor extracellular domain at endosomal pH. Science 2002;298:2353–2358.
  • Hussain MM, Strickland DK, Bakillah A. The mammalian low-density lipoprotein receptor family. Annu Rev Nutr 1999;19:141–172.
  • Kirchhausen T. Clathrin. Annu Rev Biochem 2000;69:699–727.
  • Chen WJ, Goldstein JL, Brown MS. NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor. J Biol Chem 1990;265:3116–3123.
  • Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, et al. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: Informa Healthcare,2001:2863–2913.
  • van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, et al. Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. Circulation 2011;123:1167–1173.
  • Burnett JR, Ravine D, van Bockxmeer FM, Watts GF. Familial hypercholesterolaemia: a look back, a look ahead. Med J Aust 2005;182:552–553.
  • Wierzbicki AS, Graham CA, Young IS, Nicholls DP. Familial combined hyperlipidaemia: under-defined and under-diagnosed? Curr Vasc Pharmacol 2008;6:13–22.
  • Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 2003;111:1795–1804.
  • Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993;72:171–176.
  • Pisciotta L, Oliva CP, Pes GM, Di Scala L, Bellocchio A, Fresa R, et al. Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison. Atherosclerosis 2006;188:398–405.
  • Defesche J, Stephenson S, Kostner G, Hegele R, Gaudet D, Freiberger T, et al. Familial hypercholesterolemia (FH). Report of a second WHO consultation, Geneva, 4 September 1998. Geneva: World Health Organisation: 1999. WHO/HGN/FH/CONS/99.2. http://whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf. Accessed on 21 November 2011.
  • Betteridge D. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. Br Med J 1991;303:893–896.
  • Liyanage KE, Burnett JR, Hooper AJ, van Bockxmeer FM. Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution. Crit Rev Clin Lab Sci 2011;48:1–18.
  • Russell DW. Cholesterol biosynthesis and metabolism. Cardiovasc Drugs Therapy 1992;6:103–110.
  • Dietschy JM. Regulation of cholesterol metabolism in man and in other species. J Mol Med 1984;62:338–345.
  • Edwards PA, Fogelman AM. Studies on purified mammalian HMG-CoA reductase and regulation of enzyme activity. In: Preiss B ed Regulation of HMG-CoA Reductase. Orlando: Academic Press, 1985:133–148.
  • Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 1990;343:425–430.
  • Laws P, Spark J, Cowled P, Fitridge RA. The role of statins in vascular disease. Eur J Vasc Endovasc Surgery 2004;27:6–16.
  • Espenshade PJ, Hughes AL. Regulation of sterol synthesis in eukaryotes. Annu Rev Genet 2007;41:401–427.
  • Wang DQH. Regulation of intestinal cholesterol absorption. Annu Rev Physiol 2007;69:221–248.
  • Graf GA, Li WP, Gerard RD, Gelissen I, White A, Cohen JC, et al. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J Clin Invest 2002;110:659–670.
  • Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000;290:1771–1775.
  • Garcia-Calvo M, Lisnock JM, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci USA 2005;102:8132–8137.
  • Patterson MC, Vanier MT, Suzuki K, Morris JA, Carstea E, Neufeld EB, et al. Niemann-Pick disease type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW et al., The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw Hill. 2001;3:3611–3633.
  • Marais AD. Familial hypercholesterolaemia. Clin Biochem Rev 2004;25:49–68.
  • Nguyen P, Leray V, Diez M, Serisier S, Bloc’h JL, Siliart B, et al. Liver lipid metabolism. J Anim Physiol Anim Nutr 2008;92:272–283.
  • White DA, Bennett AJ, Billett MA, Salter AM. The assembly of triacylglycerol-rich lipoproteins: an essential role for the microsomal triacylglycerol transfer protein. Br J Nutr 1998;80:219–229.
  • Daniels TF, Killinger KM, Michal JJ, Wright RW Jr, Jiang Z. Lipoproteins, cholesterol homeostasis and cardiac health. Int J Biol Sci 2009;5:474–488.
  • Babin PJ, Gibbons GF. The evolution of plasma cholesterol: Direct utility or a “spandrel” of hepatic lipid metabolism? Prog Lipid Res 2009;48:73–91.
  • Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW, Brown MS, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA 2003;100:12027–12033.
  • Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA 1993;90:11603–11607.
  • Yokoyama C, Wang X, Briggs MR, Admon A, Wu J, Hua X, et al. SREBP-1, a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene. Cell 1993;75:187–197.
  • Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 1997;99:846–854.
  • Sato R, Yang J, Wang X, Evans MJ, Ho Y, Goldstein JL, et al. Assignment of the membrane attachment, DNA binding, and transcriptional activation domains of sterol regulatory element-binding protein-1 (SREBP-1). J Biol Chem 1994;269:17267–17273.
  • 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;109:1125–1132.
  • Shimano H. Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Prog Lipid Res 2001;40:439–452.
  • Südhof TC, Van der Westhuyzen DR, Goldstein JL, Brown MS, Russell DW. Three direct repeats and a TATA-like sequence are required for regulated expression of the human low density lipoprotein receptor gene. J Biol Chem 1987;262:10773–10779.
  • 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.
  • Sanchez HB, Yieh L, Osborne TF. Cooperation by sterol regulatory element-binding protein and Sp1 in sterol regulation of low density lipoprotein receptor gene. J Biol Chem 1995;270:1161–1169.
  • Leigh SEA, Foster AH, Whittall RA, Hubbart CS, Humphries SE. Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 2008;72:485–498.
  • Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 2009;325:100–104.
  • Baranowski M. Biological role of liver X receptors. J Physiol Pharmacol 2008;59:31–55.
  • Russell DW, Setchell KDR. Bile acid biosynthesis. Biochemistry 1992;31:4737–4749.
  • Kuipers F, Stroeve JHM, Caron S, Staels B. Bile acids, farnesoid X receptor, atherosclerosis and metabolic control. Curr Opin Lipidol 2007;18:289–297.
  • Costet P. Molecular pathways and agents for lowering LDL-cholesterol in addition to statins. Pharmacol Ther 2010;126:263–278.
  • Varret M, Abifadel M, Rabès J. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet 2008;73:1–13.
  • Bourbon M, Duarte MA, Alves AC, Medeiros AM, Marques L, Soutar AK. Genetic diagnosis of familial hypercholesterolaemia: the importance of functional analysis of potential splice-site mutations. J Med Genet 2009;46:352–357.
  • Cartegni L, Chew SL, Krainer AR. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet 2002;3:285–298.
  • Liguori R, Argiriou A, Simone VD. A rapid method for detecting mutations of the human LDL receptor gene by complete cDNA sequencing. Mol Cell Probes 2003;17:15–20.
  • Cameron J, Holla L, Kulseth MA, Leren TP, Berge KE. Splice-site mutation c. 313 + 1, G > A in intron 3 of the LDL receptor gene results in transcripts with skipping of exon 3 and inclusion of intron 3. Clin Chim Acta 2009;403:131–135.
  • Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. Genome Biol 2002;3:0004.0001-0004.0010.
  • Bashirullah A, Cooperstock RL, Lipshitz HD. Spatial and temporal control of RNA stability. Proc Natl Acad Sci USA 2001;98:7025–7028.
  • van Der Velden AW, Thomas AAM. The role of the 5′untranslated region of an mRNA in translation regulation during development. Int J Biochem Cell Biol 1999;31:87–106.
  • Jansen RP. mRNA localization: message on the move. Nat Rev Mol Cell Biol 2001;2:247–256.
  • Chen JM, Férec C, Cooper DN. A systematic analysis of disease-associated variants in the 3 regulatory regions of human protein-coding genes I: general principles and overview. Hum Genet 2006;120:1–21.
  • Wilson GM, Vasa MZ, Deeley RG. Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3 untranslated region. J Lipid Res 1998;39:1025–1032.
  • Muallem H, North KE, Kakoki M, Wojczynski MK, Li X, Grove M, et al. Quantitative effects of common genetic variations in the 3 UTR of the human LDL-receptor gene and their associations with plasma lipid levels in the Atherosclerosis Risk in Communities study. Hum Genet 2007;121:421–431.
  • Holla L, Nakken S, Mattingsdal M, Ranheim T, Berge KE, Defesche JC, et al. Effects of intronic mutations in the LDLR gene on pre-mRNA splicing: Comparison of wet-lab and bioinformatics analyses. Mol Genet Metab 2009;96:245–252.
  • Huang LS, Miller DA, Bruns GA, Breslow JL. Mapping of the human APOB gene to chromosome 2p and demonstration of a two-allele restriction fragment length polymorphism. Proc Natl Acad Sci USA 1986;83:644–648.
  • Law SW, Lee N, Monge JC, Brewer HB, Sakaguchi AY Jr, Naylor SL. Human apoB-100 gene resides in the p23--> pter region of chromosome 2. Biochem Biophys Res Commun 1985;131:1003–1012.
  • Navaratnam N, Morrison JR, Bhattacharya S, Patel D, Funahashi T, Giannoni F, et al. The p27 catalytic subunit of the apolipoprotein B mRNA editing enzyme is a cytidine deaminase. J Biol Chem 1993;268:20709–20712.
  • Mahley RW, Innerarity TL. Lipoprotein receptors and cholesterol homeostasis. Biochem Biophys Acta 1983;737:197–222.
  • Segrest JP, Jones MK, De Loof H, Dashti N. Structure of apolipoprotein B-100 in low density lipoproteins. J Lipid Res 2001;42:1346–1367.
  • Whitfield AJ, Barrett PHR, van Bockxmeer FM, Burnett JR. Lipid disorders and mutations in the APOB gene. Clin Chem 2004;50:1725–1732.
  • Borén J, Lee I, Zhu W, Arnold K, Taylor S, Innerarity TL. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J Clin Invest 1998;101:1084–1093.
  • Innerarity TL, Mahley RW, Weisgraber KH, Bersot TP, Krauss RM, Vega GL, et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia. J Lipid Res 1990;31:1337–1349.
  • Weisgraber KH, Innerarity TL, Newhouse YM, Young SG, Arnold KS, Krauss RM, et al.Familial defective apolipoprotein B-100: enhanced binding of monoclonal antibody MB47 to abnormal low density lipoproteins. Proc Natl Acad Sci USA 1988;85:9758–9762.
  • Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, McCarthy BJ. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989;86:587–591.
  • Tybjærg-Hansen A, Steffensen R, Meinertz H, Schnohr P, Nordestgaard BG. Association of mutations in the apolipoprotein B gene with hypercholesterolemia and the risk of ischemic heart disease. N Engl J Med 1998;338:1577–1584.
  • Pullinger CR, Hennessy LK, Chatterton JE, Liu W, Love JA, Mendel CM, et al. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest 1995;95:1225–1234.
  • Gaffney D, Reid JM, Cameron IM, Vass K, Caslake MJ, Shepherd J, et al. Independent mutations at codon 3500 of the apolipoprotein B gene are associated with hyperlipidemia. Arterioscler Thromb Vasc Biol 1995;15:1025–1029.
  • Soufi M, Sattler AM, Maerz W, Starke A, Herzum M, Maisch B, et al. A new but frequent mutation of apoB-100--apoB His3543Tyr. Atherosclerosis 2004;174:11–16.
  • Linsel-Nitschke P, Heeren J, Aherrahrou Z, Bruse P, Gieger C, Illig T, et al. Genetic variation at chromosome 1p13.3 affects sortilin mRNA expression, cellular LDL-uptake and serum LDL levels which translates to the risk of coronary artery disease. Atherosclerosis 2010;208:183–189.
  • Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189–197.
  • Kjolby M, Andersen OM, Breiderhoff T, Fjorback AW, Pedersen KM, Madsen P, et al. Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export. Cell Metab 2010;12:213–223.
  • Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee R, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307–312.
  • Costandi J, Melone M, Zhao A, Rashid S. Human resistin stimulates hepatic overproduction of atherogenic apoB-containing lipoprotein particles by enhancing apoB stability and impairing intracellular insulin signaling. Circ Res 2011;108:727–742.
  • Seidah NG, Prat A. The proprotein convertases are potential targets in the treatment of dyslipidemia. J Mol Med 2007;85:685–696.
  • Seidah NG, Benjannet S, Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al.The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003;100:928–933.
  • Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, et al. NARC-1/PCSK9 and its natural mutants. J Biol Chem 2004;279:48865–48875.
  • Hunt SC, Hopkins PN, Bulka K, McDermott MT, Thorne TL, Wardell BB, et al. Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred. Arterioscler Thromb Vasc Biol 2000;20:1089–1093.
  • Naureckiene S, Ma L, Sreekumar K, Purandare U, Frederick Lo C, Huang Y, et al. Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch Biochem Biophys 2003;420:55–67.
  • Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 2007;15:545–552.
  • 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.
  • Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J. Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci USA 2008;105:1820–1825.
  • Zhang DW, Lagace TA, Garuti R, Zhao Z, McDonald M, Horton JD, et al. 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.
  • Lalanne F, Lambert G, Amar MJA, Chétiveaux M, Zaïr Y, Jarnoux AL, et al. Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 2005;46:1312–1319.
  • Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci 2007;32:71–77.
  • Lagace TA, Curtis DE, Garuti R, McNutt MC, Park SW, Prather HB, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006;116:2995–3005.
  • Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA 2005;102:2069–2074.
  • Mousavi S, Berge K, Leren T. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J Intern Med 2009;266:507–519.
  • Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003;34:154–156.
  • Leren T. Mutations in the PCSK9 gene in Norwegian subjects with autosomal dominant hypercholesterolemia. Clin Genet 2004;65:419–422.
  • Naoumova RP, Tosi I, Patel D, Neuwirth C, Horswell SD, Marais AD, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene. Long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 2005;34:154–156.
  • Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK 9. Nat Genet 2005;37:161–165.
  • Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264–1272.
  • Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007;193:445–448.
  • Maxwell KN, Breslow JL. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 2004;101:7100–7106.
  • Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004;279:50630–50638.
  • Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho Y, et al. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA 2005;102:5374–5379.
  • Fruchart JC. PCSK9: The functional relevance of fenofibrate-statin combination therapy to reduce residual cardiovascular risk. Int J Diab Mellitus 2010. Published online 03 January 2011. Doi:10.1016/j.ijdm.2010.11.001.
  • Norman D, Sun XM, Bourbon M, Knight BL, Naoumova RP, Soutar AK. Characterization of a novel cellular defect in patients with phenotypic homozygous familial hypercholesterolemia. J Clin Invest 1999;104:619–628.
  • Khachadurian AK, Uthman SM. Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients. Nutr Metab 1973;15:132–140.
  • Eden ER, Naoumova RP, Burden JJ, McCarthy MI, Soutar AK. Use of homozygosity mapping to identify a region on chromosome 1 bearing a defective gene that causes autosomal recessive homozygous hypercholesterolemia in two unrelated families. Am J Hum Genet 2001;68:653–660.
  • Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Science 2001;292:1394–1398.
  • He G, Gupta S, Yi M, Michaely P, Hobbs HH, Cohen JC. ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2. J Biol Chem 2002;277:44044–44049.
  • Dell’Angelica EC. Clathrin-binding proteins: Got a motif? Join the network! Trends Cell Biol 2001;11:315–318.
  • Davis CG, Van Driel IR, Russell DW, Brown MS, Goldstein JL. The low density lipoprotein receptor. Identification of amino acids in cytoplasmic domain required for rapid endocytosis. J Biol Chem 1987;262:4075–4082.
  • Fasano T, Sun XM, Patel DD, Soutar AK. Degradation of LDLR protein mediated by gain of function PCSK9 mutants in normal and ARH cells. Atherosclerosis 2009;203:166–171.
  • Brautbar A, Ballantyne CM. Pharmacological strategies for lowering LDL cholesterol: statins and beyond. Nat Rev Cardiol 2011;8:253–265.
  • Charlton Menys V, Durrington P. Human cholesterol metabolism and therapeutic molecules. Exp Physiol 2008;93:27–42.
  • Sharrett AR, Ballantyne C, Coady S, Heiss G, Sorlie P, Catellier D, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins AI and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108–1113.
  • Yusuf S. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Commentary. Lancet 2002;360:7–22.
  • LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al.Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425–1435.
  • Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 2010;376:333–339.
  • Zhou Q, Liao JK. Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr Pharm Des 2009;15:467–478.
  • Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005;45:89–118.
  • Carlson LA. Nicotinic acid: the broad spectrum lipid drug. A 50th anniversary review. J Intern Med 2005;258:94–114.
  • Jones PH, Davidson MH, Kashyap ML, Kelly MT, Buttler SM, Setze CM, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with rosuvastatin in patients with mixed dyslipidemia: a phase 3 study. Atherosclerosis 2009;204:208–215.
  • Insull W Jr. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. Southern Med J 2006;99:257–273.
  • Pandor A, Ara R, Tumur I, Wilkinson A, Paisley S, Duenas A, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta analysis of randomized controlled trials. J Intern Med 2009;265:568–580.
  • Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH, et al.Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431–1443.
  • Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on serum markers of cardiovascular disease risk: a systematic review. Atherosclerosis 2006;189:19–30.
  • Nambi V, Ballantyne CM. Combination therapy with statins and omega-3 fatty acids. Am J Cardiol 2006;98:34–38.
  • Nemati MH, Astaneh B. Optimal management of familial hypercholesterolemia: treatment and management strategies. Vasc Health Risk Manag 2010;6:1079.
  • Stein EA. Other therapies for reducing low-density lipoprotein cholesterol: medications in development. Endocrinol Metab Clinics North Am 2009;38:99–119.
  • Wetterau JR, Gregg RE, Harrity TW, Arbeeny C, Cap M, Connolly F, et al. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 1998;282:751–754.
  • Cuchel M, Bloedon LAT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007;356:148–156.
  • Crooke RM, Graham MJ, Lemonidis KM, Whipple CP, Koo S, Perera RJ. An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. J Lipid Res 2005;46:872–884.
  • Crooke R, Baker B, Wedel M. Cardiovascular therapeutic applications. In: Crooke ST ed Antisense Drug Technology; Principles, Strategies and Applications. 2nd ed. Boca Raton: CRC Press, 2007:601–639.
  • Merki E, Graham MJ, Mullick AE, Miller ER, Crooke RM, Pitas RE, et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein (a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein (a) transgenic mice. Circulation 2008;118:743–753.
  • Yu RZ, Kim TW, Hong A, Watanabe TA, Gaus HJ, Geary RS. Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metab Dispos 2007;35:460–468.
  • Akdim F, Visser ME, Tribble DL, Baker BF, Stroes ESG, Yu R, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol 2010;105:1413–1419.
  • Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:998–1006.
  • Visser ME, Akdim F, Tribble DL, Nederveen AJ, Kwoh TJ, Kastelein JJP, et al.Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J Lipid Res 2010;51:1057–1062.
  • Mayne J, Dewpura T, Raymond A, Cousins M, Chaplin A, Lahey KA, et al. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis 2008;7:22.
  • Duff CJ, Scott MJ, Kirby IT, Hutchinson SE, Martin SL, Hooper NM. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem J 2009;419:577–584.
  • Chan JCY, Piper DE, Cao Q, Liu D, King C, Wang W, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci USA 2009;106:9820–9825.
  • Ni YG, Di Marco S, Condra JH, Peterson LB, Wang W, Wang F, et al. A PCSK9-binding antibody that structurally mimics the EGF (A) domain of LDL-receptor reduces LDL cholesterol in vivo. J Lipid Res 2011;52:78–86.
  • Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res 2007;48:763–767.
  • Veedu RN, Wengel J. Locked nucleic acids: promising nucleic acid analogs for therapeutic applications. Chem Biodiversity 2010;7:536–542.
  • Gupta N, Fisker N, Asselin MC, Lindholm M, Rosenbohm C, Ørum H, et al. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PloS One 2010;5:e10682.
  • Frank-Kamenetsky M, Grefhorst A, Anderson NN, Racie TS, Bramlage B, Akinc A, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA 2008;105:11915–11920.
  • Hollams EM, Giles KM, Thomson AM, Leedman PJ. mRNA stability and the control of gene expression: implications for human disease. Neurochem Res 2002;27:957–980.
  • Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 2004;10:1344–1351.
  • Abidi P, Zhou Y, Jiang JD, Liu J. Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine. Arterioscler Thromb Vasc Biol 2005:2170–2176.
  • Brusq JM, Ancellin N, Grondin P, Guillard R, Martin S, Saintillan Y, et al. Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine. J Lipid Res 2006;47:1281–1288.
  • Kong WJ, Wei J, Zuo ZY, Wang YM, Song DQ, You XF, et al.Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism 2008;57:1029–1037.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.