Skip to main content
SpringerLink
Log in

Cholesterinrücktransport und HDL-Funktion

Cholesterol efflux and HDL function

  • Übersichten
  • Published:
Der Kardiologe Aims and scope

Zusammenfassung

Zwischen Veränderungen des High-density-lipoprotein(HDL)-Stoffwechsels und der Atherosklerose besteht eine kausale Beziehung. Um diese Zusammenhänge therapeutisch zu nutzen, sind Kenntnisse über die grundlegenden Prozesse des HDL-Stoffwechsels unumgänglich. Verschiedene Proteine sind entweder als Strukturproteine der Lipoproteine (Apo A-I, Apo A-II, Apo E), als Enzyme oder Transportproteine (z. B. Lecithin-Cholesterin-Acyltransferase [LCAT] oder Cholesterinestertransferprotein [CETP]) oder als zelluläre Transportsysteme (ABCA1, ABCG1, SR-B1) in den HDL-Stoffwechsel involviert. Diese Proteine sind notwendig um den Cholesterinefflux sicherzustellen, aber auch um die antiinflammatorischen, -oxidativen und -thrombotischen Eigenschaften von HDL zu vermitteln. Die Komplexität des HDL-Stoffwechsels macht es schwierig vorherzusagen, ob Interventionen im HDL-Bereich proatherogen, antiatherogen oder neutral sind. Die epidemiologischen wie auch genetischen Daten sprechen aber dafür, dass sich Modulationen am HDL-System letztendlich auch in einer veränderten Atheroskleroserate widerspiegeln. Somit bieten HDL-modifizierende Interventionen einen interessanten Ansatz, das unter Statintherapie weiter bestehende residuale Risiko zu vermindern.

Abstract

Changes in high-density lipoprotein (HDL) metabolism are causally linked to atherosclerosis. Knowledge about HDL metabolism is necessary to use this relationship as a therapeutic approach to address atherosclerosis. Different proteins are involved in HDL metabolism and include structural proteins, such as apolipoprotein A1 (apoA1), apoA2 and apoE, enzymes or transport proteins, such as lecithin-cholesterol acyltransferase (LCAT) or cholesteryl ester transfer protein (CETP) and cellular transporters, such as ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor B1 (SR-B1). These components are necessary to warrant cholesterol efflux and also for the anti-inflammatory, antioxidative and antithrombotic properties of HDL. Because of the complexity of HDL metabolism it is difficult to predict whether interventions affecting HDL levels or function will be proatherogenic, antiatherogenic or neutral. However, the epidemiological as well as the genetic data indicate that modulations of the HDL system will influence atherosclerosis. Therefore, HDL modifying interventions are an interesting approach to address residual risks associated with statin therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Abbreviations

ABCA1:

„ATP-binding cassette transporter A1“

ABCG1:

„ATP-binding cassette transporter G1“

Apo:

Apolipoprotein

CETP:

Cholesterinestertransferprotein

HDL:

„High density lipoprotein“

HL:

Hepatische Lipase

IDL:

„Intermediate density lipoprotein“

LDL:

„Low density lipoprotein“

LCAT:

Lecithin-Cholesterin-Acyltransferase

PLTP:

Phospholipidtransferprotein

SR-B1:

„Scavenger receptor B1“

TG:

Triglyzeride

VLDL:

„Very low density lipoprotein“

Literatur

  1. Adorni MP, Zimetti F, Billheimer JT et al (2007) The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res 48:2453–2462

    Article  PubMed  CAS  Google Scholar 

  2. Al-Sarraf A, Al-Ghofaili K, Sullivan DR et al (2010) Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature. J Clin Lipidol 4:420–426

    Article  PubMed  Google Scholar 

  3. Annema W, Nijstad N, Tolle M et al (2010) Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A(2). J Lipid Res 51:743–754

    Article  PubMed  CAS  Google Scholar 

  4. Ansell BJ, Fonarow GC, Fogelman AM (2007) The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 18:427–434

    Article  PubMed  CAS  Google Scholar 

  5. Baigent C, Blackwell L, Emberson J et al (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 376:1670–1681

    Article  PubMed  CAS  Google Scholar 

  6. Barter PJ, Rye KA, Tardif JC et al (2011) Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial. Circulation 124:555–562

    Article  PubMed  CAS  Google Scholar 

  7. Calabresi L, Simonelli S, Gomaraschi M et al (2011) Genetic lecithin:cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis 222(2):299-306

    Article  PubMed  Google Scholar 

  8. Camont L, Chapman MJ, Kontush A (2011) Biological activities of HDL subpopulations and their relevance to cardiovascular disease. Trends Mol Med 17:594–603

    Article  PubMed  CAS  Google Scholar 

  9. Candini C, Schimmel AW, Peter J et al (2010) Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol. Atherosclerosis 213:492–498

    Article  PubMed  CAS  Google Scholar 

  10. Cefalu AB, Noto D, Magnolo L et al (2009) Novel mutations of CETP gene in Italian subjects with hyperalphalipoproteinemia. Atherosclerosis 204:202–207

    Article  PubMed  CAS  Google Scholar 

  11. Drew BG, Rye KA, Duffy SJ et al (2012) The emerging role of HDL in glucose metabolism. Nat Rev Endocrinol 8:237–245

    Article  PubMed  CAS  Google Scholar 

  12. Franceschini G, Sirtori CR, Capurso A IInd et al (1980) A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest 66:892–900

    Article  PubMed  CAS  Google Scholar 

  13. Frikke-Schmidt R, Nordestgaard BG, Stene MC et al (2008) Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299:2524–2532

    Article  PubMed  CAS  Google Scholar 

  14. Grunfeld C, Feingold KR (2008) HDL and innate immunity: a tale of two apolipoproteins. J Lipid Res 49:1605–1606

    Article  PubMed  CAS  Google Scholar 

  15. Ji A, Wroblewski JM, Cai L et al (2012) Nascent HDL formation in hepatocytes and role of ABCA1, ABCG1, and SR-BI. J Lipid Res 53:446–455

    Article  PubMed  CAS  Google Scholar 

  16. Ji J, Watts GF, Johnson AG et al (2006) High-density lipoprotein (HDL) transport in the metabolic syndrome: application of a new model for HDL particle kinetics. J Clin Endocrinol Metab 91:973–979

    Article  PubMed  CAS  Google Scholar 

  17. Ji Y, Jian B, Wang N et al (1997) Scavenger receptor BI promotes high density lipoprotein-mediated cellular cholesterol efflux. J Biol Chem 272:20982–20985

    Article  PubMed  CAS  Google Scholar 

  18. Khera AV, Cuchel M, De La Llera-Moya M et al (2011) Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 364:127–135

    Article  PubMed  CAS  Google Scholar 

  19. Kontush A, Chapman MJ (2006) Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 58:342–374

    Article  PubMed  CAS  Google Scholar 

  20. Martinez LO, Jacquet S, Esteve JP et al (2003) Ectopic beta-chain of ATP synthase is an apolipoprotein A-I receptor in hepatic HDL endocytosis. Nature 421:75–79

    Article  PubMed  CAS  Google Scholar 

  21. Matsuura F, Wang N, Chen W et al (2006) HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest 116:1435–1442

    Article  PubMed  CAS  Google Scholar 

  22. Navab M, Reddy ST, Van Lenten BJ et al (2009) The role of dysfunctional HDL in atherosclerosis. J Lipid Res 50(Suppl):S145–149

    Article  PubMed  Google Scholar 

  23. Niesor EJ, Magg C, Ogawa N et al (2010) Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res 51:3443–3454

    Article  PubMed  Google Scholar 

  24. Nofer JR, Van Eck M (2011) HDL scavenger receptor class B type I and platelet function. Curr Opin Lipidol 22:277–282

    Article  PubMed  CAS  Google Scholar 

  25. Packard CJ, Demant T, Stewart JP et al (2000) Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J Lipid Res 41:305–318

    PubMed  CAS  Google Scholar 

  26. Parhofer KG, Barrett PH (2006) Thematic review series: patient-oriented research. What we have learned about VLDL and LDL metabolism from human kinetics studies. J Lipid Res 47:1620–1630

    Article  PubMed  CAS  Google Scholar 

  27. Persegol L, Verges B, Foissac M et al (2006) Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation. Diabetologia 49:1380–1386

    Article  PubMed  CAS  Google Scholar 

  28. Reiner Z, Catapano AL, De Backer G et al (2011) ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 32:1769–1818

    Article  PubMed  Google Scholar 

  29. Roselaar SE, Daugherty A (1998) Apolipoprotein E-deficient mice have impaired innate immune responses to listeria monocytogenes in vivo. J Lipid Res 39:1740–1743

    PubMed  CAS  Google Scholar 

  30. Schmit, Barlage S (2006) High-density-Lipoproteine und Atherosklerose. In: Schwandt P, Parhofer K (Hrsg) Handbuch der Fettstoffwechselstörungen. Schattauer, Stuttgart, S 483–518

  31. Sniderman AD, Williams K, Contois JH et al (2011) A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 4:337–345

    Article  PubMed  Google Scholar 

  32. Sorrentino SA, Besler C, Rohrer L et al (2010) Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 121:110–122

    Article  PubMed  CAS  Google Scholar 

  33. Tall AR (2009) The effects of cholesterol ester transfer protein inhibition on cholesterol efflux. Am J Cardiol 104:39E–45E

    Article  PubMed  CAS  Google Scholar 

  34. Terasaka N, Yu S, Yvan-Charvet L et al (2008) ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet. J Clin Invest 118:3701–3713

    Article  PubMed  CAS  Google Scholar 

  35. Von Eckardstein A (2006) Störungen im Stoffwechsel der High-density-Lipoproteine. In: Schwandt P, Parhofer K (Hrsg) Handbuch der Fettstoffwechselstörungen. Schattauer, Stuttgart, S 112–146

  36. Wang N, Lan D, Chen W et al (2004) ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. Proc Natl Acad Sci U S A 101:9774–9779

    Article  PubMed  CAS  Google Scholar 

  37. Wang Y, Zhu X, Wu G et al (2008) Effect of lipid-bound apoA-I cysteine mutants on lipopolysaccharide-induced endotoxemia in mice. J Lipid Res 49:1640–1645

    Article  PubMed  CAS  Google Scholar 

  38. Zhang Y, Da Silva JR, Reilly M et al (2005) Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo. J Clin Invest 115:2870–2874

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehungen hin: Vortragshonorare, Honorare für Advisory Board Tätigkeit, Honorare für DMC-Tätigkeit und/oder Forschungsunterstützung von folgenden Unternehmen: Abbott, Astra-Zeneca, Berlin-Chemie, BMS, Fresenius, Genzyme, Kaneka, Kowa, MSD, Novartis, Roche.

Author information

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik II, Klinikum der Ludwig-Maximilians-Universität München, Campus Großhadern, Marchioninistr. 15, 81377, München, Deutschland

    K. Parhofer

Authors
  1. K. Parhofer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Parhofer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parhofer, K. Cholesterinrücktransport und HDL-Funktion. Kardiologe 6, 329–336 (2012). https://doi.org/10.1007/s12181-012-0438-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12181-012-0438-3

Schlüsselwörter

Keywords

Search

Navigation