Metabolism and Protective Properties of HDL

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1 Metabolism and Protective Properties of HDL A riddle wrapped in a mystery inside an enigma Jacques Genest MD Cardiovascular Research Laboratories McGill University Health Center

2 Disclosure J. Genest MD 2013 Advisory Board, Speaker s Bureau, Consultant, Grants, Clinical Trials Merck * Pfizer Novartis AMGEN * Roche * AstraZeneca Sanofi/Regeneron * Lilly Valeant Genzyme * Aegerion Stock ownership: none; Off label use: none * Scientific Advisory Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS, CAPREE steering Committees; REVEAL, ACCELERATE, AMG145, Lilly Clinical Trials.

3 The Controversy A low level of HDL-C is a major independent risk factor for atherosclerotic cardiovascular disease. However, in randomized, controlled trials, high-dose niacin or inhibitors of cholesteryl ester transfer protein did not improve CV outcomes despite significantly increasing the HDL-C level. Furthermore, genetic variants associated with HDL-C levels are often not associated with CVD. These observations suggest that HDL cholesterol may not be causally associated with CVD N Engl J Med 2014;371:

4 HDL Metabolism Complexity of HDL HDL Biogenesis HDL Metabolism

5 HDL Metabolism: The Simplified View Circ Res. 2014;114:

6 Human Plasma Lipidome (Quenhenburger N Engl J Med 2011;365: )

7 Human Plasma Lipidome

8 Apolipoprotein AI

9 NH2- Adenosine Triphosphate Binding Cassette Transporter A1 (ABCA1) Full-transporter Phospholipid and (cholesterol) efflux to apoa-i Early HDL maturation LxR/RxR apoa-i - COOH cholesterol & phospholipid ATP ADP+P i ATP ADP+P i

10 HDL Biogenesis Model Iatan I et al. JLR 2011

11 HDL Biogenesis

12 Nascent HDL Particles Sorci-Thomas JLR 2012

13 CE C HDL Biogenesis

Two-D PAGGE Analysis of HDL O pre - b a [nm] - 17.0-12.2-9.

14 Two-D PAGGE Analysis of HDL O pre - b a [nm] pre - b 1 - LpA - I a - LpA - I Apo AI-containing lipoproteins Hafiane A. CLC 2013 R17; P18

15 Lipoprotein Metabolism Chylomicron LPL FFA Chylo Remnant HL Liver Exogenous Pathway Intestine ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Free Cholesterol HL Peripheral Cells Steroidogenic Cells Liver Nascent HDL LCAT HDL3 HDL2 LDL ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Tg CETP PLTP Endogenous Pathway LPL CE 3 Liver HL VLDL IDL FFA Feces

genes have identified (ApoAI, ABCA1, LCAT ) Novel genes: PCSK5,

16 Genes involved in HDL regulation HDL-C factors: Environmental Genetic: heritability 50% Known genes: º Mutations in several genes have identified (ApoAI, ABCA1, LCAT ) Novel genes: PCSK5, WWOX 16 Kathiresan S, Cupples L et al. Nat Genet (2009) 41(1): 56-65

17 HDL Functions Cellular Cholesterol Efflux Anti-oxidant Anti-inflammatory Vascular Endothelial function Anti-thrombotic

18 Figure 1 Pleiotropic biological functions of apolipoprotein A-I Shah, P. K. (2011) Targeting endogenous apo A-I a new approach for raising HDL Nat. Rev. Cardiol. doi: /nrcardio

19 ABCA1 Mediated Cellular Cholesterol Efflux LxR/RxR

20 HDL Cholesterol efflux: Biomarker of CVD N Engl J Med 2014;371:

21 CVD, HDL-C and Efflux Capacity N Engl J Med 2014;371:

22 Cholesterol Efflux and CVD Khera AV. N Engl J Med 2011;364:127-35

23 Cholesterol Efflux and CVD Arterioscler Thromb Vasc Biol. 2013;33:

24 hscrp (mg/l) HDL-Mediated Cellular Cholesterol Efflux in CAS A B * * * Control ACS1 ACS2 CAD Hafiane A. CLC 2013 P10

25 HDL-Mediated Cellular Cholesterol Efflux in CAS *** *** *** Hafiane A. CLC 2013 P10

26 Antioxidant Properties of HDL

27 Antioxidant Properties of HDL LDL LDL-ox PL, FFA LOOX CE-OOX HOPDE HPETE PL-ox POVPC PGPC PAPC O 2- OH Apo AI, J 12-Lipooxygenase a-toc HDL Paraoxonase (PON) Glutathion peroxidase (GPX) PAF-acetyl hydrolase (PAF-AH) Lp-PLA2

31 Dehydrative cyclization of isoprostanoid hydroperoxy endoperoxides generates epoxyisoprostanes. Salomon R G Circulation Research. 2012;111: Copyright American Heart Association, Inc. All rights reserved.

32 Antioxidant Properties of HDL No consensus has yet emerged on the proper biomarker of HDL anti-oxidant function.

33 Endothelial cells and HDL HDL exerts beneficial effects on VEC Increase enos stability, mrna and pnos Decrease in NF-kB-mediated inflammatory gene expression Increases endothelial progenitor cells

34 HDL- Vascular endothelial Cell Interaction Campbell S, Genest J, 2012

ACS1 HDL ACS2 HDL Medium 200 Hypo a Healthy HDL HDL stimulation of Human Aortic Endothelial enos 150 150 enos (ps1177: positive

35 ACS1 HDL ACS2 HDL Medium 200 Hypo a Healthy HDL HDL stimulation of Human Aortic Endothelial enos enos (ps1177: positive phosphorylation) enos (pt495: negative phosphorylation) Loading controls (Ponceau S staining) 37 Choi, H 2013 Unpublished

36 HDL healthy prevents NF-KB nuclear translocation/activation Bessler et al. JCI Confocal microscopy of GFP-anti RelA/p65

38 HDL and Endothelial Progenitor Cells Sorrentino SA et al. Circulation 2010;121;

39 Circ Res. 2014;114:

40 Cholesterol efflux ABCA1, ABCG1 and SR-BI Anti-apoptic recruitment of endothelial progenitor cells (EPC) Anti-inflammatory inhibit VCAM-1 expression and adhesion molecules Antioxidative anti-oxldl, inactivate LOOH and oxphospholipase Anti-infectious trypanosome lytic factor and LPS inactivation HDL Vasodilatory NO release, prostacyclin (PGI2) production and enos activation Anti-thrombotic inhibition of platelet aggregation and prostacyclin (PGI2) production Hafiane A. Cholesterol 2013

41 The HDL Proteome Over 200 proteins have been identified as part of the HDL proteome ( eome.html

43 Enriched in ACS Enriched in controls clusterin carbonic_anhydrase_i multimerin_2 apolipoprotein_a-iv antithrombin cystatin_c peptidoglycan_recognition_protein_2 alpha-2-glycoprotein_1_zinc-binding inter-alpha_(globulin)_inhibitor_h2 gelsolin angiotensinogen alpha-2-hs-glycoprotein lumican retinol binding protein 4 paraoxonase_3 apolipoprotein_m apolipoprotein_d apolipoprotein_a-ii glycosylphosphatidylinositol_specific_phospholipase_d1 lecithin-cholesterol_acyltransferase apolipoprotein_f vitamin_d_binding_protein heparin_cofactor transferrin paraoxonase_1 apolipoprotein_c-iii transthyretin coagulation_factor_ii_(thrombin) apolipoprotein_c-i apolipoprotein_a-i serum_amyloid_a4_constitutive albumin apolipoprotein_e cathelicidin_antimicrobial_peptide alpha-1-microglobulin/bikunin_precursor apolipoprotein_h C1_protease_inhibitor ceruloplasmin_(ferroxidase) orosomucoid_1 isocitrate_dehydrogenase_3_(nad+)_alph surfactant_protein_b beta-2-microglobulin alpha-1-b_glycoprotein alpha-1_antiproteinase_antitrypsin orosomucoid_2 afamin fibronectin_1 complement_component_1s prenylcysteine_oxidase_1 vitronectin inter-alpha_(globulin)_inhibitor_h4 apolipoprotein_c-ii haptoglobin-related_protein phospholipid_transfer_protein chromosome_1_open_reading_frame_56 integrin_alpha_2b alpha-1_antiproteinase_antitrypsin hemopexin apolipoprotein_c-iv fibrinogen_alpha_chain apolipoprotein_l_1 profilin_1 complement_component_3 complement_factor_b complement_component_4b leucine-rich_alpha-2-glycoprotein_1 alanyl_(membrane)_aminopeptidase serum_amyloid_a_isotype_1_protein

44 HDL Proteome in CVD Riwanto M et al. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation. 2013;127:

45 Independent confirmation of differentially expressed proteins by Western analysis or ELISA

46 Independent confirmation of differentially enriched proteins by Western analysis or ELISA - Controls

47 Electron paramagnetic resonance spectroscopy (EPR) PLoS One Aug 28;8(8):e doi: /journal.pone

48 The HDL Lipidome Specific lipid species may have a physiological role in HDL function Kontush A et al. J. Lipid Res. 2013;54:

49 Physicochemical properties and lipid class composition of HDL particle subpopulations. Kontush A et al. J. Lipid Res. 2013;54: by American Society for Biochemistry and Molecular Biology

50 Specifically, the content of phosphatidylserine revealed positive correlations with all metrics of HDL functionality, reflecting enrichment of phosphatidylserine in small, dense HDL3.

51 HDL- Vascular endothelial Cell Interaction Campbell S, Genest J, 2012

52 Cellular Cholesterol Efflux Anti-oxidant Anti-inflammatory Vascular Endothelial function Anti-thrombotic The Challenge Develop Biomarkers of HDL Function That can be tested in outcome studies, be reproducible and brought to high throughput.

53 The Short Term Identify Responders, Sub groups HDL Biomarkers presently limited in predicting outcomes IVUS may be the least bad surrogate currently available New imaging modalities ( 18 FDG) and PET/CT scanning High bar of regulatory agencies

54 The Long Term HDL is a Biologically SOUND Target Need to identify new pathways of HDL biogenesis and metabolism Study the structure of HDL in health and in disease (proteomics, lipidomics) Design clinical trials that are highly focused (initially)

55 Points to Take Home HDL particles are complex Genes involved in HDL biogenesis may make better therapeutic targets than genes involved in HDL remodeling (Lipases, CETP) New Gene, new pathways

High density lipoprotein metabolism

High density lipoprotein metabolism Lipoprotein classes and atherosclerosis Chylomicrons, VLDL, and their catabolic remnants Pro-atherogenic LDL HDL Anti-atherogenic Plasma lipid transport Liver VLDL FC