Metabolism and Atherogenic Properties ofLDL
Dr Manal Al-Kindi
MD,DCH, FRCPA,AACB,ABCL
Chemical Pathologist & Lipidiologist
Royal Hospital
Muscat
The Sixth IAS-OSLA Course on
Lipid Metabolism and Cardiovascular Risk
Muscat, Oman, February 14-17,2020
Disclosure
• Non
Epidemiology
CVD Risk Factors
Age, Race, Sex4,5
Increased Cardiovascular
Risk
History of CV Event6
Smoking1
Dyslipidemia7
(LDL-C, HDL-C, TG, Lp(a))
Type 2 Diabetes, Metabolic Syndrome1
Modifiable factors
Non-modifiable factors
Obesity1
Genetics3
(e.g., HeFH, HoFH)
Sedentary Lifestyle and Diet1
Hypertension1
Inflammation?2
. Ridker PM, et al. Eur Heart J. 2014; 35(27):1782-1791. 3. Sharifi M, et al. Heart. 2016;102:1003-1008. 4. JellingerPS, et al. Endocr Pract. 2012;18:1-78. 5. Roger VL, et al. Circulation. 2012;125:e2-e220. 6. Stone NJ, et al. J Am CollCardiol. 2014;63:2889-2934.
Increased CV risk is due to modifiable and non-modifiable risk factors
At
INTERHEART Study
High GlobalCV Risk
Acceleratedherosclerosis and
CV disease
S. Yusuf et al. Lancet 2004; 364:937-52
ApoB / ApoAI
LDL accounted for ~ 50% of the population attributable risk LDL-C is a Major Modifiable CV Risk Factor
Effects of Increasing TC Levels on the Risk for CHD in the Presence of Other Risk Factors
05
10152025303540
185 210 235 260 285 310 335
Low HDL
Smoking
Hyperglycemia
Hypertension
No Other Risk Factors
Schaefer EJ, adapted from the Framingham Heart Study
Serum Cholesterol (mg/dL)
0
5
10
15
20
25
30
(2.60) (3.25)(3.90)(4.50) (5.15) (5.80)(6.45) (7.10) (7.75) (8.40)(9.05)
Cholesterol and CHD: Seven Countries Study
Total Cholesterol
CHDmortality
rates(%)
Verschuren WMM et al. JAMA. 1995;274:131-136.
100 125 150 175 200 225 250 275 300 325 350
Northern EuropeUnited StatesSouthern Europe, InlandSouthern Europe,MediterraneanSiberia, Japan
TC mg/dLTC(mmol/L)
Patients with Genetically Lower LDL have Better CV Event Reduction
Ference BA, et al. J Am Coll Cardiol. 2015;65(15):1552-1561.
10%
20%
30%
.003 .005 .078 .104 .130 .155 .181 .207 .233 .259 .285 .311 .330 .363 .389 .389 .440 .466 .492 .518 .5440
Lower LDL-C (mmol/L)
Pro
po
rtio
nal
Ris
k R
ed
uct
ion
(SE
) lo
g sc
ale
PCSK9 46Lrs11591147
ALLHAT-LLT
SEARCH
Pharmacologically Lower LDL-C
A to Z
Genetically Lower LDL-C
GISSI-P
NPC1L1 LDL-C ScoreHMGCR LDL-C Score
IMPROVE-IT
Combined NPC1L1 & HMGCR LDL-C Score
LDLRrs6511720
LDLRrs2228671
PCSK9rs11206510
ABCG5/8rs4299376
HMGCRrs12916
PCSK9rs2479409
NPC1L1rs217386
HMGCR LDL-C Score
NPC1L1 LDL-C Score
Genetic has a Greater effect than Pharmacologically Lower LDL-C− Possibly due to Lifetime Lower LDL levels
The Evidence Reviewed:
To avoid selection bias we evaluated the totality of evidence from separate meta-analyses of prospective epidemiologic studies, Mendelian randomization and other genetic studies, together with randomized clinical trials for causality of LDL in ASCVD
The database included more than 200 studies involving over 2 millionparticipants with over 20 million person-years of follow-up and morethan 150,000 cardiovascular events
LDL and ASCVD: Key Findings
➢ Cumulative LDL burden determines the initiation andprogression of ASCVD.
➢ There is a dose-dependent, log-linear association between absolute LDL-C level and CV risk. This association is independent of other CV risk factors and consistent across the multiple lines of evidence.
➢ Evidence accrued from >30 randomized trials involving >200,000 individuals and 30,000 cardiovascular events evaluating treatments specifically designed to lower LDL consistently show that reducing LDL-C reduces the risk of CV events.
➢ This benefit is proportional to the absolute reduction in LDL-C.European Heart Journal. doi:10.1093/eurheartj/ehx144.
Implications
• Cumulative LDL arterial burden is a central determinant of theinitiation and progression of ASCVD• The lower the LDL-C level attained by agents which primarilytarget LDL receptors, the greater the clinical benefit accrued.• Both proportional (relative) risk reduction and absolute risk
reduction relate to the magnitude of LDL-C reduction.• Lowering LDL-C in individuals at high cardiovascular risk
earlier rather than later appears advisable, especially in those with FH.
European Heart Journal. doi:10.1093/eurheartj/ehx144.
Endogenous Lipid Transport Pathway
TG/CE
B48
cholesterol
(exogenous)
CE/TG
B100
Dietary Carbohydrate
glucose pyruvate Acetyl CoA
mitochondriaAcetyl CoA
TG
FFA FFA TG VLDL
LIVER
VLDL
CMr Cholesterol
(endogenous)
ELDL receptor
Plasma
VLDL Assembly
VLDL1
VLDL2 LDL
Rem IDL
LPL
LPL
LDL
Rem IDL
LDLr/LRP
LDLr/LRP
HL
HL
Heterogeneity of VLDL and its Remnants
VLDL and Metabolism of Derivate LDL
VLDL1 VLDL2
Sf 60-400 20-60
TG/Col ratio 3.2 1.3
Transference to LDL% 17 ± 5 35 ± 5
LDL FCR of derivedLDL 0.2 ± 0.04 0.32 ± 0.06
(pools/day-1)
Adapted from de Demant e Packard Eur Heart J 1998;19 supl H:7-10
Lipoprotein Metabolism
- TGs - TGs
More Triglyceride Less Triglyceride
Lower Cholesterol Concentration
Higher Cholesterol Concentration
-Apolipoproteins
LPL HL
Lipoprotein Sub-Classes
1.20
1.10
1.06
1.02
1.006
0.95
5 10 20 40 60 801000
ChylomicronRemnants
VLDL
LDL
HDL2
HDL3DL3
Particle Size (nm)
Dens
ity (g
/ml)
Chylomicron
VLDLRemnants
Lp(a)
IDL
Atherogenic(found in plaque)
pre-β2 HDLpre-β1 HDL
5
NON HDL
Anti atherogenic
LDL-Cholesterol Hemostasis
Hepatic LDLRs Play a Central Role in Cholesterol Homeostasis
LDL particles consist mostly of cholesteryl esters packaged with a protein moiety called apolipoprotein B (apoB),
1 apoB molecule in each LDL particle.
LDL particles are the primary carriers of plasma cholesterol in humans, and high LDL levels have a strong and direct relationship with the development ofatherosclerosis.
The liver is responsible for the clearance and catabolism of plasma LDL, and hepatocyte expression of LDL receptors (LDLRs) are central to this process by binding and removing LDL from the plasma.
LDL/LDLR complex is internalized into the hepatocyte via clathrin-coated vesicles, thereby removing LDL from the blood. The affinity of the hepatic LDL receptor for apoBon LDL enables LDLRs to clear plasma LDL effectively.
Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad
Sci U S A. 2009;106:9546-9547
Recycling of LDLRs Enables Efficient Clearance of LDL-C Particles
Clathrin-coated vesicles containing internalized LDL/LDLR complexes fuse with endosomes, resulting in dissociation of the LDLs from LDLRs due to the acidic environment.
The free LDLRs then recycle back to the surface of the hepatocyte to bind and clear additional LDL from the blood.
Free LDL particles in the endosomes are transported to the lysosomes and degraded into lipids and amino acids.
The ability of hepatic LDLRs to be recycled is a key determinant of hepatic efficacy in lowering plasma LDL.
Brown MS, et al. Proc Natl Acad Sci 1979;76:3330-3337. Qian YW, et al. J Lipid Res. 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547
PCSK9 Regulates the Surface Expression of LDLRs by Targeting for LiposomalDegradation
PCSK9 is a proprotein that is produced in hepatocytes, and secreted into the plasma as functional PCSK9.Extracellular PCSK9 binds to the LDLR on the surface of the hepatocyte and is internalized within theendosome.LDLR/PCSK9 complex is routed to lysosome for degradation, preventing recycling of LDLR back to hepatocyte surface.By preventing LDLRs from recycling back to the surface, PCSK9 reduces the concentration of LDLRs on the surface of hepatocytes, resulting in a lower LDL clearance rate and elevated levels of plasma LDL. Brown MS, et al. Proc Natl Acad Sci
1979;76:3330-3337. Qian YW, et al. J Lipid
Res. 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad Sci U S A.
2009;106:9546-9547
ER TGN
EndosomeLysosome
LDL-R
PCSK9
pre-PCSK9
A:LDL-R pathway in
absence of PCSK9
B:Intracellular
PCSK9 route
C:Extracellular
PCSK9 route
MaturePCSK9
LDL
apoB
PCSK9
Deg
rada
tion
Michael S. Brown and Joseph L. GoldsteinNobel Prize in Physiology or Medicine onOctober 15, 1985.
LDL receptor discovery introduced three general concepts to cell biology: receptor-mediated endocytosis
receptor recycling feedback regulation of receptors.
Low-Density Lipoprotein (LDL) Consists of Multiple Distinct Subclasses Differing in Size and Lipid Content*
Berneis KK, Krauss RM. J Lipid Res. 2002;43:1363-1379.
Association with Cardiovascular Disease Risk
Large
Small
Less Atherogenic
* Distribution of subclasses is independent of LDL-C.
More Atherogenic
12
3
4
⚫ ↓ clearance by LDL-R⚫ ↑ arterial entry⚫ ↑ arterial retention⚫ ↑ oxidation
LDL particles comprise ~ 90% of
circulating apoB-containing
lipoproteins
• Under most conditions, LDL-C concentration and LDL particle number are highly correlated
LDL cholesterol terrible at predicting the amount of LDL particles in certain disease states.
Large LDL (Pattern A) Small LDL (Pattern B)
• Carries more cholesterol per particle
• Elevated in FH• Elevated with high sat fat
• Low in countries with low fat
diet(Costa Rica)
• Oxidized more rapidly
• Elevated in metabolic syndrome/
insulin resistance ,DM , Obesity
• Associated with low HDL-C, high TG
• Altered endothelial function Altered
fibrinolysis
Sacks and Campos, J Clin Endocrinol Metab 2003;88:4525-4532.
Increased small dense LDL particles associated with reduced IHD survival
St-Pierre AC et al. Arterioscler Thromb Vasc Biol. 2005;25:553-9.
N = 2072 men without IHD at baseline;13-yearfollow-up 1.00
0.90
0.80
Survival probabilities
0 2 4 6 8Follow-up (years)
10 12
P < 0.0001
Levels of smal dense LDL low normal high
IHD = ischemic heart disease
Pathogenicity of LDL & LDL : oxidation and inflammation
Diaz et al. N Engl JMed 1997;337:408–416
LDL : oxidation and inflammation
The Initial Accumulation of Foam Cells Is Seen as a Fatty Streak
Fatty streak
Arterial lumen
The atherosclerotic process can occur in any artery—
coronary, cerebral, or peripheral
1. Samson S, et al. Cholesterol. 2012;2012:571846. 2. Hall JE, et al. In: Guyton and Hall Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier; 2011:819-830.
As atheromatous plaques develop, remodeling occurs where the subendothelialspace expands in an outward direction, preserving the lumen, which appears normal when viewed with techniques restricted to luminal imaging such as angiography.
Ischemic Heart Is One Manifestation of Clinical ASCVD
ASCVD = atherosclerotic cardiovascular disease.Grundy SM, et al. J Clin Lipidol. 2014;8:29-60.
Stable Atherosclerosis Thrombotic Events
Plaque rupture
Fatty streak develops
Lipids accumulate, atheroma grows
Stable plaque Platelet adhesion,
activation, and aggregation
Clinical ASCVD is a systemic, progressive disease that affects multiple vascular beds and can lead to CV events, including stroke
Thrombus formation
Journal of thrombosis and hemostasis 2018;16:418-428
Effects of LDL-C Lowering on Atherosclerotic
Effects of LDL-C Lowering onAtherosclerotic Plaques
Libby P. Eur Heart J. 2015 ; 36:472–474.
Conclusion
• LDL Levels regulated by complexmechanisms• LDLRs Play a Central Role in Cholesterol Homeostasis
• Heterogeneous group ofparticles• Strong evidence that LDL is a strong risk factor forCVD• Pro-atherogenic properties
–Endothelial dysfunction–Pro-inflammatory–Pro-thrombotic
• Lowering LDL-C has an effect in onAtherosclerotic Plaques