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Primary dyslipidaemias and ATS

Eliška Marklová
Charles University Faculty of Medicine & Teaching Hospital Department of Paediatrics

Hradec Králové Czech Republic
CEEPUS 2003, Zadar, CR

Terminology
• hyperlipopoteinemia, HLP • hyperlipidemia, HL • dyslipidemia, DL

Hyperlipoproteinemia is a metabolic disorder characterized
by abnormally elevated concentrations of specific lipoprotein particles in the plasma.

Hyperlipidemia (↑ plasma cholesterol and/or triglyceride)
is present in all hyperlipoproteinemias.

Dyslipidemia - abnormal cholesterol (TC, LDL-C, or HDL-C)
and/or TG concentrations.

The primary form includes:
• chylomicronemia,

• hypertriglyceridemia,

• hypercholesterolemia, • mixed hyperlipoproteinemia, • dysbetalipoproteinemia, • combined hyperlipoproteinemia Mortality/Morbidity: If uncontrolled, there is a higher mortality from cardiovascular and cerebrovascular disease. Age: It may be present in children and young adults but is seen more frequently in later life.

.

The secondary form is caused by other diseases, such as:
„Normal“ values
Total cholesterol HDL – C Triglycerides LDL – C < > < < 5.5 1.1 1.9 3,4 mmol/L mmol/L mmol/L mmol/L < 200 mg/dl > 35 mg/dl < 200 mg/dl < 130 mg/dl

diabetes mellitus, pancreatitis, renal disease, or hypothyroidism.

Classification:
Fredrickson – WHO;
others: King MW,Brescia; Szabó G, Szeged,

OMIM, Bethesda

Currently, genetic DL
• Fam↑cholesterolemia • Fam comb.↑lipidemia • Polygenic↑cholest-ia

Vademecum Metabol.
• Hypercholesterolaemias • Mixed hyperlipidaemias • Hypertriglyceridaemias • Disorders of HDL metb • Disorders of LDL + TG

Classification

HLP-Phen Lipop Classificat

ATS

Familial hypercholesterolemia
Dominantly inherited disorder - deficiency in a cell surface LDL-R (the receptor regulates
LDL degradation and cholesterol synthesis)

1

Receptor-media ted uptake of LDL is one of the best understood exa mples of receptor-media ted endocytosis. LDL is a protein -lipid complex that transports c holesterol -fatty acid esters in the blood strea m. LDL normally supplies c holesterol to cells. Defects in the endocytic process result in high blood levels of LDL. High LDL predisposes individuals for atherosclerosis.

- high cholesterol (since birth) - high LDL-C leads to premature atherosclerosis, xanthomas
of skin and tendons TC>240 mg/dl LDL>190 mg/dl
Apo-B100 Apo-E

Five classes of LDL-R mutations
1 2 3 4 5 Null (no protein synthesis) Transport defect (Golgi) LDL binding defect Internalization-defective Recycling-defective

LDL-R bind LDL particles and endocytoses them via clathrin-coated vesicles

FH Sites for LDL-R defects
1 2 4 5
Receptors accumulate in coated pin region Exocytosis of receptor

LDL-R is recycled

3
Receptor Receptor synthesis processing in ER in Goldgi

Binding to receptor Endocytosis of LDL

Familial Ligand-Defective Apoprotein B
 Genetics: autosomal co-dominant; 1:700 (heterozyg.)  Apo-B-100 is a ligand for LDL-R  Defective apo B-100  Abnormal interaction LDL ⇔ LDL-R  Clinically identical to Familial hypercholesterolemia
ApoB-100 Apo-E

Hyperlipoproteinemia (a)
 Genetics: autosomal dominant; 6 phenotypes  Abnormal LDL= „sinking“ pre-beta LP Apo-(a) attached to Apo-B-100 of LDL Risk factor for atherotrombosis especially in combination with hyperhomocystinaemia

Apo-(a)

ApoB-100

Familial hyper-β -lipoproteinemia
 common, autosomal recessive  elevation of both LDL-C and TG; ↑ LDL

Type II

 defect of HMG CoA reductase activity regulation  xanthoma tuberosum and tendinosum, corneal arcus ↑ risk of atherosclerosis  affects cca 1-2% of the population; cca 10% of patients with myocardial infarction before 60 years come from families with this disease LDL (β -elpho- fraction)

Familial dys-β -lipoproteinemia

Type III

Broad beta-disease; Remnant removal disease; Apo-E deficit

 Apo-E (3+4) normal role in CM- + VLDL-remnants uptake  Defective recognition of apo-E2 by the LDL-R  Apo-E2/E2 homozygote - VLDL overproduction  ↑ VLDL-C and TG  ↓ HDL and LDL  xanthomas + atherosclerosis  Variant apo-E4 binding to remnants CM
CM + VLDL-remnants - broad

β -elpho- fraction)

Type III –continue Broad beta-disease
Broad „ β -band“ is represented by chylomicrons remnants and IDL

CM LDL HDL

β

α

Familial combined hyperlipidemia
 genetics: autosomal dominant

(Type IV)

 ↑cholesterol and triglycerides, VLDL + LDL  frequent genetic dyslipidemia; incidence: 1:300  pathophysiology: not clear (VLDL hyperproduction)  phenotype: HLP IV, II, V („chameleon of lipidology“)
 milder risk of atherosclerosis /(LDL-R defect)
LDL (β -elpho- fraction) VLDL (pre-β -elphofraction)

Type IV

pre-β

Structure of HDL Particle
A-I A-I

CE
TG

A-II
A-I, A-II = apolipoprotein A-I, A-II;

CE = cholesteryl ester; TG = triglycerides

Production of HDL by liver and intestine
Liver Intestine

A-I

A-I

A-II HDL HDL

A-I, A-II = apolipoprotein A-I, A-II

The HDL protein complex
 ATP-bind cassette protein 1 (ABC1)  Apo-A1 activates LCAT  Lecithin:cholesterol acyl transferase (LCAT)
catalyzes acyl group transfer from phosphatidylcholine to cholesterol ester facilitates the removal of excess free cholesterol

 Cholesterol ester transfer protein (CETP)
catalyzes cholesterol ester transfer from HDL to VLDL or LDL

Metabolism of HDL and Reverse Cholesterol Transport
Bile
FC

Mature HDL A-I
CE

Nascent HDL A-I LCAT
FC

Macrophage FC SRA CE

SR-BI Liver LDL-R

CE

ABC1

CETP
CE B

o ati xid O

n

VLDL / LDL
CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LCAT = lecithin:cholesterol acyltransferase ABC1 =ATP-bind cassette protein1 LDL-R = low-density lipoprotein receptor SR-BI = scavenger receptor BI,A

Primary (Genetic) causes of low HDL
 ABC 1 (=ATP-binding cassette protein)  Tangier disease ♦ Homozygous ♦ Heterozygous
 Familial hypo-α -lipoproteinemia (some families)

 ApoA-I (apoA-I: HDL structure, LCAT activator)  Complete apoA-I deficiency  ApoA-I mutations (eg, ApoA-IMilano)  LCAT

(= lecithin:cholesterol acyl transferase)

 Complete/partial LCAT deficiency (Fish-eye disease)

 Unknown genetic etiology  Familial hypo-α -lipoproteinemia (most families)  Familial combined hyperlipidemia with low HDL-C  Metabolic syndrome

HDL Metabolism in Tangier Disease
Mature HDL

A-I LCAT

Nascent HDL A-I
FC

ABC1

FC

CE

Rapid catabolism

Macrophage

LCAT = lecithin : cholesterol acyltransferase ABC1 = ATP-bind cassette protein1

Tangier Disease
 Autosomal co-dominant disorder -

Tangier Island, Virginia U.S.

ABC1 gene mutations in both alleles  Extremely marked ↓ HDL-C + apoA-I  Markedly accelerated catabolism of apoA-I + II
 Pathologic ↑↑ of cholesterol in macrophages and other

cells of RES;↑ risk of premature atherosclerosis  Cholesterol accumulation:
 Enlarged orange tonsils  Hepatosplenomegaly  Peripheral neuropathy
ABC1 = ATP-bind cassette protein 1

ApoA-I Deficiency / Mutation
 Modest to marked ↓ HDL-C  Rapid catabolism of apoA-I

+ apoA-I

 Premature atherosclerotic disease

Mature HDL

A-I LCAT

Nascent HDL

A-I
FC FC ABC1 Macrophage
CE

Rapid catabolism

LCAT = lecithin : cholesterol acyltransferase ABC1 = ATP-bind cassette protein1

HDL metabolism in LCAT deficiency
LCAT gene: complete/partial (Fish-eye disease) ↓ HDL-C, ↓
Mature HDL apoA-I levels (rapid catabolism); corneal arcus, atherosclerosis

A-I LCAT

Nascent HDL A-I
FC
CE

ABC1

FC

Macrophage Rapid catabolism
LCAT = lecithin : cholesterol acyltransferase
ABC1 = ATP-bind cassette protein1

Primary (Genetic) causes of ↑HDL-C
 CETP • CETP deficiency  Hepatic lipase • Hepatic lipase deficiency  Unknown genetic etiology • Familial hyperalphalipoproteinemia
CETP = cholesteryl ester transfer protein

HDL metabolism in CETP deficiency
delayed catabolism

HDL
A-I
CE

LCAT

A-I
FC Nascent HDL

ABC1

FC

CE

Macrophage

CETP
B
VLDL/LDL

 Autosomal co-dominant  CETP gene mutatation  ↑ apoA-I, HDL-C enriched in CE  Possible ↑ risk of atherosclerosis

LCAT = lecithin : cholesterol acyltransferase; ABC1 = ATP-bind cassette protein1; CETP = cholesteryl ester transfer protein

Home
Phenotype Elevated Particles I IIa IIb III IV V Lipid Possible Defect Frequency ATS Abnormality LP lipase LDL-R defect HMG-CoA reductase Apo-E deficiency Very rare Common Common Rare Not seen *** *** *** *

Chylomicron TG LDL LDL and VLDL IDL VLDL LDL-C LDL-C, TG TC, TG TG

VLDL Common overproduction Apo-CII deficiency

Chylomicron TG and VLDL

Uncommon *