Metabolism of LipoproteinsHyperlipoproteinemia

Cardiovascular diseases caused by atherosclerosis

• In Europe > 4 million CVD deaths/year

• 43% men and 55% women die of CVD

• 2002: 2557 CVD/100 000 hospitalized

• 2003: CVD treat. costs: 168 757 mil. €

Lipoproteins

• Micels transporting cholesterol esters and triglycerides in plasma Lipoprotein classes:

• CHYLOMICRONs (TG)

• VLDL (TG)

• IDL (TG+CHE)

• LDL (CHE)

• HDL (CHE)

Lipoprotein. class

Density (g/ml)

Diameter (nm)

Protein % Phospho-lipids %

Triglycerides %

HDL 1.063-1.21 5 – 15 33 29 8

LDL 1.019 – 1.063

18 – 28 25 21 4

IDL 1.006-1.019 25 - 50 18 22 31

VLDL 0.95 – 1.006 30 - 80 10 18 50

CHYLO-MIKRONS

< 0.95 100 - 500 1 - 2 7 84

Lipoprotein structure

LDL molecule

Apoproteins

• Protein moiety of Lp

• Classification A,B,C,D,E,H,M

• Function:-hydrophilic properties

-receptor ligands

-enzyme cofactors

Classification of lipoproteins

Density EF

Chylomicrons Chylomicrons

VLDL pre-beta

IDL slow pre-beta

LDL beta

HDL alpha

Apoproteins

• A-I (28,300)- main apoprotein of HDL• activates LCAT

• A-II (8,700) – as a dimer namely in HDL• enhances activity of hepatic lipase

• B-48 (240,000) – only in chylomicrones– coded by apo-B-100 gene, edited mRNA stop-codone

at 48% length of the chain, binds to different receptors than B-100

• B-100 (500,000) – main apoprotein of VLDL, IDL, LDL

• ligand of apoB100:E receptor (LDL receptor)

• C-I (7,000) – present in CHM, VLDL, HDL• LCAT activation

• C-II (8,800) – present in CHM, VLDL, HDL • LPL activation

• C-III (8,800) – present in CHM, VLDL, IDL, HDL• LPL inhibition

• D (32,500) – present in HDL• equivalent - cholesterol ester transfer protein (CETP)

• E (34,100) – present in CHM, VLDL, IDL HDL• ligand of apo B100:E receptoru ( LDL receptoru)

• H (50,000) – present in CHM as -2-glycoprotein I (TAG metabolism)

• M – present in HDL (reverse cholesterol transport)

Apoproteins

Main lipoprotein classes

• Chylomicrones (intestine-dietary fat)– density < 1.006– diameter 80 - 500 nm– Dietary fat (esp. TAG)– apoB-48, apoA-I, apoA-II, apoA-IV, apoC-

II/C-III, apoE– ELFO- on the start line

Chylomicrones

• formed in enterocytes, resynthetised TG, less cholesterol-ester

• Transported in the lymph ductus thoracicus and v. subclavia (systemic circulation)

• TG hydrolized by lipoprotein lipase (LPL) present on capillary endothelium of peripheral tissues

• CHM remnants taken up by hepatocytes (CHM receptor binds apoE-III and apoE-IV isoforms)

Cholesterol and lipid transport by lipoproteins

Main lipoprotein classes

• VLDL– density >1.006– diameter 30 - 80nm– Formed in the liver, nascent VLDL contain

mainly TG, less CHE– apoB-100, apoE, apoC-II/C-III– EF - pre-beta fraction

VLDL

• nascent VLDL – interaction with HDL, receive apoC-II and apoC-III, equimolar exchange of TG for CH-E with HDL)

• VLDL TG hydrolized by LPL in peripheral tissues resulting in formation ofVLDL remnants (IDL)

• IDL – cca. 50% taken up in the liver by apoB100:E receptor - cca. 50% degradation by HL resulting in LDL formation

Main lipoprotein classes

• IDL (intermediate density lipoproteins)– density: 1.006 - 1.019– diameter: 25 - 35nm– TG a CHE– apoB-100, apoE, apoC-II/C-III– EF slow pre-beta– highly atherogenic

Main lipoprotein classes

• LDL (low density lipoproteins)– density: 1.019 - 1.063– diameter: 18-25nm– cholesterol esters– apoB-100– EF beta fraction– highly atherogenic

Cholesterol and lipid transport by lipoproteins

Main lipoprotein classes

• HDL (high density lipoproteins)– density: 1.063-1.210– diameter: 5-12nm– cholesterol esters – apoA-I, apoA-II, apoC-II/C-III and apoE– EF alpha fraction

HDL

– formed in liver and enterocytes– nascent – discoid micels of PL monolayer,

with apoA-I, apoA-II, apoE – lecithin-cholesterol acyl transferase (LCAT)

in periph. tissues transfers CHE into the HDL-core which becomes spheric - HDL3

(smaller HDL)

HDL3

– HDL3

• Binds to the cell membranes of peripheral tissues and aquires free cholesterol from them

• LCAT – esterification of free cholesterol to CHE and its storage in the core of the particle

• More CHE aquisition HDL3 becomes bigger and transforms to HDL2a

• HDL2a and VLDL exchange in equimolar ratio 1:1 CHE za TG --- HDL2b

Function of HDL

• REVERSE CHOLESTEROL TRANSPORT

• donor of apoproteins to other LPs

Lp(a)

• independent Lp class (at least 19 polymorphisms described)

• structure similar to LDL• apoB-100 binds apo(a)• apo(a) – primary structure

asplasminogen• highly atherogenic

LDL receptor

• First described by Michael Brown a Joseph Goldstein (Nobelova cena v roce 1985)

• studies of familir hypercholesterolemia• also named as apo B-100:E receptor• present in the liver and all peripheral tissues

LDL receptor (839 aa)

Extracellular domain binds apo-B-100/apo-E

Intracellular domain –responsible for LDL recpetors clustering in coated pits of cellular membranes

Atherosclerosis

• Most common cause of death in developed industrial countries

• High socioeconomic impact• Multifactorial detrmination• Fibroproliferative inflammation• Hyperlipoproteinemia- important but

modifiable RF

Aterosklerotický plát

PRIMARY HYPERLIPOPROTEINEMIAS

• Primary genetic precondition

• Phenotype determined also by exogenic factors (diet, physical in-activity)

Primary HL-classification

• TG increased

• CHOL increased

• Both TG and CHOL increased

Primary hypertriglyceridemia

• Fredrickson: tFredrickson: typ Iyp IV V • TG 3-12 mmol/l• Frequency 1/500 ?• Primary incr. VLDL synthesis, low LPL activity

(identical phenotype in metabolic syndrom - IR)• Clinical signs: eruptive xanthomas• R: premature ATS, ac. pancreatitis (TG>18,0)• Th: diet, fibrates, nacin

Primary hyper-CHYLOMIKRON-emia

rare

• Fredrickson: tFredrickson: typ Iyp I • high chylomicrons, defect of LPL

or apo CII• autosomal recessive disorder,

frequ. 1/1000 000• TG 20-200 mmol/l• Clin.signs.: eruptive - tuberous xanthomas,

hypersplenism, acute pancreatitis• diet – fat max. 15 % of total calories

Primary monogenic hypercholesterolemia (FH, ABD)

• Fredrickson: tFredrickson: typ Iyp II aI a• Chol. >9,0 mmol/l, (homozyg. 14,5-23 mmol/l)• Gen. defect of LDL receptoru (FH)

or gen. defect of Apo B100 (ABD)• autosomal dominant hered., frequency heterozyg.

1/500-1/700, homozyg. 1/1000 000• Clinical signs: xanthelasmata, tendineous

xanthomas, arcus lipoides corneae• R: very high risk of premature ATS• Th: statin, ezetimibe, resins, (niacin),

in homozygous forms – LDL-apheresis

Primary monogenic hyperchol. type ARH (rare)

• SYN. SYN. Autosomal recessive hyperchol.Autosomal recessive hyperchol.• Chol. 13,5-18 mmol/l• Gen. defect of ARH protein, which binds the

plasma-terminal of LDL receptor >>impaired LDL-R internalization

• Autosomal recesssive disorder• Clinical signs: xanthelasmata, tendineous

xanthomas, arcus lipoides corneae• R: very high risk of premature ATS• Th: LDL-apheresis

Primary polygenic hypercholesterolemia

• Fredrickson: tFredrickson: typypee I II aI a

• Chol. 5,5-9,0 mmol/l

• Down-regulation of LDL-R in liver (a/o periph. tissues) due to high dietary SFA and cholesterol (animal fat)

• Polygenic disease

• Clinical signs: xanthelasmata

• R: high risk of premature ATS

• Th: statin, ezetimibe, resins, (niacin),

Hyperlipidemia Lp(a)

• Lp(a) > 0,3 g/l

• Chol. 5-6 mmol/l,

• normal HDL-chol. and TAG

• Dg: direct estimation necessary !

• Et: increased Lp(a) synthesis in the liver

• R: premature ATS

• Th: lower cholesterol, (niacin)

Primary combined hyperlipidemia (common)

• Most frequent form of primary HLMost frequent form of primary HL

• Fredrickson: tFredrickson: typ yp II bII b

• Increased VLDL and LDL concentrations

• Chol. 5,5-10 mmol/l, TG 2-9 mmol/l

• Clnical signs: no xanthomas

• R: premature ATS

• Th: diet, statins, fibrates (combination)

Primary dysbetalipoproteinemia

• Fredrickson: tFredrickson: typ Iyp III II

• Increased VLDL remnants (IDL) and CHM remnants

• Chol. 7-20 mmol/l, TG 4,5-12 mmol/l

• Genotype E2/E2 + other gen.factor?

• Severe xanthomas (tuberoeruptive, tuberose, palmar)

• R: prematue ATS (CHD, PVD)

• Th: diet, fibrats, statin, (niacin)

SECONDARY HYPERLIPOPROTEINEMIAS

AlcoholHypothyroidismT2DM and decomp. T1DMHypercorticalism, corticosteroid therapyHormonal contraceptives Nephrotic syndromAcute nonfulminant hepatitisLymfomas, leukemias PlasmocytomaSLE Rheumatoid arthritisAnorexia neurosaGlycogenosis type I (Gierke)

THERAPY

• DIET

• HYPOLIPIDEMIC DRUGS

DIETARY PRINCIPLES

• Lower body weight (BMI < 25.0)• Increase physical activity-caloric balance !• Dietary cholesterol < 300 (200) mg/D• Dietary fat 25-30% of total calories• SFA:MUFA:PUFA=7:10:10 (%)• Fibres 20-30 g/D• Phytosterols cca. 2 g/D• Limit alcohol intake !• Quit smoking !

HYPOLIPIDEMIC DRUGS

• STATINS

• FIBRATES

• EZETIMIBE

• RESINS

• NIACIN

STATINS

• Cholesterol lowering

• HMG-CoA reductase inhibitors

• Very potent

• Mild decrease of TG

• atorvastatin, simvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin

EZETIMIBE

• Cholesterol absorption inhibitor

• Block NPC1L1 channel

• Cholesterol lowering

• In combination with statin very effective

Ezetimibe (Zetia)

N

OH

O

F

OH

F

EZETIMIBE

This drug blocks the intestinal absorption of cholesterol. A dose of 10 mg qd leads toa 19% reduction of LDL; shows real promise in combo product with statins (Schering-Plough and Merck)

RESINS

• Cations binding bile acids in the gut

• Cholestyramine, colestipol, colesevelam

Bile sequestering resins

HC

H2C

HC

H2C

CHH2C

N(CH3)3

n

CHOLESTYRAMINE

H2NHN

HN

HN

(CH2)6N(CH3)3

HN

(CH2)9-CH3

OH

HN

(CH2)6N(CH3)3

HN

(CH2)9CH3

H2N. n HCl

. n HCl

. n HCl

. n HCl . n HCl . n HCl

. n HCl. n HCl

COLESEVELAM

FIBRATES

• PPARs alpha agonists

• Lower TG, increase HDL-chol.

• Mild decrease of chol. (TC, LDL-C)

• Fenofibrate, bezafibrate, ciprofibrate

NICOTINIC ACID (Niacin)

N

COOH

NICOTINIC ACID (NIACIN)

A water soluble vitamin of the B family;nicotinamide is not active

Cholesterol, TG and Lp(a) loweringHDL-chol. increasing

Severe side effects (flush, GI symptoms, hyperglycemia, gout)TREDAPTIVE (combination with laropiprant (PGD inhibitor)

DIAGNOSTIC

• Total. chol., HDL-chol., TAG, Lp(a)• LDL-chol. (Friedewald‘s equ.)-primární th. Cíl• nonHDL-chl. (Total chol. - HDL-chol.) –

secondary th. goal.• apo B event. , apo A1 (sec.th.goal)---------------------------------------------------------------Other specialised diagnostic methods• Calculation of atherogenic index of plasma (AIP)=logTAG/HDL-ch

• Genotype LDL-R, apo-B, apo-E

• Ultracentrifugation-accurate estimation of chol. and TG in v CHM, VLDL, IDL, LDL, HDL

• Electrophoresis (unusual)

nonHDL-cholesterol

Cholesterol within all atherogenic lipoproteins (not only LDL, but also VLDL, IDL, chylomikronech i Lp(a) !

FRIEDEWALD‘S FORMULAFOR LDL-chol.

LDLchol. = TCH – HDLchol – TAG/2,2

TCH-total cholesterolTAG-triglycerides

http://lipidsonline.org/slides/slide01.cfm?tk=85&pg=1

http://www.lipidsonline.org/slides/slide01.cfm?q=coronary+heart+disease&pg=8

TREATMENT GOALS

• Depend on the risk level• 4 levels• SCORE tables: in primary prevention only

(w/o CVD, PVD or stroke) • Secondary prevention patients reperesent the

highest risk group

• New EAS guidelines 2011

VERY HIGH RISK• SEC. PREVENTION: CVD, PVD, STROKE

• SCORE ≥ 10 %• DM 2T• DM 1T with organ complications (MAU)

• CRF moderate or severe (GFR 60 ml/min/1,73m2)

• Asymptomatic atherosclerosis (carotids, aorta, peripheral arteries, coron.calcium score, ankle/brachial index)

HIGH RISK

• SCORE ≥ 5 - <10 %• Total.chol.> 8,0 mmol/l, LDL-chol.> 6,0 mmol/l

• BP ≥ 180/110, HT w.nephro-/retinopathy

• Positive family history ( M<55 y, W<65 y)

MODERATE RISK• SCORE ≥1 - < 5%

Risk value may be underestimated if: • Positive family history • Phisical inactivity• Dyslipidemia high TG / lowHDL-chol• Hyper Lp(a)• Hyperfibrinogenemia

• Hyperhomocysteinemia (?)

LOW RISK

• SCORE < 1%

TREATMENT GOALS IN BASIC LIPID PARAMETERS

Lowrisk

Moderarisk

Highrisk

VeryHighrisk

LDL cholestrol

< 3,0 mmol/l < 3,0 mmol/l < 2,5 mmol/l < 1,8 mmol/l

Non HDL chol. < 3,8 mmol/l < 3,8 mmol/l < 3,3 mmol/l < 2,6 mmol/l

HDL chol/apoA1

muži > 1,0 mmol/l / 1,2 g/lženy > 1,2 mmol/l / 1,4 g/l

Triglycerides < 1,7 mmol/l

*LDL-cholesterol is the primary therapeutical goal In very high risk patients is lowering of the LDL chol. by 50% an option

GOAL for APO B

Low risk Moderate risk High risk Very highrisk

Apo B < 1,0 g/l < 0,8 g/l

* Apo B – below 0,75 g/l may be of profitable