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Metabolism of Lipoproteins Hyperlipoproteinemia

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Title: Metabolism of Lipoproteins Hyperlipoproteinemia


1
Metabolism of Lipoproteins Hyperlipoproteinemia
2
Cardiovascular diseases caused by atherosclerosis
  • In Europe gt 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.

3
Lipoproteins
  • Micels transporting cholesterol esters and
    triglycerides in plasma Lipoprotein classes
  • CHYLOMICRONs (TG)
  • VLDL (TG)
  • IDL (TGCHE)
  • LDL (CHE)
  • HDL (CHE)

4
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 lt 0.95 100 - 500 1 - 2 7 84
5
Lipoprotein structure
6
LDL molecule
7
Apoproteins
  • Protein moiety of Lp
  • Classification A,B,C,D,E,H,M
  • Function-hydrophilic properties
  • -receptor ligands
  • -enzyme cofactors

8
Classification of lipoproteins
  • Density EF
  • Chylomicrons Chylomicrons
  • VLDL pre-beta
  • IDL slow pre-beta
  • LDL beta
  • HDL alpha

9
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 apoB100E receptor (LDL receptor)

10
Apoproteins
  • 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 B100E receptoru ( LDL receptoru)
  • H (50,000) present in CHM as b-2-glycoprotein I
    (TAG metabolism)
  • M present in HDL (reverse cholesterol
    transport)

11
Main lipoprotein classes
  • Chylomicrones (intestine-dietary fat)
  • density lt 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

12
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)

13
Cholesterol and lipid transport by lipoproteins
14
Main lipoprotein classes
  • VLDL
  • density gt1.006
  • 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

15
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
  • apoB100E receptor
  • - cca. 50 degradation by HL
  • resulting in LDL formation

16
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

17
Main lipoprotein classes
  • LDL (low density lipoproteins)
  • density 1.019 - 1.063
  • diameter 18-25nm
  • cholesterol esters
  • apoB-100
  • EF beta fraction
  • highly atherogenic

18
Cholesterol and lipid transport by lipoproteins
19
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

20
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)

21
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 11
    CHE za TG --- HDL2b

22
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23
Function of HDL
  • REVERSE CHOLESTEROL TRANSPORT
  • donor of apoproteins to other LPs

24
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

25
LDL receptor
  • First described by Michael Brown a Joseph
    Goldstein (Nobelova cena v roce 1985)
  • studies of familir hypercholesterolemia
  • also named as apo B-100E receptor
  • present in the liver and all peripheral tissues

26
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
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29
Atherosclerosis
  • Most common cause of death in developed
    industrial countries
  • High socioeconomic impact
  • Multifactorial detrmination
  • Fibroproliferative inflammation
  • Hyperlipoproteinemia- important but modifiable RF

30
Aterosklerotický plát
31
PRIMARY HYPERLIPOPROTEINEMIAS
  • Primary genetic precondition
  • Phenotype determined also by exogenic factors
    (diet, physical in-activity)

32
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Primary HL-classification
  • TG increased
  • CHOL increased
  • Both TG and CHOL increased

38
Primary hypertriglyceridemia
  • Fredrickson typ IV
  • 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 (TGgt18,0)
  • Th diet, fibrates, nacin

39
Primary hyper-CHYLOMIKRON-emia rare
  • Fredrickson typ 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

40
Primary monogenic hypercholesterolemia (FH, ABD)
  • Fredrickson typ II a
  • Chol. gt9,0 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

41
Primary monogenic hyperchol. type ARH (rare)
  • SYN. Autosomal recessive hyperchol.
  • Chol. 13,5-18 mmol/l
  • Gen. defect of ARH protein, which binds the
    plasma-terminal of LDL receptor gtgtimpaired LDL-R
    internalization
  • Autosomal recesssive disorder
  • Clinical signs xanthelasmata, tendineous
    xanthomas, arcus lipoides corneae
  • R very high risk of premature ATS
  • Th LDL-apheresis

42
Primary polygenic hypercholesterolemia
  • Fredrickson type II 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),

43
Hyperlipidemia Lp(a)
  • Lp(a) gt 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)

44
Primary combined hyperlipidemia (common)
  • Most frequent form of primary HL
  • Fredrickson typ II 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)

45
Primary dysbetalipoproteinemia
  • Fredrickson typ III
  • 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)

46
SECONDARY HYPERLIPOPROTEINEMIAS
  • Alcohol
  • Hypothyroidism
  • T2DM and decomp. T1DM
  • Hypercorticalism, corticosteroid therapy
  • Hormonal contraceptives
  • Nephrotic syndrom
  • Acute nonfulminant hepatitis
  • Lymfomas, leukemias Plasmocytoma
  • SLE Rheumatoid arthritis
  • Anorexia neurosa
  • Glycogenosis type I (Gierke)

47
THERAPY
  • DIET
  • HYPOLIPIDEMIC DRUGS

48
DIETARY PRINCIPLES
  • Lower body weight (BMI lt 25.0)
  • Increase physical activity-caloric balance !
  • Dietary cholesterol lt 300 (200) mg/D
  • Dietary fat 25-30 of total calories
  • SFAMUFAPUFA71010 ()
  • Fibres 20-30 g/D
  • Phytosterols cca. 2 g/D
  • Limit alcohol intake !
  • Quit smoking !

49
HYPOLIPIDEMIC DRUGS
  • STATINS
  • FIBRATES
  • EZETIMIBE
  • RESINS
  • NIACIN

50
STATINS
  • Cholesterol lowering
  • HMG-CoA reductase inhibitors
  • Very potent
  • Mild decrease of TG
  • atorvastatin, simvastatin, cerivastatin,
    fluvastatin, pravastatin, lovastatin

51
EZETIMIBE
  • Cholesterol absorption inhibitor
  • Block NPC1L1 channel
  • Cholesterol lowering
  • In combination with statin very effective

52
Ezetimibe (Zetia)
This drug blocks the intestinal absorption of
cholesterol. A dose of 10 mg qd leads to a 19
reduction of LDL shows real promise in combo
product with statins (Schering- Plough and Merck)
53
RESINS
  • Cations binding bile acids in the gut
  • Cholestyramine, colestipol, colesevelam

54
Bile sequestering resins
55
FIBRATES
  • PPARs alpha agonists
  • Lower TG, increase HDL-chol.
  • Mild decrease of chol. (TC, LDL-C)
  • Fenofibrate, bezafibrate, ciprofibrate

56
NICOTINIC ACID (Niacin)
A water soluble vitamin of the B
family nicotinamide is not active
Cholesterol, TG and Lp(a) lowering HDL-chol.
increasing Severe side effects (flush, GI
symptoms, hyperglycemia, gout) TREDAPTIVE
(combination with laropiprant (PGD inhibitor)
57
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DIAGNOSTIC
  • Total. chol., HDL-chol., TAG, Lp(a)
  • LDL-chol. (Friedewalds 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)

59
nonHDL-cholesterol
  • Cholesterol within all atherogenic lipoproteins
    (not only LDL, but also VLDL, IDL, chylomikronech
    i Lp(a) !

60
FRIEDEWALDS FORMULA FOR LDL-chol.
  • LDLchol. TCH HDLchol TAG/2,2
  • TCH-total cholesterol
  • TAG-triglycerides

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63
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

64
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)

65
HIGH RISK
  • SCORE 5 - lt10
  • Total.chol.gt 8,0 mmol/l, LDL-chol.gt 6,0 mmol/l
  • BP 180/110, HT w.nephro-/retinopathy
  • Positive family history ( Mlt55 y, Wlt65 y)

66
MODERATE RISK
  • SCORE 1 - lt 5
  • Risk value may be underestimated if
  • Positive family history
  • Phisical inactivity
  • Dyslipidemia high TG / lowHDL-chol
  • Hyper Lp(a)
  • Hyperfibrinogenemia
  • Hyperhomocysteinemia (?)

67
LOW RISK
  • SCORE lt 1

68
TREATMENT GOALS IN BASIC LIPID PARAMETERS
Low risk Modera risk High risk Very High risk
LDL cholestrol lt 3,0 mmol/l lt 3,0 mmol/l lt 2,5 mmol/l lt 1,8 mmol/l
Non HDL chol. lt 3,8 mmol/l lt 3,8 mmol/l lt 3,3 mmol/l lt 2,6 mmol/l
HDL chol/apoA1 muži gt 1,0 mmol/l / 1,2 g/l ženy gt 1,2 mmol/l / 1,4 g/l muži gt 1,0 mmol/l / 1,2 g/l ženy gt 1,2 mmol/l / 1,4 g/l muži gt 1,0 mmol/l / 1,2 g/l ženy gt 1,2 mmol/l / 1,4 g/l
Triglycerides lt 1,7 mmol/l lt 1,7 mmol/l lt 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
69
GOAL for APO B
Low risk Moderate risk High risk Very high risk
Apo B lt 1,0 g/l lt 0,8 g/l
Apo B below 0,75 g/l may be of profitable
70
The End
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