5- Lipoprotein metabolism and disorders Prof. Dr. Gül Nihal Özdemir.pdf

Describes the common lipoprotein disorders including their mechanical causation. Dyslipidemia and hyperlipidemia are well described including the varying roles of LDL cholesterol.

1. Lipoprotein metabolism
and disorders
Prof. Dr. Gül Nihal Özdemir
PediatricHematology

2. Lipoproteins
•Lipids, such as cholesterol and triglycerides, are insoluble in plasma.
•Circulating lipid is carried in lipoproteins that transport the lipid to various
tissues for energy utilization, lipid deposition, steroid hormone production,
and bile acid formation.
•Apoprotein+ lipids: lipoproteins

3. Lipoproteins
•The five major lipoproteins
•Chylomicrons—Chylomicrons are very large particles that carry dietary lipid.
•Very low density lipoprotein—Very low density lipoprotein (VLDL) particles carry
endogenous triglycerides and to a lesser degree cholesterol.
•Intermediate-density lipoprotein—Intermediate density lipoprotein (IDL) particles
carry cholesterol esters and triglycerides.
•Low-density lipoprotein—Low density lipoprotein (LDL) particles carry cholesterol
esters
•High-density lipoprotein—High density lipoprotein (HDL) particles carry cholesterol
esters.

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6. LIPID METABOLISM
•Exogenous
•Endogenous

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8. EXOGENOUS
•The exogenous pathway starts with the intestinal absorption of dietary cholesterol
and fatty acids.
•Within the intestinal cell, free fatty acids combine with glycerol to form triglycerides.
•Triglycerides and cholesterol are assembled intracellularlyas chylomicrons.
•Through circulationLipoproteinlipaseenzymehydrolyzes chylomicronstothe
core triglycerides and releasefree fatty acids.
•The free fatty acids are then used as an energy source, converted to triglyceride, or
stored in adipose tissue.
•The end-products of chylomicron metabolism are chylomicron remnants

9. ENDOGENOUS
•The endogenous pathway of lipid metabolism begins with the synthesis of very
low density lipoprotein (VLDL) by the liver.
•The packaging of hepatic triglycerides toVLDL requires the action of the enzyme
microsomal triglyceride transfer protein (MTP).
•The triglyceride core VLDL particles is hydrolyzed by lipoprotein lipase.
•During lipolysis, the core of the VLDL particle is reduced, generating VLDL
remnant particles (also called intermediate density lipoprotein [IDL]).
•The hydrolysis of triglycerides releases free fatty acids that are then used as an
energy source, converted to triglyceride, or stored in adipose tissue.

10. ENDOGENOUS
•The liver removes approximately 40–60% of IDL. The remainder of IDL is
remodeled by hepatic lipase (HL) to form LDL.
•Approximately 70% of circulating LDL is cleared by LDL receptor–
mediated endocytosis in the liver.
•Lipoprotein(a)[Lp(a)] is a lipoprotein similar to LDL in lipid and protein
composition, but it contains an additional protein calledapolipoprotein(a).

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13. HDL METABOLISM AND REVERSE
CHOLESTEROL TRANSPORT
•All nucleated cells synthesize cholesterol, but only hepatocytes and
enterocytes can effectively excrete cholesterol from the body, into either the
bile or the gut lumen.
•In the liver, cholesterol is secreted into the bile, either directly or after
conversion to bile acids.
•Cholesterol in peripheral cells is transported from the plasma membranes of
peripheral cells to the liver and intestine by a process termed “reverse
cholesterol transport” that is facilitated by HDL

14. DYSLIPIDEMIA
•Dyslipidemiais
•total cholesterol, low density lipoproteinscholesterolortriglyceridelevels above
the 90th percentile
•OR
•high density lipoprotein cholesterol levels below the 10th percentile for the
general population

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16. DYSLIPIDEMIAAND
ATHEROSCLEROSIS
•Abnormal lipoprotein metabolism is a major predisposing factor to
atherosclerosis.
•It is estimated that a dyslipidemia is present in over 70 percent of patients
with premature coronary heart disease.

17. DYSLIPIDEMIA
•The disturbance in lipoprotein metabolism is often familial.Inheritanceis polygenic
and the expression of dyslipidemia is strongly influenced by factors such as obesity
(particularly central obesity/visceral adiposity) and the saturated fat and cholesterol
content of the diet.
•There is a less common, but important, group of familial disorders that are
monogenic.

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19. DYSLIPIDEMIA
•Type I –Serum concentration of chylomicrons elevated; triglyceridesconcentrations are elevated to >99th
percentile.
•Type IIa–Serum concentration of low density lipoprotein (LDL) cholesterol elevated; the total cholesterol
concentration is >90th percentile. Concentrations of triglyceride and/or apolipoproteinB may also be ≥90th
percentile.
•Type IIb–Serum concentrations of LDL and very low density lipoprotein (VLDL) cholesterol elevated;
total cholesterol and/or triglycerides may be ≥90th percentile and apolipoproteinB ≥90th percentile.
•Type III –Serum concentration of VLDL remnants and chylomicrons elevated; total cholesterol and
triglycerides >90th percentile.
•Type IV –Serum concentrations of VLDLelevated; total cholesterol may be >90th percentile and may also see
triglyceride concentrations >90th percentile or low high density lipoprotein.
•Type V –Elevated serum concentrations of chylomicrons and VLDL; triglycerides >99th percentile

20. HYPERLIPOPROTEINEMIAS
•HYPERCHOLESTEROLEMIA
•FamilialHypercholesterolemia:
•AD
•Mutationsin LDL receptors
•VeryhighLDL cholesterol
•Premature cardiovasculardisease, tendonxanthomas

22. HYPERLIPOPROTEINEMIAS
•HYPERCHOLESTEROLEMIA
•AutosomalRecessiveHypercholesterolemia:
•AR
•Rare
•Mutationsin LDL receptorsmediatedendocytosisin liver
•Severe hypercholesterolemia

23. HYPERLIPOPROTEINEMIAS
•HYPERCHOLESTEROLEMIA
•Sitosterolemia:
•AR
•Excessiveabsorptionof plantbasedsterols
•Severe hypercholesterolemia
•Premature cardiovasculardisease, tendonxanthomas

24. HYPERLIPOPROTEINEMIAS
•HYPERCHOLESTEROLEMIA WITH HYPERTRIGLYCERIDEMIA
•FamilialcombinedHyperlipidemia:
•AD
•Moderateelevationin LDL, TG andreducedHDL
•Itis themostcommonprimarylipiddisorder
•XantomasareNOT seen
•Premature cardiacdiseaseis present

25. HYPERLIPOPROTEINEMIAS
•HYPERCHOLESTEROLEMIA WITH HYPERTRIGLYCERIDEMIA
•FamilialDysbetalipoproteinemia:
•Mutationsin apolipoproteinE (apoE)
•Mixed typeof hyperlipidemia
•ElevatedTG andcholesterol
•HDL is normal (not lowas in othertypes)
•Palmarxanthomas
•Tuberoeruptivexanthomas

26. Palmarxanthomas: orangeyellowdiscolorationof thecreasesof thehands

27. Tuberoeruptivexanthomas: grapelikeclusterson theknees, buttocksandelbows

28. HYPERLIPOPROTEINEMIAS
•HYPERTRIGLYCERIDEMIA
•Type I Hyperlipidemia(Familialchylomicronemia):
•AR
•Deficiencyof lipoproteinlipase
•ElevatedTG richplasmachylomicrons
•HDL decreased
•Plasmahas a turbidapperanceevenafterfasting
•Inchildhoodmaycausepancreatitis

29. Eruptivexanthomas: on arms, kneesandbuttocks

31. HYPERLIPOPROTEINEMIAS
•HYPERTRIGLYCERIDEMIA
•Type IV Hyperlipidemia(Familialhypertriglyceridemia):
•AD
•High TG levels
•LowHDL
•Thediagnosisrequiresat least1 firstdegreerelativewithhyperTG

32. HYPERLIPOPROTEINEMIAS
•HYPERTRIGLYCERIDEMIA
•Hepaticlipasedeficiency:
•Rare
•AR
•High TG
•HDL alsoincreased

33. HYPERLIPOPROTEINEMIAS
•HDL DISORDERS
•PrimaryHypoalphalipoproteinemia:
•MostcommonHDL disorder
•IsolatedlowHDL

34. HYPERLIPOPROTEINEMIAS
•HDL DISORDERS
•TangierDisease:
•VerylowHDL levels
•Freecholaccumulationin reticuloendothelialsystem: tonsillarhypertrophy
withorangecolourhepatosplenomegaly
•Intermittenperipheralneuropathyduetocholaccumulation

36. HYPERLIPOPROTEINEMIAS
•DISORDERS OF apo-B LIPOPROTEINS
•Abetalipoproteinemia:
•Mutationsin themicrosomalTG transfer protein
•AR
•Transfer of lipidstochylomicronsin thesmallintestine
•Absenceof chylomicrons, VLDL, LDL amdverylowcholandTG levels
•Fatmalabsorption, diarrhea, failuretothrive

37. HYPERLIPOPROTEINEMIAS
•DISORDERS OF apo-B LIPOPROTEINS
•Abetalipoproteinemia:
•Fatdependantvitamine deficiency
•Vitamin E deficiencycausesataxiaandspasticity
•Progressivepigmentedretinopathyassociatedwithnightandcolorvision
problemsleadingtoblindness
•On peripheralbloodsmearacanthocytosis

39. HYPERLIPOPROTEINEMIAS
•DISORDERS OF apo-B LIPOPROTEINS
•Smith-Lemli-OpitzSyndrome:
•Multiplecongenitalanomaliesanddevelopmentaldelay
•Lowplasmachol
•AR
•Cholesterolsynthesisdefect