Lipid transport 2020

Coronary heart disease due to atherosclerotic process is the major cause of death.Lipids have been implicated for enhanced atherosclerosis. The major lipids involved are triacy glycerol and cholesterol which are transported in the plasma by lipoproteins. So a better understanding of lipid transport and its abnormalities is essential for medical and health professional students.

1. LIPID TRANSPORT
Dr.S.Sethupathy, M.D.,Ph.D.,
Professor of Biochemistry,
Rajah Muthiah Medical College,
Annamalai University.

2. Plasma lipoproteins
Lipoproteins are involved in the transport of
lipids to tissues. (TGL and CHO)
They are molecular complexes of lipids and
proteins.
The protein content of lipoproteins is called
Apolipoprotein.
Inner core -non polar hydrophobic lipids such
as cholesterylester and triacylglycerol
Outer coat –amphipathic lipids such as
phospholipids, free cholesterol and
Apolipoprotiens.

3. LIPID TRANSPORT

4. Chylomicrons
very low density lipoproteins (VLDL)
low density lipoproteins (LDL)
intermediate density lipoprotein (IDL)
high density lipoproteins (HDL).

5. Lipoprotein Apoliprotein
contents
Chylomicron A, B48, C, E
VLDL B100, C, E
IDL B100, E
LDL B100
HDL A, C, E
Free fatty acids Albumin

6. Separation of lipoproteins by ultra
centrifugation.
The lipoprotein with more fat (TGL)
floats as it is less denser than water.
The lipoprotein with more protein
gets sedimented easily as they have
high density.
Lab blood centrifuge –2500-3000 rpm
Ultracentrifuge –40000 –50000 rpm
Chylomicrons , VLDL , IDL, LDL, HDL

7. Separation of lipoproteins by
electrophoresis
Based on charges, the lipoproteins are
separated by electrophoresis.
If the protein content is more with the
charges, move faster in an electric field and
moves longer distance. Ex: Protein rich
lipoprotein HDL is the farthest moving band
in serum Electrophoretic pattern (EPP)
Chylomicrons will not move as it has least
charges and has high fat content.

8. Ultracentifuagationand
electrophoresis

10. Functions of lipoproteins
Chylomicrons transport dietary triacylglyerol
to peripheral tissues. It is involved in
exogenous fat transport pathway.
VLDL is involved in endogenous fat transport
pathway ie: It transports triacylglycerol from
liver to other tissues.
LDL transports cholesterol to tissues.
HDL removes cholesterol from extra hepatic
tissues and transports it to liver for excretion.
-Reverse cholesterol transport pathway.

11. Lipid transport

12. Chylomicrons
Nascent chylomicrons -synthesized in the
small intestine mucosal cells -dietary
triacylglycerol, cholesteryl ester,
phospholipids and Apo B48 and Apo A
They enter lymphatics and reach circulation
In circulation, nascent chylomicrons get Apo C
and E from HDL to form mature chylomicrons.
Apo CII activates LPL on luminal surface of
endothelial cells (mainly in the skeletal
muscle, adipose tissue and heart tissues).

13. Chylomicron metabolism

14. LPL hydrolyzes triacylglycerols present in
chylomicrons
Insulin increases the LPL activity.
So in diabetes , sr.TGL is increased.
After release of TGL from chylomicrons and
transfer of Apo A and Apo CII to HDL, they
become smaller called chylomicron
remnants with Apo B48 and Apo E.
Now it is taken up by liver thro the
chylomicron remnant receptor
The plasma half life of chylomicrons is about
1 hour.

15. LPL-Lipoprotein lipase
HSPG –Heparin Sulphate
peptidoglycans
Heart, adipose,muscle, lactating
mammary gland

16. VLDL
VLDL is synthesized in liver.
Nascent VLDL with Apo B100 secreted into
the blood
In the circulation, nascent VLDL obtains Apo
E and Apo CII from HDL to form mature VLDL
LPL acts on triacylglycerol in VLDL
VLDL size is decreased and forms smaller IDL
particle with Apo B100 and Apo E as CII has
been transferred to HDL.

17. It becomes cholesterol rich LDL
with ApoB100 after Apo E has
been transferred to HDL.
Some IDL taken up the hepatic
receptors -Apo B100 and Apo E .
VLDL transports endogenous
triglycerides to from liver to
peripheral tissues for energy
needs.

18. LDL
LDL formed from VLDL in the circulation
It is cholesterol rich and contains Apo B100.
It transports cholesterol from liver to peripheral
tissues. The half life about 2 days.
LDL taken up by receptor mediated
endocytosis.
LDL receptors are located in special regions
called Clathrin-coated pits.
The Apo 100 binds to Apo B100 receptor.
Endosome fuses with lysosomes.
Receptor is recycled and returns to the cell
surface.

20. About 70% of LDL is degraded in liver and
the rest in extra hepatic tissues.
Cell membrane uses free cholesterol or it
is esterified by Acyl CoA-cholesterol acyl
transferase (ACAT) and stored as
cholesteryl ester in the cells.
Uptake of LDL is enhanced by insulin,
triiodothyronine.
In diabetes mellitus and hypothyroidism,
there will be hypercholesterolemia which
increases the risk of atherosclerosis.

23. Scavenger receptors
They are present on the macrophages.
Scavenger receptor is unregulated by
intracellular cholesterol leading to
accumulation
Become lipid loaded foam cells.
Walls of arteries results -fatty streaks -
atherosclerotic plaques due to fibrotic
changes.
Increased level of oxidized level in plasma is a
risk factor for coronary atherosclerosis.
LDL transports cholesterol from liver to the
peripheral tissues.

24. Scavenger receptor-foam cell

25. HDL
HDL transports cholesterol from peripheral tissues to
liver.
HDL acts as a reservoir of Apo C and Apo E in blood
and exchanges them with Chylomicrons and VLDL.
HDL is synthesized in liver and small intestine.
It appears as a disc shaped particle and contain Apo
A, C and E but no cholesterol.
The Apo A1 of HDL activates plasma lecithin-
cholesterol acyl transferase (LCAT) enzyme.
C2 of lecithin contains PUFA.
The cholesterol from cell is transferred to HDL by
ATP binding cassette transporter protein.

26. Lecithin cholesterol acyl
transferase

27. Cholesterylester is formed which moves into
the interior of HDL disk
HDL becomes spherical (HDL 3) due o
accumulation of cholesterylester.
The hepatic scavenger receptor B1 is involved in
uptake of HDL.
In liver, cholesterol is used for the synthesis of
bile acids or excreted in to bile as such.
This completes the reverse cholesterol transport
pathway mediated by HDL.
Cholesterylester from HDL is transferred to
VLDL, IDL and LDL by cholesterylester transfer
protein (CETP) in exchange for triacylglycerol.

28. Reverse cholesterol transport

29. HDL –good LDL -bad

30. Lipid profile
Total serum cholesterol -140-200 mg/dl
Sr.triacylglycerol -50-150 mg/dl
Sr. HDL cholesterol -40 -60 mg/dl
Sr.LDL cholesterol -60 -100 mg/dl
In male -HDL chol. Should be more than
40mg/dl
In female -HDL chol. Should be more than
50mg/dl

31. Blood sample for lipid profile
Fasting –10-12 hrs -Serum ( clotted sample)
It does not contain chylomicrons
Sr. Total Cholesterol , Sr.TAG, Sr.HDL
cholesterol are estimated.
Fridewald formula for calculation of LDL
cholesterol ( reliable for sr.T.Cho < 400mg/dl)
VLDLc= TAG/5
LDLc = Total cho -( HDLc + VLDLc)
 = Total cho -( HDLc + TAG/5)

32. Based on TAG and cholesterol

33. Familial hyperlipidemias-
Fredrickson classification
Type I Hyperlipoproteinemia
Rare, A.R -Increased sr. chylomicron -
due to deficiency LPL or Apo CII pt
Clinical features: Abdominal pain due
to pancreatitis, lipemia retinalis,
eruptive skin xanthomas, hepato
spleenomegaly.

35. Eruptive xanthomas

36. Diagnosis: Serum TAG is increased.
Serum cholesterol is normal.
A creamy layer appears on the top of
plasma kept for 24 Hours which is due
to chylomicrons.
Treatment : Restriction of fat intake
and inclusion of MCT oils such as
palm kernel oil, coconut oil and SCT
fats such as butter, cream.

37. EPP –hyperlipidemias
I.Chylomicron IIa.LDL IIb.LDLandVLDL
III.IDL IV.VLDL V.HDL

38. Type IIaHyperlipoproteinemia
(Familial hypercholesterolemia)
A.Dominantdisorder -elevated blood LDL level-
due to LDL receptor deficiency.
Clinical features: Xanthelasma, arcussenilis
(the grayingof the eye), tendon xanthomas.
Atherosclerosis and coronary heart disease are
common.
Diagnosis: Serum cholesterol is 2-3 times
increased.
Serum TAG is normal. LDL and Apo B in serum is
elevated.Serum is clear.

39. Xanthelasma

40. Tendon xanthomas

41. Normal Arcussenilis

42. Treatment: Diet SFA, MUFA, PUFA in the
ratio of 1:1:1. and total 30% calories
Cholesterol intake -less than 300 mg per day.
Animal fats should be avoided.
Intake of fiber rich diet
Exercise increases the HDL level
Statin drugs -HMG-CoA reductase inhibitors
reduce serum cholesterol
Cholestyramine, a bile acid binding resin by
increasing the excretion of bile acids
Niacin reduces both TGL and Cho.

43. Type IIbHyperlipoproteinemia
(Familial combined hyperlipidemia)
AR, elevated blood LDL and VLDL
Overproduction of Apo B & LDL receptor deficiency.
Clinical features: Xanthelasma, arcussenilis, tendon
xanthomas.
Diagnosis: BothSerum TAG and cholesterol are
increased.
Serum is slightly turbid. Both LDL and VLDL are
increased. Apo B is increased.
Treatment : Drugs Statins, fibrate, niacin are used.
Niacin reduces LDL cholesterol , VLDL cholesterol
and triacylglycerol.

44. Type III Hyperlipoproteinemia
(Familial dysbetalipoproteinemiaor
Broad beta disease)
AR -elevated blood IDL level.
It is due to defect in Apo E synthesis.
VLDL remnants are not taken up by liver.
Clinical features: Tubero-eruptive xanthomas
and palmar xanthomas. Coronary disease is
common.
Diagnosis: Due to cholesterol rich IDL,
Serum cholesterol is much increased.

45. Palmar xanthomas

46. Serum TAG is slightly elevated.
Serum is turbid.
Broad beta band in EPP.
Treatment : Drugssuch as fibrate
and statins.
Fibrate induces the LPL activity and
promotes TAG clearance.
It increases the LDL uptake.
Increase the synthesis of Apo A and
so HDL in liver.

47. Type IV Hyperlipoproteinemia
(Familial hypertriglyceridemia)
AR-Elevated blood VLDL -increased synthesis and
decreased elimination.
Clinical features: Pancreatitis can occur at very high
TAG levels. Eruptive xanthomas present.
Diagnosis: Due to TAG rich VLDL, Serum
triglycerides is much increased.
Sr.cholesterol is slightly elevated. Sr.is turbid.
Treatment: Diet -less carbohydrates and
cholesterol.
Drugssuch as fibrate, niacin and statins are used.

48. Type V Combined Hyperlipidemia
AR -elevated sr.chylomicron and VLDL levels.
Increased VLDL synthesis and decreased LPL
activity.
Eruptive xanthomas and pancreatitis occur.
Diagnosis: TAG increased and cholesterol not.
Serum -creamy upper layer -chylomicrons -
bottom is turbid due to VLDL.
Treatment : Drugssuch as Niacin and fibrates
used. Carbohydrate intake is restricted. PUFA
intake is useful.-

49. Secondary hyperlipidemias
LDL increased in :
Hypothyroidism, Nephrotic syndrome and
Obstructive liver disease
TAG increased in:
Glycogen storage disease, diabetes type II,
Obesity, pregnancy, sepsis, stress, acute hepatitis,
renal failure, multiple myeloma, alcohol, steroids,
oral contraceptives, anticonvulsants

51. Abetalipoproteinemia-RBC spiny
projections-Acanthocytes

52. Tangier disease

53. Orange yellow tonsils-Tangier

54. Thank you