CVS lipoprotein metabolism

1. Lipoproteins and their metabolism
By Don. Siyum A.

2. Complex between protein and lipid, are of two types
 Structural lipoproteins
 Present in cellular and subcellular membranes widely
distributed in tissues
 Lung surfactant (lecithin protein complex)
 Rhodopsin of rods
 Transport lipoproteins
 Present in blood plasma
 Apo(lipo)protein + lipid (C, CE, PL & TG).
Lipoproteins

3. Typical Structure of
Lipoproteins

4. Lipoproteins and Lipid transport
Why lipoproteins required?
 Lipids are insoluble in plasma
Types of lipoproteins- 4 major types
 Chylomicrons
 Very Low-Density Lipoproteins (VLDL)
 Low- Density Lipoproteins (LDL)
 High Density Lipoproteins (HDL)
How we distinguish lipoproteins from each other?
 Density , Lipid and protein composition , Role
in lipid transport 4

5. Fig: Electrophoresis pattern of plasma lipoprotein

6. Composition and Properties of Human
Lipoproteins

8. Chylomicrons VLDL LDL HDL Albumin-FFAs
complex
Source Intestine Liver/intestine VLDL Liver/intestine Liver-Adipose tissue
Electrophoretic
band
Origin Pre-β β α Plasma albumin
Diameter (nm) 75 – 1200 30-80 18-25 9-12 (HDL2); 5-
(HDL3)
-
Density (g/mL) 0.93 0.93-1.006 1.019-1.063 1.063-1.125(HDL2);
1,125-1.21(HDL3)
>1.281
Apoproteins ApoB48; CI, II,
and III; AI, II
and IV; E
ApoB100; CI,
II and III; E
ApoB100,
CI, II and
III, E
ApoAI, II, IV; CI, II
and III; E
-
% Protein 1.0 – 2.0 7.0 – 10.0 21.0 33 – 57 99
% Triglycerides 80-95 55-80 5-15 5-10 0
% Phospholipids 3-9 10-20 20-25 20-30 0
% Cholesterol
esters
2-7 5-15 40-50 15-25 0
FFAs 0 1 1 0 (HDL2); 6(HDL3) 100

9. Function of lipoproteins
 Transport of Exogenous Lipids
Chylomicrons
 Transport of Endogenous Lipids
VLDL, LDL, HDL

11. • Structural stability to the lipoproteins, e.g. Apo-B-integral proteins
• As ligands for lipoprotein-receptor
• apo B-100 and apo E for the LDL receptor,
• apo E for LDL receptor-related protein (LRP) (for chylomicron
remnant)
• apo A-I for the HDL receptor.
• As enzyme cofactors regulating LP metabolism
• apo-CII for lipoprotein lipase (LPL)
• apo A-I for lecithin:cholesterol acyltransferase (LCAT)
• As enzyme inhibitors
• apo A-II and apo C-III are inhibitors for LPL
• apo C-I for cholesteryl ester transfer protein (CETP)
Function of apoproteins/ apolipoproteins/

13. PLASMA LIPOPROTEIN METABOLISM

14. A. Chylomicrons
Source & fate of exogenous lipids
Source: dietary lipids (TG, Cholesterol,phospholipids, CE…)
Cholesterol: Intestinal cholesterol and plant sterol
absorption is mediated by Niemann- Pick C1-like 1 protein
(NPC1L1)
 Dietary cholesterol is esterified by the type 2 isozymes
of acyl coenzyme A:cholesterol acyltransferase (ACAT)
 Plant sterols are not esterified and incorporated into
chylomicrons
 Plant sterols returned to intestinal lumen via two ATP-
binding cassette (ABC) half-transporters,

15. Absorption of cholesterol and export in to blood

17. Dietary Triacylglycerol (TG)
 Re-esterification of TG in ER is regulated by diacylglycerol transferase
 TGs are transferred by microsomal TG transfer protein (MTP) to the site of
synthesized apoB-48
Formation of Nascent Chylomicron by intestinal epithelial cells
 Assembly of chylomicron with addition of apoB-48, apoA-I, apoA-IV, and some C
& E
Maturation of Chylomicron in plasma
 Acquire apoprotein from HDL in plasma: apoE and apoC-I, C-II, and C-III
 The apparent molecular wt of apoB-48 is 48% that of apoB-100.

21. Overview of the formation of triglyceride deposits in the adipose
tissue .

22. Metabolism of Circulating Chylomicron
Removal of TG
 tissues capillaries luminal surface have anchored LPL
mainly adipose tissue, skeletal and cardiac muscle(for
80% of TG), spleen, lung, renal medulla, aorta,
diaphragm and breast tissue of lactating women.
Liver capillaries : hepatic lipase
In adipose tissue (but not in muscle), insulin stimulates
lipoprotein lipase synthesis
 insulin resistance are often associated with an
increased concentration of total plasma triglycerides

23. About LPL
 Adipose tissue LPL has high Km, (cardiac) muscle has
lower Km
 ApoC-II & phospholipids are activator cofactors for LPL.
 Loss of 90% of the chylomicron TG and apo C (which
returns to HDL) while apo E is retained.

24. • Remnant attachment (lack 90% TG and apo C II)to liver
(aided by Apo E) & processed by Hepatic lipase
• apo-E mediates remnant uptake by interacting with the
hepatic LDL receptor or LRP.
• Apo protein , TG ,CE and phospholipids= Hydrolyzing in
lysosome
• LRP is the back-up receptor responsible for the uptake of
apoE-enriched remnant of chylomicron (similar for LDL)
• Blood normally contains no chylomicrons after a 12-hour
fast
uptake of Chylomicron Remnants

25.  What will happen if an individual is LPL deficient
?
 What will happen if an individual is an apo CII
deficient ?
 Hypertriglycerolemma

26. Summary: Metabolic fate of chylomicrons
HL=Hepatic Lipase; LRP, LDL receptor-related protein
High affinity of the muscle LPL permits to use Fatty acids of VLDL & Chylomicron
* Low affinity of Adipose LPL. So, lipid storage is during meal
26

27. Hypertriglyceridemia
 abnormally high quantity of chylomicrons, VLDL, or
both.
 plasma triglycerides in the fasting state: >150 mg/dL (1.7
mM).
 Severe hypertriglyceridemia: > 1,000 mg/dL (>11 mM)
 VLDL is formed at an excessive rate, or
 chylomicrons and VLDL are removed at an abnormally low rate

28.  Hypertriglyceridemia increases risk of
cardiovascular disease (mechanism unknown)
 major risk of very severe hypertriglyceridemia is
pancreatitis and tuberous xanthomas
Factors
 insulin resistance (as in all obese and most type 2
diabetic patients), hypothyroidism, excessive alcohol
intake, certain medications, pregnancy, and genetic
predisposition (lipoprotein lipase, apolipoprotein C-II,
or apolipoprotein E)

29. Reading Assignment
Association of the following with reduction of hypertriglyceridemia
 Life style
 Statin
 Fibrate drugs
 Fish oil (ω-3 fatty acids)
 Nicotinic acid (niacin)

30. B. Very-Low-Density Lipoproteins (VLDL)
Source:
 The liver
 main fats:- triglycerides , cholesterol and cholesteryl
esters
Factors Increasing Liver Lipogenesis (TG & VLDL)
(1) the fed state
(2) diets high in carbohydrate
(3) high levels of circulating free fatty acids
(4) ingestion of ethanol
(5) presence of high concentrations of insulin

31. Fig: Synthesis and assembly of Lipoprotein in liver cells.

33. • Sources of VLDL apoproteins
• Liver (constitutive): ApoB-100, also apoE, and apo C-I & C-
III ( TAG transfer protein)
• Plasma HDL: Most of the apoE & ApoC II
Metabolism of VLDL
• LPL in capillaries of muscle and adipose tissue depletes TAG
• TAG transfer to HDL and Cholesterol from HDL to VLDL (CE
transfer protein)
• decreased in size and increase in density = converted to IDL

34. Fate of IDL
• 40% - 60% of IDL cleared from plasma by the liver LDL
receptors and LRP recognizing apoB-100 & apo-E (Apo C is
returned to HDL)
• Depending on their need or cholesterol, hepatocytes and
peripheral cells display LDL receptors on their surface
• LRP is enhanced by insulin & is abundant on liver, brain, and
placenta
• LRP not significantly affected by intracellular cholesterol
concentration
• IDL is converted to LDL by removal of TGs (hepatic lipase)
• The apo E redistribute to HDL.

35. Ratio of triglyceride/cholesterol by weight
 VLDL 5 : 1
 IDL 1 : 1
 LDL 1 : 10

36. C. Low-Density Lipoprotein (LDL)
The most important function of LDL is to supply
cholesterol to the extrahepatic tissue
 ApoB-100 is the ligand that binds LDL to its
receptor
 Thyroxine and estrogen enhance LDL receptor gene
expression, lowering LDL-cholesterol.
 liver secretes the enzyme Proprotein convertase

37. Fig: Endocytosis and degradation
of lipoprotein particles.
FIG : The structure of the
LDL receptor.

38.  Deficiency of LDL receptors: A defect in LDL receptors
results in the elevation of plasma LDL-C
 Deficiency of LDL receptors is observed in type IIa
hyperbetalipoproteinemia. This disorder is associated
with a very high risk of atherosclerosi s(particuIarly of
coronary artery).

39.  About 3% of Caucasians are heterozygous for a loss-of -
function mutation in the PCSK9 gene and have better
survival of LDL receptors and about a 15% reduction in
LDL cholesterol.
 Gain-of - function mutations in PCSK9 are uncommon
and lead to hypercholesterolemia

40. D. High-Density Lipoproteins (HDL)
Synthesized by the liver and intestine
preβ-HDL:- Small-sized & contains phospholipids, free
cholesterol, and a variety of apolipoproteins,
predominantly apoA-I, apoA-II, apoC-I, and apoC-II.
 Contain very low levels of TGs or cholesterol esters
Nascent HDL (Discoid) →HDL 3 rich in A-I and apo A-II,
(spherical) → HDL2 rich in Apo E (round)
Export of Cholesterol From Peripheral Cells (Reverse
Cholesterol Transport)

42.  Lecithin: Cholesterolacyl Transferase (LCAT) bind to the disk from the circulation
(activated by apo AI)
 LCAT convert the surface phospholipid and free cholesterol into lysolecithin (which
then bind to plasma albumin) and Cholesterol ester
 VLDL exchange lipids with HDL (cholesteryl ester transfer protein (CETP) ).This is
why low HDL observed in hypertriglyceridemia.
 HDL off load some of their CE in the liver and in steroidogenic organs (SCARB1, SRB1,
SRBI) equilibrate CE in HDL with cellular CE

44.  HDL is a reservoir of apolipoproteins:
HDL particles serve as a circulating
reservoir of apo C II (an activator of
lipoprotein lipase), and apo E (
required for the receptor-mediated
endocytosis of chylomicron remnants)

46. Definition:
• Elevation of plasma cholesterol or LDL cholesterol and/or
triacylglycerol
• Accompanied by low HDL level that contributes to the
development of atherosclerosis.
Causes: Primary (genetic) disorder / Secondary to a metabolic
disease or condition.
Primary genetic dyslipidemias, hyperlipidemia
Single or multiple genetic mutations that results in
- Overproduction or defective clearance of TGs and LDL
cholesterol
- Underproduction or excessive clearance of HDL.
Overview of Hyperlipidemias (Dyslipidemias)

47.  Abetalipoproteinemia autosomal recessively inherited disorder
characterized by an absence of lipoprotein particles that carry
apoprotein B-48 or B-100 ( chylomicrons, VLDL, IDL, and LDL).
The disease is due to a deficiency of MTP.
 Familial hypobetalipoproteinemia is caused by heterozygosity of
truncated apolipoprotein B. Patients develop a fatty liver due to
reduced export of triglycerides.
 CETP defect: hypertriglyceridemia with HDL cholesterol levels
below 20 mg/ dL (0.5 mM).
 a deficiency of functional apolipoprotein A-I, ABCA1, or LCAT
:- Patients have HDL cholesterol levels lower than 20 mg/ dL (0.5
mM) without marked hypertriglyceridemia may have.

48. • Familial hypercholesterolemia
Secondary dyslipidemias : occur mainly in adults.
• Sedentary lifestyle, age, Excessive dietary saturated fat ,
cholesterol, and trans-fatty acids, disease, e.g., Diabetes
mellitus, Alcoholism, Endocrine abnormality e.g
Hypothyroidism, Primary biliary cirrhosis, Other cholestatic
liver diseases, Use of drugs that perturb LP formation or
catabolism
Hyperlipidemia is a major cause of atherosclerosis
E.g. Coronary heart disease (CHD)

49. Laboratory measurement of
Cholesterol
 Clinical laboratories routinely measure total cholesterol,
HDL cholesterol, and triglycerides in plasma samples
 LDL cholesterol is usually calculated (Friedewald
equation)
 LDL cholesterol = total cholesterol – HDL cholesterol
– (total triglycerides/5)
 If all concentrations are in mg/dLI the TG correction factor
is 0.2 ;if all concentrations are calculated in units of mM,

50. Reference
 Harper’s Illustrated Biochemistry
 Marks’ medical Biochemistry
 Lippincot Illustrated Biochemistry