Normal Physiology of Lipoproteins Types of lipoproteins Abnormalities related to lipoproteins

1. Abnormalities in Lipoproteinemia
Mr. JaineelDharod
Dept. of Pharmacology

2. Index
Introduction
Definition
Ranges
Structure
Classification
Functions
Abnormalities

3. Lipoprotein:
➢ Lipids absorbed from the diet and synthesized by the liver and
adipose tissue must be transported between various cells and organs
for utilization and storage.
➢ Lipids are insoluble in water, the problem of transportation in the
aqueous plasma is solved by associating nonpolar lipids
(triacylglycerol's and cholesteryl esters) with amphipathic lipids
(phospholipids and cholesterol) and proteins to make water-
miscible lipoproteins.

4. Definition:
 A lipoprotein is a biochemical assembly that contains both proteins
and lipids, bound to the proteins , which allow fats to move through
the water inside and outside cells.
 The proteins serve to emulsify the lipid molecules.
 Many enzymes, transporters, structural proteins, antigens, and toxins
are lipoproteins.

5. Ranges:

6. Structure
 Lipoproteins consist of a nonpolar core and a single surface layer of
amphipathic lipids
 The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl
ester and is surrounded by a single surface layer of amphipathic
phospholipid and cholesterol molecules
 These are oriented so that their polar groups face outward to the aqueous
medium
 The protein moiety of a lipoprotein is known as an apolipoprotein or
apoprotein.

8. Classification
Lipoproteins can be classified in three ways-
1) Based on density-
They are separated by Ultracentrifugation.
Depending upon the floatation constant (Sf), Five major groups of
lipoproteins have been identified that are important physiologically
and in clinical diagnosis.
✓ Chylomicrons,
✓ VLDL
✓ IDL
✓ LDL
✓ HDL

9. (i)Chylomicrons,
-derived from intestinal absorption of triacylglycerol and other lipids;
-Density < 0.95 while
-mean diameter 100- 500 nm
(ii)Very low density lipoproteins (VLDL),
-derived from the liver for the export of triacylglycerol;
-density 0.95- 1.006
-mean diameter 30-80 nm.
(iii)Intermediate density lipoproteins (IDL)
- derived from the catabolism of VLDL,
-density 1.006-1.019
-mean 25-50nm.

10. iv) Low-density lipoproteins (LDL),
-representing a final stage in the catabolism of VLDL;
-density1.019-1.063
-mean diameter 18-28 nm
(iv) High-density lipoproteins (HDL),
-involved in cholesterol transport and also in VLDL and chylomicron
metabolism.
-Density 1.063-1.121
-mean diameter 5-15 nm.

12. 2) Based on electrophoretic mobilities
➢ Lipoproteins may be separated according to their electrophoretic
properties into - pre β, β, and broad beta lipoproteins.
➢ The mobility of a lipoprotein is mainly dependent upon protein
content.
➢ Those with higher protein content will move faster towards the
anode and those with minimum protein content will have
minimum mobility.

13. ▪ HDL are -α , VLDL pre- β, LDL-β , and IDL are broad beta
lipoproteins.
▪ Free fatty acid and albumin complex although not a lipoprotein is
an important lipid fraction in serum and is the fastest moving
fraction.
▪ Chylomicrons remain at the origin since they have more lipid
content.
▪ VLDLs with less protein content than LDL move faster than
LDL, this is due to nature of apoprotein present.

14. 3) Based on nature of Apo- protein content
❑One or more apolipoproteins (proteins or polypeptides) are present
in each lipoprotein.
❑The major apolipoproteins of HDL (α-lipoprotein) are designated A.
❑The main apolipoprotein of LDL (β -lipoprotein) is apolipoprotein B (B-
100), which found also in VLDL.
❑Chylomicrons contain a truncated form of apo B (B-48) that is
synthesized in the intestine, while B-100 is synthesized in the liver.
❑Apo E is found in VLDL, HDL, Chylomicrons.

16. LDL – Low Density Lipoproteins

17. ✓ They are products of VLDL and IDL metabolism, and the most
cholesterol rich of all lipoproteins.
Low density lipoprotein is sometimes called "bad cholesterol“
LDL are the principal cholesterol and fat transporter in human
blood thatcarries cholesterol from the liver to the body tissues
and cells.
Function of LDLs :

18.  Despite cholesterol's negative reputation, it's nevertheless an
important biomolecule that serves a number of vital purposes in
the body.
 Appropriate levels of LDL cholesterol can positively impact health in
many ways.
 In metabolism their function is mediating by cellular uptake via
receptor - mediated endocytosis followed by lysosomal degradation ,
and is strongly dependent on the lipid distribution .

19.  Apart from their well-established role as lipid transporter,
 LDL particles are intimately involved in the progression of
cardiovascular diseases such as atherosclerosis or stroke, which are
among the most prevalent causes ofdeath.
 Raised plasma levels of LDL are linked to an increased risk for disease.

20. Metabolism of LDL
➢ About 40 to 60% of all LDL are cleared by the liver in a process
mediated by apo B and hepatic LDL receptors.
➢ The rest are taken up by either hepatic LDL or non-hepatic non-
LDL (scavenger) receptors.
Hepatic LDL receptors are down-regulated by :
 delivery of cholesterol to the liver by chylomicrons, and by
increased dietary saturated fat.
 They can be up-regulated by decreased dietary fat andcholesterol.

21. Non-hepatic scavenger receptors
 most notably on macrophages.
 take up excess oxidized circulating LDL not processed by hepatic
receptors.
 Monocytes rich in oxidized LDL migrate into the sub-endothelial
space and become macrophages.
 These macrophages are then take up more oxidized LDL and
form foamcells within atherosclerotic plaques .

22. HDL – High Density Lipoproteins

23.  HDL type is the smallest of the lipoprotein particles.
 It is the densest because it contains the highest proportion of protein
to lipids.
 Its most abundant apolipoproteins .

24. FUNCTION OF HDL:
High density lipoprotein (HDL) particles are protective particles that
have functions in the body.
They :
➢ Play a key role in protecting against heart disease via their role in
reverse cholesterol transport, or the transport of excess
cholesterol out of the body.
➢ Are also part of the innate immune system due to their ability to
bind a number of toxic substances in the blood.

25.  HDL is synthesized and secreted from both liver and intestine .
 However, apo C and apo E are synthesized in the liver and
transferred from liver HDL to intestinal HDL when the latterenters
the plasma.
 A major function of HDL is to act as a repository for the apo C and
apo E required for the metabolism of chylomicrons and VLDL.
Synthesis of HDL

26.  LCAT and the LCAT activator apo A-I—bind to the discoidal
particles, and the surface phospholipid and free cholesterol are
converted into cholesteryl esters and lysolecithin .
 The nonpolar cholesteryl esters move into the hydrophobic interior
of the bilayer, whereas lysolecithin is transferred to plasma
albumin.
 Thus, a nonpolar core is generated, forming a spherical,
pseudomicellar HDL covered by a surface film of polar lipids
and apolipoproteins.
 This aids the removal of excess unesterified cholesterol from
lipoproteins and tissues .

27. Chylomicron
Chylomicron (from the Greek chylø, meaning juice or milky
fluid, and micron, meaning small particle) are lipoprotein particles
that consist of:
 Triglycerides (85–92%),
 Phospholipids (6–12%),
 Cholesterol (1–3%),
 Proteins (1–2%).

28. Function of chylomicron
✓ Chylomicrons transport lipids absorbed from the intestine to adipose,
cardiac and skeletal muscle tissue, where their triglyceride components are
hydrolyzed by the activity of lipoprotein lipase and the released free fatty
acids are absorbed by the tissue.
✓ When a large portion of the triacylglycerol core have been hydrolyzed,
chylomicron remnants are formed and are taken up by the liver, hereby
transferring dietary fat also to the liver.
✓ It transports dietary fats and cholesterol from intestines to tissues.

29. Metabolism of chylomicron
 The enzyme lipoprotein lipase, with apolipoprotein (apo)C-II as a co-factor,
hydrolyzes chylomicron triglyceride allowing the delivery of free fatty acids
to muscle and adipose tissue.
 As a result, a new particle called a chylomicron remnant is formed. This
particle is enriched in cholesteryl ester and fat-soluble vitamins and contains
apoB-48 andapoE.
 It is rapidly removed from the circulation by the liver. ApoE is the moiety
required forrapid hepatic removal.
 Its activity is inhibited by C apolipoproteins, especially apoC-I.

30.  The particle must first achieve a size that allows it to be "sieved" through the
endothelial fenestre
 Here, it may
 1) be removed directly by LDL receptors.
2) acquire additional apoE that is secreted free into the space, and then be
removed directly by the LDL receptor-related protein (LRP);
3) it may be sequestered in the space. Sequestration occurs by binding of
apoE to heparan sulfate proteoglycans and/or binding of apoB to hepatic
lipase.

31. Very-low-density lipoprotein (VLDL)
It is a type of lipoprotein made by the liver.

32. Function of VLDL
• VLDL transports endogenous triglycerides, phospholipids, cholesterol, and
cholesteryl esters.
• It functions as the body's internal transport mechanism for lipids.
• In addition it serves for long-range transport of hydrophobic intercellular
messengers, like the morphogen.

33. Metabolism of VLDL
 VLDL metabolism is very similar to Chylomicrons metabolism.
 The main lipid found in VLDL is also triacylglycerol, but in this case triacylglycerols come
from excess fatty acids on diet or an increase in the hepatic synthesis of fatty acids as a
consequence of excess carbohydrates in diet.
 Fats coming from the hepatocytes uptake of Chylomicrons remnants are also a source of
triacylglycerols for VLDL.
 Additionally to triacylglycerols, VLDL contains around 35 % of free and esterified
cholesterol, 35 % of phospholipids, and various apoproteins, including ApoB-100.
 VLDL, in the same way than Chylomicrons, acquires in the blood stream Apo C-II and Apo E.
The functions of these apoproteins in VLDL are similar to their functions in Chylomicrons:
Apo C-II activates Lipoprotein Lipase and as a consequence, VLDL triacylglycerols are
hydrolyzed, so the proportion of cholesterol increases.

34. IDL (intermediate density lipoprotein)
 -It’s formed from the degradation of very low-density lipoproteins.
 Their size is, in general, 25 to 35 nm in diameter, and they contain primarily
a range of triacylglycerols and cholesterol esters.

35. Function of IDL
 It enables fats and cholesterol to move within the water-based
solution of thebloodstream.
 Each native IDL particle consists of protein that encircles various
fatty acids, enabling, as a water - soluble particle, these fatty
acids to travel in the aqueous blood environment as part of the fat
transport system within the body.
 In general, IDL, somewhat similar to low-density lipoprotein (LDL),
transports a variety of triglyceride fats and cholesterol and, like
LDL, can also promote the growth ofatheroma.

37. Abnormalities
✓ Hypolipoproteinemia
✓ Hyperlipoproteinemia

38. Hypolipoproteinemia

39. Hyperlipoproteinemia

40. Hyperlipoproteinemia

41. Hyperlipoproteinemia
 It is also known as hyperlipidaemia or hyperlipoproteinemia
 In this case it is defined as a presence of raised or abnormal levels of
lipids and/or lipoproteins in the blood
 This is abnormality is common in the general population, and is one of the
most important modifiable risk factors for coronary heart disease (CHD).
 Dyslipidaemia is generally characterized by increased fasting
concentrations of total cholesterol (TC), LDL cholesterol (LDL-C), and
triglycerides (TG), in conjunction with decreased concentrations of HDL
cholesterol (HDL-C)

42.  On diagnosing hyperlipoproteinemia, hyperlipidaemic status
should be evaluated to determine whether it is primary lipoprotein
disorder or secondary to any of a variety of metabolic diseases.
 The diagnosis of primary hyperlipoproteinemia is made after
secondary causes have been excluded.

43. Hereditary Hyperlipoproteinemia's
✓ Familial Lipoprotein lipase deficiency (Type I Hyperlipoproteinemia).
✓ Characterized by high levels of chylomicrons and triglycerides and a
deficiency of lipoprotein lipase, an enzyme that accelerates the
breakdown of lipoproteins.
✓ Disease onset is usually in infancy.
✓ Type 1 has a pure elevation of triglycerides in the chylomicron fraction.
✓ These people sometimes get pancreatitis and abdominal pains, but they
do not seem to have an increase in vascular disease

44.  Type II, broken into two subtypes, type II-a and type II-b.
 Have elevated cholesterol.
 Some have elevated triglycerides also.
 The familial (genetic) versions of Type 2 often develop
xanthomas, which are yellow fatty deposits under the skin of the
knuckles, elbows, buttocks or heels.
 They may also have smaller yellow patches on the eyelids.
 Both subtypes display high levels of blood cholesterol.
 People with type II-b also have high levels of triglycerides in their
blood. Disease onset is usually after age 20.
Type II Familial hypercholesterolemia

46. DYSBETALIPOPROTEINEMIA
▪ also called broad beta disease.
▪ Accumulation of IDL, VLDL and chylomicron remnant.
▪ Elevated level of total cholesterol and triglycerides
▪ The disorder caused by Apo-E or Apo-E receptor.
▪ Diabetes, hypothyroidism are associated with type III
disorders.
▪ Type 3 appears in one in 10,000 people and elevates both
triglycerides and cholesterol with consequent vascular disease,
▪ Disease onset is usually in adults.

47. Abetalipoproteinemia
✓ Elevates only triglycerides and does not increase the risk of vascular
disease
✓ Genetic defect in the synthesis of Apo-B.
✓ Both chylomicron and VLDL are affected.
✓ Fat malabsorption occurs because chylomicron can not be formed by
intestine.
✓ Disease onset is usually during puberty or early adulthood.

48. Secondary hyperlipoproteinemia
 Diabetes mellitus, because it alters the way the body handles its energy
needs, also affects the way it handles fats. The result is elevated triglycerides
and reduced HDL cholesterol. This effect is amplified by obesity
 Hypothyroidisms a common cause of lipid abnormalities. The thyroid hormone
affects the rate of many chemical processes in the body, including the clearing of
fats from the blood. The consequence is usually an elevation of cholesterol
 Kidney disease affects the blood's proteins and consequently the composition
of the fat packages. It usually raises the LDLs
 Liver disease, depending on its stage and severity, can raise or lower any of the
blood fats
 Alcohol raises triglycerides
 Cigarettes smoking lowers HDL cholesterol, as does malnutrition and obesity.

49. ➢ Usually high lipid levels are asymptomatic
➢ Occasionally when fat levels are high, it can be deposited in skin and
tendons forming bumps called xanthomas (eyes and Achilles tendon)
➢ Very high triglyceride levels may cause liver to enlarge
➢ High lipids increase the risk of developing pancreatitis, which causes
severe abdominal pain and is sometimes fatal
➢ Human coronary atherosclerosis is a chronic inflammatory disease that is
superimposed on a background of lipid abnormalities.
➢ In humans, oxidized LDL in plasma and within atherosclerotic lesions is
strongly associated with coronary artery disease, acute coronary
syndromes, and vulnerable plaques

50. Factors
 Levels of lipoproteins and lipids (LDL) increase slightly with age.
Other factors associated with increase of these are:
 familial history
 Obesity
 diet high in saturated fat
 Inactivity
 alcohol consumption

51. Thank You