1. Lipoproteins Metabolism

2. Introduction
Lipid compounds are relatively water insoluble. Therefore, they are transported in plasma (aqueous) as lipoproteins

3. Lipoproteins and Related Clinical Problems
Atherosclerosis
Hypertension
Coronary heart diseases
Lipoproteinemias (hypo- and hyper-)
Fatty liver

4. Lipoprotein Structure
Protein part:
Apoproteins or apolipoproteins
Apoproteins proteins may be structural or transferred
Lipid part:
Each lipoprotein contains different types of lipids in various combinations
Type of lipids in a lipoprotein is governed according to the type of lipoprotein

5. Lipoprotein Structure
Spherical molecules of lipids and proteins (apoproteins) = amphipathic molecules
Outer coat:
Proteins
- Apoproteins
Lipids (amphipathic)
- Phospholipids (PL)
- free Cholesterol
Inner core:
Lipids (hydrophobic)
- Triglycerides (TG)
- Cholesterol ester (CE)
Lipoprotein Structure

6. Apolipoproteins (Apoproteins)
Five major classes (A-E) divided by structure & function
Each class has subclasses as Apo A, Apo CII
Functions:
Some are required as structural proteins (i.e. they are essential structural components of the lipoprotein particles & can not be produced without them)
Some are activators for enzymes of lipoprotein metabolism
Some are recognition sites for cell-surface receptors

7. Types of Lipoproteins
Types of lipoproteins are different in lipid & protein composition & therefore, they differ in:
- Size & density
- Electrophoretic mobility

8. Types and Composition of Lipoproteins
Chylomicrons
Very low density
Lipoprotein (VLDL)
Low density
Lipoprotein (LDL)
High density
Lipoprotein (HDL)
Types and
Composition of
Lipoproteins

9. Size & Density of
Lipoproteins

10. Lipoprotein Electrophoresis

11. Plasma Lipoproteins For triacylglycerol transport (TG-rich):
- Chylomicrons: TG of dietary origin
- VLDL: TG of endogenous (hepatic) synthesis
For cholesterol transport (cholesterol-rich):
- LDL: Mainly free cholesterol
- HDL: Mainly esterified cholesterol

12. Chylomicrons Synthesis: in intestinal mucosal cells Function:
Transport dietary lipids from GIT to tissues (& liver).
Responsible for physiological milky appearance of plasma (up to 2 hours after meal)
Structure:
Lowest density
Largest size
Highest % of lipids and lowest % proteins
Highest triacylglycerol (dietary origin)

13. Type I hyperlipoprotemia
Apo E
mediates uptake
Chylomicrons metabolism

14. Lipoprotein Lipase Function of lipoprotein lipase
Extracellular enzyme anchored by heparan sulphate to the capillary walls of most tissue especially those of adipose tissue,
cardiac & skeletal muscles
BUT: Adult liver does not have this enzyme
Its synthesis & transfer to luminal surface of the capillary is stimulated by insulin (in fed state)
Activated by apoC-II
Function of lipoprotein lipase
Lipoprotein lipase hydrolyses circulating TG in chylomicrons to fatty acids & glycerol
Fatty acids are stored (in adipose) or used for energy (in muscles)
Glycerol is transferred to the liver (to be used for glycolysis, gluconeogenesis or lipid synthesis)
Deficiency of lipoprotein lipase (or apo CII) :
causes type 1 hyperlipoproteinemia (familial lipoprotein lipase deficiency)
accumulation of chylomicrons in plasma (hypertriglyceridemia)

15. Very Low Density Lipoproteins (VLDL)
- Synthesis: in the liver
- Structure: composed predominantly of triglycerides (TG)
- Function : is to carry lipids (mainly TG) from the liver to tissues.
In peripheral tissues, TG are degraded by lipoprotein lipase to FA &
glycerol.
Fatty liver (hepatic steatosis)
Occurs when TG synthesis in liver is more than VLDL secretion
As in cases of:
- Obesity
- Uncontrolled DM
- Chronic ethanol ingestion

16. Metabolism of VLDL

17. Low Density Lipoproteins (LDL)
LDL is produced in the circulation as the end product of VLDLs
Compared to VLDLs:
It contains only apo B-100 Smaller size & more dense (less lipids)
Lipid contents:
Less triglycerides (TG)
More cholesterol (C) & cholesterol ester (CE)
Function of LDL
LDL transport cholesterol from liver to peripheral tissues
Uptake of LDL at tissue level by LDL receptor-mediated endocytosis recognized by apo B-100

18. Receptor-Mediated Endocytosis
1- LDL (through apo 100), binds to LDL receptors in peripheral tissues forming a
complex
2- Internalization of the complex by endocytosis to inside cells.
3- Release of cholesterol inside the cells for: Utilization, storage (as cholesterol ester) or excretion
4- Degradation of LDL: into amino acids, PL & FAs
5- Degradation or recycling of receptor
Deficiency of functional LDL receptors:
Causes elevation of LDL in blood (& therefore blood cholesterol is elevated)
Type II hyperlipidemia (familial hypercholesterolemia)

19. LDL: Receptor-mediated endocytosis

20. LDL Receptor-Mediated Endocytosis: Regulation
Cholesterol derived from LDL causes:
1- Decrease de novo synthesis of cholesterol (by inhibition of HMG
CoA reductase)
2- Inhibition of LDL receptor synthesis at gene level
thus, limiting further entry of LDL cholesterol into cells.
3- In case cholesterol is not used immediately:
Cholesterol is esterified to cholesterol esters (CE) by:
acyl CoA: cholesterol acyltransferace (ACAT).
Cholesterol esters can be stored in cells.
ACAT is enhanced in cases of increased intracellular cholesterol.

21. Low Density Lipoprotein Cholesterol (LDL-C)
calculation
LDL-C = Total cholesterol – [ HDL-C + TG/2.2 ]
in case of mmol/L or 5 in case of mg/dL

22. Coronary Heart Disease Risk Factors
Positive Risk Factors:
Age ≥ 45 y for men , ≥55 y for females or premature menopause
Family history of premature CHD
Current cigarette smoking
Hypertension ( BP≥ 140/90 or taking antihypertensive drugs
HDL-C concentration < 40 mg/dL (< 1.0 mmol/L)
Diabetes mellitus = CHD risk equivalent
Metabolic syndrome (multiple metabolic risk factors)
Negative Risk Factors:
HDL-C concentration ≥ 60 mg/ dL (≥ 1.6 mmol/L) ; its presence removes one risk factor from the total count

23. Categories of Risk for LDL Cholesterol Goals
LDL goal mg/dL
< 100
<130
<160
Risk Category
CHD & CHD risk equivalents
Multiple (2+) risk factors
0-1 risk factor
For cholesterol the molar concentration can be changed to mass concentration by the formula: mg/dL =mmol/L x 38.7

24. High Density Lipoproteins (HDL)
Synthesis:
by intestine and liver
Nascent HDL: Disk-shaped Contains apo A-I, C-II and E Contains primarily phospholipid (PC)
Mature HDL (HDL2): First, the HDL3 collects cholesterol (C) from peripheral tissues & other lipoproteins. Then, Cholesterol is converted to CE (by PCAT) to form HDL2.
CE is transported to liver by HDL2.

25. HDL Metabolism

26. Composition of LDL and HDL Mostly free cholesterol
Low density lipoprotein (LDL)
Mostly free cholesterol
High density lipoprotein (HDL)
Mostly cholesterol ester
More % protein
More % phospholipids

27. Functions of HDL Reservoir of apoproteins e.g. Apo C-II and E to VLDL
Uptake of cholesterol: From peripheral tissue (& other lipoproteins)
Esterification of cholesterol: Enzyme: PCAT/LCAT Activator: Apo A-I Substrate: Cholesterol, Co-substrate: PC Product: Cholesterol ester (& Lyso-PC)
Reverse cholesterol transport
transports cholesterol from peripheral tissues to liver

28. Cholesteryl Ester Transfer Protein
VLDL CE
PL ,TAG
HDL
Cholesteryl Ester Transfer Protein

29. Why Is HDL a Good Cholesterol carrier?
Inverse relation between plasma HDL levels and atherosclerosis …. How?
Reverse cholesterol transport involves: Efflux of cholesterol from peripheral tissues and other lipoproteins to HDL3
Esterification of cholesterol & binding of HDL2 to liver (and steroidogenic cells) by scavenger receptor class B (SR-B1)
Selective transfer of cholesterol ester into these cells
Release of lipid-depleted HDL3

30. Lp (a) Simulates LDL but apo(a) covalently linked to apo B-100
Competes with plasminogen to plasminogen activator
Genetical element
Estrogen decreases it while trans fats increases it

31. Abnormalities in lipoprotein metabolism
Hyperlipoprotenemias
1- Type I hyperlipoproteinemia:
Familial lipoprotein lipase deficiency
- Due deficiency of lipoprotein lipase or apo C-II
- Slow clearance of TG–rich lipoproteins in plasma (chylomicrons & VLDL)
- Hypertriacylglyceremia (increased TG in blood)
- Treated by reducing fat in diet
2- Type II hyperlipoproteinemia :
Familial hypercholesterolemia
- Due to deficiency of functional LDL receptors
- Reduced clearance of LDL
- Elevation of plasma cholesterol (but plasma TG remains normal)
- Predispose to atherosclerosis & CHD

32. Abnormalities in lipoprotein metabolism cont.
3- Type III hyperlipoproteinemia
familial dysbetalipoproteinemia or broad B disease
- Due to abnormal apo E (on chylomicrons)
- Reduction of clearance of chylomicron remnants by liver
- Accumulation of chylomicron remnants in plasma.
- Hyperchloesterolemia
- Predispose to atherosclerosis & CHD
4- Type IV hyperlipoproteinemia
Familial hypertriacylglycerolemia
- Increased production of VLDL
- Commonly associated with type II DM & obesity
- Elevated blood TG & cholesterol
- Predispose to atherosclerosis & CHD.

33. Abnormalities in lipoprotein metabolism cont.
Hypolipoproteinemia
1- Abetalipoproteinemia
- defect in triacylglycerol transfer protein (MTP) responsible for loading of apo-100 with
lipid with no chylomicrons & no VLDL synthesis
- No chylomicrons synthesis in intestine  ↓ blood TG
- No VLDL synthesis in liver  ↑ TG in liver
- No VLDL synthesis  no LDL  ↓ blood cholesterol
2- Familial hypobetalipoproteinanemia
- ↓ apo B-100 synthesis
- ↓ VLDL  ↓ blood TG & ↑ TG in liver
- ↓ LDL  ↓ blood cholesterol