1. Lipoprotein Structure, Function, and Metabolism
Lipid Transport
Lipoprotein Structure, Function, and Metabolism

2. Introduction
Fats are triacylglycerols containing saturated fatty acids - solid at room temp - usually from animal source (however, coconut & palm oil are saturated).
Oils are triacylglycerols containing mono- or polyunsaturated fatty acids - liquid at room temp
- usually from plant sources (however, fish oils are polyunsaturated).
Phospholipids are triacylglycerols that have had a FA replaced with a phosphate linked FA group.
The major dietary sterol is cholesterol.

3. Health issues
Excessive dietary fat intake is associated with obesity, diabetes, cancer, hypertension and atherosclerosis.
Not more than 35% of energy intake should come from fat. Saturated fat should not make up more than 15% of the total fat intake.
Omega-3 fatty acids (20 carbons) from fish may protect against atherosclerosis. American Heart association recommends 2-3 fish meals per weak. Fish oil supplements should be avoided because they may be contain concentrated toxins accumulated by the fish.  

4. FUNCTIONS OF LIPIDS: Major components of cell membranes.
Biosynthesis of fat soluble vitamins.
Biosynthetic precursors (e.g. steroid hormones from cholesterol)
Protection (e.g. kidneys are shielded with fat in fed state)
Insulation

5. LIPID DIGESTION
Stomach - lingual lipase and gastric lipase attack triacylglycerols and hydrolyse a limited number of FA.
Small Intestine - acid chyme (stomach contents) stimulates mucosa cells to release hormone (choleocystokinin) which stimulates gall bladder and pancreas to release bile and digestive enzymes respectively (bile acids help emulsify fat droplets thus increasing their surface area).
Other mucosa cells release secretin which causes pancreas to release bicarbonate rich fluid to neutralise chyme.

6. Enzymic digestion of lipids in small intestine
2-monoacylglycerol

7. Lipid transport in the circulation
Lipids are insoluble in plasma. In order to be transported they are combined with specific proteins to form lipoproteins:
Proteins (apoproteins)
Non polar lipids in core (TAG and cholesterol esters)
Cholesterol

8. The four classes of lipoprotein (all contain characteristic amounts TAG, cholesterol, cholesterol esters, phospholipids and apoproteins)
Class
Diameter (nm)
Source and function
Major apoliproteins
Chylomicrons (CM)
500
Intestine. Transport of dietary TAG
A, B48, C(I,II,III) E
Very low density lipoproteins (VLDL) 43
Liver. Transport of endogenously synthesised TAG
B100, C(I,II,III) , E
Low density lipoproteins
(LDL) 22
Delivers cholesterol to peripheral tissues
B100
High density lipoproteins
(HDL) 8
Liver. Removes “used” cholesterol from tissues and takes it to liver.
A, C(I,II,III), D, E
Increasing density

9. Apolipoproteins Provide structural stability to Lp
Serve as ligands for interaction w/Lp receptors that help determine disposition of individual particles
Act as cofactors for enzymes involved in plasma lipid and Lp metabolism

10. There are many types of apolipoproteins
Apoprotein
Lipoproteins
Function(s)
Apo B-100
VLDL, IDL, LDL
Secretion of VLDL from liver
Structural protein of VLDL, IDL, and HDL
Ligand for LDL receptor (LDLR)
Apo B-48
Chylomicrons, remnants
Secretion of chylomicrons from intestine;
Apo E
Chylomicrons, VLDL, IDL, HDL
Ligand for binding of IDL & remnants to LDLR and LRP
Apo A-I
HDL, chylomicrons
Major structural protein of HDL
Activator of LCAT
Apo A-II
Unknown
Apo C-I
Modulator of hepatic uptake of VLDL and IDL (also involved in activation of LCAT)
Apo C-II
Activator of LPL
Apo C-III
Inhibitor of LPL activity

11. Plasma Lipoproteins Structure
LP core
Triglycerides
Cholesterol esters
LP surface
Phospholipids
Proteins
cholesterol

12. Composition and properties of human lipoproteins
Lipoprotein class
Density (g/mL)
Diameter (nm)
Protein % of dry wt
Phospholipid %
Triacylglycerol % of dry wt
HDL
5 – 15 33 29 8
LDL
1.019 – 1.063
18 – 28 25 21 4
IDL 18 22 31
VLDL
0.95 – 1.006 10 50
chylomicrons
< 0.95
1 - 2 7 84
Composition and properties of human lipoproteins
most proteins have densities of about 1.3 – 1.4 g/mL and lipid aggregates usually
have densities of about 0.8 g/mL

13. Plasma Lipoproteins Classes & Functions
Chylomicrons
Synthesized in small intestine
Transport dietary lipids
98% lipid, large sized, lowest density
Apo B-48
Receptor binding
Apo C-II
Lipoprotein lipase activator
Apo E
Remnant receptor binding

14. Plasma Lipoproteins Classes & Functions
Very Low Density Lipoprotein (VLDL)
Synthesized in liver
Transport endogenous triglycerides
90% lipid, 10% protein
Apo B-100
Receptor binding
Apo C-II
LPL activator
Apo E
Remnant receptor binding

15. Plasma Lipoproteins Classes & Functions
Intermediate Density Lipoprotein (IDL)
Synthesized from VLDL during VLDL degradation
Triglyceride transport and precurser to LDL
Apo B-100
Receptor binding
Apo C-II
LPL activator
Apo E

16. Plasma Lipoproteins Classes & Functions
Low Density Lipoprotein (LDL)
Synthesized from IDL
Cholesterol transport
78% lipid, 58% cholesterol & CE
Apo B-100
Receptor binding

17. LDL molecule

18. VLDL Metabolism Nascent VLDL (B-100) + HDL (apo C & E) = VLDL
LPL hydrolyzes TG forming IDL
IDL loses apo C-II (reduces affinity for LPL)
75% of IDL removed by liver
Apo E and Apo B mediated receptors
25% of IDL converted to LDL by hepatic lipase
Loses apo E to HDL

19. Plasma Lipoproteins Classes & Functions
High Density Lipoprotein (HDL)
Synthesized in liver and intestine
Reservoir of apoproteins
Reverse cholesterol transport
52% protein, 48% lipid, 35% C & CE
Apo A
Activates lecithin-cholesterol acyltransferase (LCAT)
Apo C
Activates LPL
Apo E
Remnant receptor binding

20. Functions of HDL
converts cholesterol to cholesterol esters via the LCAT reaction
transfers cholesterol esters to other lipoproteins, which transport them to the liver (referred to as “reverse cholesterol transport)

21. Coordinate Control of Cholesterol Uptake and Synthesis
Increased uptake of LDL-cholesterol results in:
inhibition of HMG-CoA reductase
reduced cholesterol synthesis
stimulation of acyl CoA :cholesterol acyl transferase (ACAT)
increased cholesterol storage
decreased synthesis of LDL-receptors
“down-regulation”
decreased LDL uptake

22. Atherosclerosis
hardening of the arteries due to the deposition of atheromas
heart disease is the leading cause of death
caused by the deposition of cholesteryl esters on the walls of arteries
atherosclerosis is correlated with high LDL and low HDL

23. Factors promoting elevated blood lipids
age
men >45 years of age; women > 55 years of age
family history of CAD
smoking
hypertension >140/90 mm Hg
low HDL cholesterol
obesity >30% overweight
diabetes mellitus
inactivity/ lack of exercise

24. Low-Density Lipoproteins (LDLs)
“Bad” cholesterol
Delivers cholesterol to cells
Can increase build-up of plaque
High levels of LDL associated with increased risk for cardiovascular disease

25. High-Density Lipoproteins (HDLs)
“Good” cholesterol
Made by liver
Circulates in the blood to collect excess cholesterol from cells
Returns cholesterol to liver for excretion in bile
Highest protein content

26. Overview of Lipoproteins

28. Cardiovascular Disease (CVD)
Main type of CVD is Atherosclerosis (AS)
Endothelial dysfunction is one of earliest changes in AS
Mechanical, chemical, inflammatory mediators can trigger endothelial dysfunction:
High blood pressure
Smoking (free radicals that oxidatively damage endothelium)
Elevated homocysteine
Inflammatory stimuli
Hyperlipidemia

29. A Healthy Endothelium
produces:
á PGI2
á NO
Maintaining an
anti-coagulant,
anti-thrombotic
surface

30. â PGI2 â NO TNFa VCAM-1 A Dysfunctional Endothelium has decreased:
Increased:
pro-inflammatory
molecules:
MCP-1
TNFa
VCAM-1
Shifting to a
pro-coagulant, pro-thrombotic surface

31. Pro-Inflammatory Molecules
Chemokines = monocyte chemoattractant protein 1 (MCP-1)
Inflammatory cytokines = tumor necrosis factor  (TNF)
Adhesion molecules = intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1)
Overexpression of all these inflammatory mediators is commonly seen in atherosclerotic lesions.

32. Endothelial Dysfunction ( endothelial activation, impaired endothelial-dependent vasodilation)
â endothelial synthesis of PGI2 (prostacylcin), & NO (nitric oxide)
PGI2 = vasodilator, âplatelet adhesion/aggregation
NO = vasodilator, âplatelet & WBC (monocyte) adhesion
á Adhesion of monocytes onto endothelium --> transmigration into subendothelial space (artery wall) --> change to macrophages
Endothelial dysfunction --> increased flux of LDL into artery wall

35. Oxidation of LDL (oxLDL)
Oxidation = process by which free radicals (oxidants) attack and damage target molecules / tissues
Targets of free radical attack:
DNA carbohydrates
Proteins PUFA’s>>> MUFA’s>>>>> SFA’s
LDL can be oxidatively damaged: PUFA’s are oxidized and trigger oxidation of apoB100 protein --> oxLDL
OxLDL is engulfed by macrophages in subendothelial space

38. Atherosclerotic Plaque
Continued endothelial dysfunction (inflammatory response)
Accumulation of oxLDL in macrophages (= foam cells)
Migration and accumulation of:
smooth muscle cells,
additional WBC’s (macrophages, T-lymphocytes)
Calcific deposits
Change in extracellular proteins, fibrous tissue formation
High risk = á VLDL (áTG) á LDL â HDL

39. Antioxidant Defense Systems
1. Prevent oxidation from being initiated
2. Halt oxidation once it has begun
3. Repair oxidative damage

40. Antioxidant Mechanisms
Antioxidant vitamins (vitamins C, E, carotenoids)
Flavanoids and other phytochemicals
Antioxidant enzyme systems
Minerals required: Mn, Cu, Zn, Se

43. Factors Associated with CVD
Genetic Variables
Being male
Being post-menopausal female
Family history of heart disease before the age of 55 (some are associated with genetic defects in LDL receptors)

44. Factors Associated with CVD
• Dietary
1. Elevated levels of LDL
--More LDL around to potentially oxidize and accumulate in artery wall
2. Low levels of HDL
--HDL carries cholesterol from artery walls back to the liver
3. Low levels of antioxidant vitamins
--Vit. E, Vit. C, Beta-carotene
4. Low levels of other dietary antioxidants
--Phenolics, flavanoids, red wine, grape juice, vegetables, fruits

45. Factors Associated with CVD
High blood pressure
• Damages the artery wall allowing LDL to enter the wall
more readily
Cigarette Smoking
Cigarette smoke products are oxidants and can oxidize LDL
Cigarette smoking compromises the body’s antioxidant vitamin status, especially Vit. C
Damages the artery wall
Activity Level
Exercise is the most effective means of raising HDL levels
Obesity

46. Homocysteine Levels Normal byproduct of certain metabolic pathways
Normally metabolized to other products
Elevated levels cause damage to artery walls = increased the oxidation of LDL
Elevated homocysteine levels are significantly correlated with increased risk to heart disease.
Vitamins B6, B12, and Folic acid normalize homocysteine levels.

47. Diet Methionine (a.a.) Homocysteine SAM CH3 SAH cysteine sulfate
Enzymes
B12, Folate
Homocysteine
SAM
1. Norepinephrine
2. Guanidinoacetate
3. Serotonin
4. Serine
Enzyme B6
cysteine
CH3
1. Epinephrine
2. Creatine
3. Melatonin
4. Choline
SAH
sulfate

48. Dietary/Lifestyle Prevention/Intervention of Heart Disease
Maintain
Endothelial
Function
Platelet
Activity
Decrease LDL
Increase HDL
Increase Antioxidants
â High Blood Pressure
w-3 PUFAs
â w -6 PUFA
â Saturated Fat
á MUFA/ â PUFA
á MUFA/ â w -6 PUFA
â Homocysteine
B6, B12, Folic Acid
á Phytochemicals
â Cholesterol
á w-3 PUFAs (fish)
áVegetables
áPhytochemicals
Aspirin
á w-3 oils (fish)
á Exercise
áFruits
Stop smoking
á Fiber
â Trans Fats
âBody weight if overweight

49. Know Your Lipid Profile
Fasting Blood Level Ideal, Healthy Level
Total Cholesterol
< 200 mg/dl
LDL-Cholesterol
< 100 mg/dl
HDL-Cholesterol
≥ 60 mg/dl
Triglycerides
< 150 mg/dl

50. Know Your Diabetes, Metabolic Risk
Fasting Healthy Pre-Diabetes Diabetes
(Metabolic Syndrome)
Blood Glucose
< 110 mg/dl
mg/dl
≥ 126 mg/dl
2 hr GTT
< 140 mg/dl
mg/dl
> 200 mg/dl
Triglyceride
< 150 mg/dl
> 150 mg/dl
Typically elevated
HDL
≥ 60 mg/dl
M < 40 mg/dl
F < 50 mg/dl
Typically low

51. The Metabolic Syndrome
Abdominal Obesity
Men
Women
> 40 inch waist
> 35 inch waist
Triglycerides
≥ 150 mg/dL
HDL cholesterol
< 40 mg/dL
< 50 mg/dL
Blood Pressure
≥ 130/ 85 mm Hg
Fasting Blood Glucose
mg/dL

52. Know Your Blood Pressure
Category
Systolic (mm/Hg)
Diastolic (mm/Hg)
Normal
120 or less
80 or less
High Normal
85-89
High Blood Pressure
140 or more
90 or more
Strive for blood pressure of 120/80 or less