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

2. Objectives HDL: Function & structure.
Mechanism of Cholesterol control and uptake.
Atherosclerosis: Definition and mechanism.

3. 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)

4. 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

5. Atherosclerosis
hardening of the arteries due to the deposition of atheroma.
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.

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

7. 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

8. 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

9. Overview of Lipoproteins

11. 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

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

13. 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

14. 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.

15. 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

18. 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>>>>>
LDL can be oxidatively damaged: PUFA’s are oxidized and trigger oxidation of apoB100 protein --> oxLDL
OxLDL is engulfed by macrophages in subendothelial space

21. 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

22. Antioxidant Defense Systems
1. Prevent oxidation from being initiated
2. Repair oxidative damage

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

25. 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)

26. 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

27. 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

28. Homocysteine Levels
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.

29. 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

30. 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

31. 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

32. 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

33. 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

34. The following phrases is correctly describe “Atherosclerosis “Except…………….
A. Hardening of Blood vessel wall.
B. High HDL and Low LDL.
C. Formation of atheroma plaque.
D. Leads to heart diseases.