1. Review of Cholesterol and Lipoproteins

2. Objectives for Presentation:
To review importance of Cholesterol and other lipids as a risk factor for heart disease
To review the components of cholesterol and their relative importance
To review cholesterol metabolism
To understand the tests for total cholesterol and its different lipoprotein components

3. Cholesterol has important functions in the human body
Necessary part of cell walls
Precursor chemical for steroid compounds: -hydrocortisone, aldosterone, estrogens, etc.
Formation of bile acids for digestion
The Liver is the major organ for synthesis and metabolism of cholesterol. The body has developed an elaborate system of cholesterol transport

4. Serum Cholesterol and CHD in 361,662 U.S. Men
96DEC11
JH/FM/JH/FM
Serum Cholesterol and CHD in 361,662 U.S. Men 18 16 14 12 10 8 6 4 2
6 Year CHD Death Rate
per 1,000 Men
140
160
180
200
220
240
260
280
300
mg/dL
Serum Cholesterol
Martin M. Lancet 1986;11:

5. Serum Cholesterol in the USA and CHD Death
96DEC03
JH/FM/KS
Serum Cholesterol in the USA and CHD Death 18 16 14 12 10 8 6 4 2
100
MRFIT
NHANES II 80
Above Cholesterol
% U.S. Population
Level 60
CHD Death /1000 /6 Year 40 20
140
160
180
200
220
240
260
280
300
mg/dL
Serum Cholesterol
Martin M. Lancet 1986;11:

6. Lipids are packaged in the bloodstream into Lipoproteins
Lipoproteins have different combinations of lipids and apoproteins
Lipoproteins carry lipids from intestine
Lipoproteins carry lipids to and from liver
Each lipoprotein has a different function
Lipoproteins are important in atherogenesis and the development of heart disease

11. Structure of HDL Particle
A-I
A-I CE TG
Speaker’s Notes/Talking Points:
The function of lipoproteins is to transport cholesterol and triglycerides (TGs) in the blood. The five major families of lipoproteins are: chylomicrons, very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), intermediate-density lipoproteins (IDLs), and high-density lipoproteins (HDLs). HDL is the smallest lipoprotein and contains the least amount of lipid. This slide shows the structure of this lipoprotein particle. HDL contains a lipid core of cholesteryl esters (CEs) and TGs surrounded by phospholipids and specialized proteins known as apolipoproteins (apos). Apos are required for the structural integrity of lipoproteins and direct their metabolic interactions with enzymes, lipid transport proteins, and cell-surface receptors (as described in subsequent slides).1 ApoA-I is a major component of all HDL particles and is synthesized in the liver and intestine (see next slide).2 ApoA-II, the second most abundant apolipoprotein in HDL, is synthesized in the liver; its function is unclear.2
References
Havel RJ, Kane JP. Introduction: structure and metabolism of plasma lipoproteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:1841–1851.
Breslow JL. Familial disorders of high-density lipoprotein metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill; 1995:2031–2052.
A-II
A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides

13. Major Lipoproteins and their function
Chylomicrons:
Chylomicrons transport triglycerides from intestine
Very Low Density Lipoproteins (VLDL) and Intermediate Density Lipoproteins (IDL) :
VLDL produced in liver . Carry cholesterol and triglycerides
Low Density Lipoproteins (LDL)
LDL result from metabolism of VLDL and IDL and carry cholesterol. LDL are important cause of heart disease
High Density Lipoproteins(HDL)
HDL is “good” cholesterol. It removes cholesterol and protects against heart disease

15. Steps Involved in Cholesterol Absorption
MTP

17. Net Cholesterol Balance in Humans

18. Plasma LCAT (lecithin cholesterol acyl transferase
Exogenous Pathway
Endogenous Pathway
Dietary fat
Bile acids and
Cholesterol
LDL
ApoB -100
LDL-R
Liver
Endogenous Cholesterol
LDL-R
Extra Hepatic Tissue
Intestine
Dietary Cholesterol
Remnant Receptor
Chylomicrons
Remnants
VLDL
IDL
HDL
ApoE B-100
ApoA-I A-II
ApoE C-II
B-48
ApoE
B-48
ApoE C-II
B-100
Plasma LCAT (lecithin cholesterol acyl transferase
Lipoprotein lipase
Lipoprotein lipase
Free fatty acids
Free fatty acids
Adipose tissue, muscle
Adipose tissue, muscle

19. LDL Levels in Populations With and Without CHD
96DEC03
JH/FM/KS
LDL Levels in Populations With and Without CHD
Frequency (%)
LDL Cholesterol (mg/dL)
Kannel W. Am J Cardiol 1995;76:69C-77C

21. Effect of Blocking Bile Acid Absorption

22. Inhibition of Cholesterol Absorption
MTP
(Inhibitors)

23. The Liver Regulates the Concentration of LDL-Cholesterol

24. Cholesterol Biosynthetic Pathway
Squalene
synthase
HMG-CoA
reductase
Dolichol
Acetyl
CoA
HMG-
CoA
Farnesyl
pyrophosphate
Mevalonate
Squalene
Cholesterol
Ras
protein
Farnesyl-
transferase
E,E,E-Geranylgeranyl
pyrophosphate
Farnesylated
proteins
Geranylgeranylated
proteins
Ubiquinones

25. Measurement of Cholesterol
Total Cholesterol is the sum of cholesterol contained in the different lipoproteins
Fasting not required
Measured in millimoles per Liter (mmol/L) in Russia
Measured in milligrams per deciliter in US
5.17 mmol/L = 200 mg/dL
conversion factor 38.7

26. Complete Lipid Panel Requires 12 hour fast
Total Cholesterol measured directly (mmol/L)
HDL is measured directly (mmolL)
Triglycerides are measured directly (mg/dL)
Conversion factor to millimoles =88.6
LDL is usually calculated :
LDL = Total Cholesterol - HDL- (Triglycerides/5)
Calculation not accurate if Triglycerides > 400 mg/dL

27. Values for Cholesterol
Total Cholesterol
< 5.17 mmol/L = Good
= Borderline High
> = High

28. Values for Low Density Lipoprotein (LDL)
< = Good
= Near Normal
= Borderline High
= High
> = Very High

29. Values for High Density Lipoprotein (HDL)
< 1.03 mmol/L = LOW
(Increased Risk)
> 1.55 mmol/L = HIGH
(Lower Risk)

30. Total Cholesterol/HDL Ratio or Coefficient of Atherogenicity
No Longer Used in New Guidelines
Reliance on LDL levels

31. Triglycerides Measured in mg/dL conversion to mmol/L = 88.6 Levels:
< 150 mg/dL = normal
= borderline high
= high
> = very high

32. Disorders of Cholesterol and Lipoproteins in 3 Categories
Specific Familial/Genetic Disorders
These comprise a small minority of patients
Secondary to other Diseases
Diabetes, Hypothyroid, Nephrotic syndrome, Renal Failure, Lupus
Dietary/Polygenic --(most common)
This is the great majority of patients with elevated cholesterol/LDL