In normal lipid digestion, bile from the gallbladder emulsifies fat to allow for absorption. Bile is formed in the liver and stored in the gallbladder. Ingested lipid is packaged mainly as a chylomicron and transported through the hepatic portal vein to the liver and then throughout the body.
The chylomicron contains primarily triglycerides; and smaller amounts of cholesterol and phospholipids. As the lipoproteins travel through the body, the different types of cholesterol are formed and re-formed.
Cholesterol is determined from 2-3 measurements taken 1-8 weeks apart.
Type of Cholesterol
Optimal
Near Optimal
Borderline
High
Very High (low)
LDL Cholesterol
<100
100-129
130-159
160-189
>190
Total Cholesterol
<200
200-239
>240
HDL Cholesterol
>60
<40
Triglycerides
<150
150-199
200-499
>499
LDL cholesterol is rarely measured in the clinical setting. LDL cholesterol is calculated by:
LDL = Total - HDL - 0.2TG
If both cholesterol and triglycerides are elevated, the formula changes:
LDL = Total - HDL- 0.16 TG
For HDL Cholesterol, is high (>60 mg/dl) is good and is low (<40 mg/dl) is bad.
Cholesterol levels in children and adolescents 2–19 years old
Total cholesterol (mg/dL)
Acceptable — less than 170
Borderline — 170–199
High — 200 or greater
LDL cholesterol (mg/dL)
Acceptable — less than 110
Borderline — 110–129
High — 130 or greater
An estimated 106.9 million American adults have total blood cholesterol levels of 200 milligrams per deciliter (mg/dL) and higher, which is above desirable levels.
Of these, 37.7 million have levels of 240 mg/dL or higher, which is considered high risk. (Statistics from CDC’s National Center for Health Statistics as published by the American Heart Association, Heart Disease and Stroke Statistics — 2005 Update.
About 17% of adult Americans have high blood cholesterol
Among African Americans, about 16.6% of women and 12.5% of men have high total cholesterol
Among whites, 17.4% of women and 17.0% of men have high cholesterol
Most people know cholesterol can be LDL and HDL, but the lipoprotein subfractions have subfractions. These subfractions are probably part of the dynamics of lipid transport.
Lipid Subfractions include:
VLDL - Very Low Density Lipoprotein
LDL - Low Density Lipoprotein
Large particles
Small particles
IDL - Intermediate Density Lipoprotein
HDL - High Density Lipoprotein
HDL2
HDL3
Where HDL and LDL particles can be found in different sizes, the smallest are the most dense.
It is well known that LDL is atherogenic, but LDL molecules that are smaller are more atherogenic.
Within the HDL particles, the smaller particles or the HDL3 are more atherogenic than the larger HDL2 particles.
The smaller particles are most likely atherogenic because of
Increased susceptibility to oxidation
Increased vascular permeability
Conformational change in apo B
Decreased affinity for LDL receptor
Association with insulin resistance syndrome
Association with high Triglycerides and low HDL
Austin MA, Edwards KL. Small, dense low density lipoproteins, the insulin resistance syndrome and noninsulin-dependent diabetes. Curr Opin Lipidol 1996;7:167-171.
Abdominal fat distribution is associated with a greater number of HDL3 particles and a reduction of HDL2 particles.
Lipids are transported in various types of cholesterol molecules. The mechanisms of cholesterol transport, illustrated here, summarize the basic components. There are more specific biochemical mechanisms that are not included.
As the name implies, a lipoprotein is composed primarily of lipids and proteins. Phospholipids, also an important component of the lipoprotein, function to make the lipoprotein soluble in plasma so that the lipoproteins can be circulated throughout the blood stream and subsequent tissues. The proteins found in each type of lipoprotein have specific functions in cholesterol or lipid metabolism. The differences in lipoproteins can be found in the amounts and type of lipid, specific protein, and amount of phospholipid characteristic to each specific molecule. These characteristic compositions are summarized below. The basic components are phospholipids (brown), triglycerides (blue), and cholesterol (gray).
Phospholipid
Triglyceride
Cholesterol
Apo Proteins A, B, C, & E
Together, these molecules make up a characteristic lipoprotein. In this case, the lipoprotein illustrated to the right is Very Low Density Lipoprotein (VLDL). It's composition is
60-70% triglyceride
10-20% cholesterol
10-12% phospholipid
With specific proteins
Apo B
Apo C
Apo E
Lipoprotein
Lipid Content
Protein Conent
Image
Chylomicron
2-10% Cholesterol
85-95% Triglyceride
4-12% Phospholipid
48% apo A
5% apo B
32% apo C
10% apo E
Very Low Density Lipoprotein
10-20% Cholesterol
50-70% Triglyceride
10-20% Phospholipid
<1% Apo A
25% Apo B
55% Apo C
15% apo E
Low Density Lipoprotein
45-60% Cholesterol
10% Triglyceride
20-30% Phospholipid
<1% Apo A
95% Apo B
2% Apo C
3% apo E
High Density Lipoprotein
25-35% Cholesterol
4-10% Triglyceride
30-50% Phospholipid
75-85% Apo A
0-3% Apo B
5-13% Apo C
1-3% apo E
Apo Little A
Lipoprotein (a) or Lp(a) is a unique lipoprotein. It is found only in humans, old world nonhuman primate and the European hedgehog.
Lp(a) acts similarly to LDL, but differs in the apoprotein. Apo(a) is the apoprotein only found on Lp(a); and linked with a disulfide bridge. Lp(a) also contains Apo B.
Lp(a) is considered a risk factor for atherosclerosis. African Americans have higher Lp(a) than Asians and Caucasians.
Lp(a) is also found oxidized in the atheroma of atherosclerosis.
The protein component of the lipoprotein molecules are called apo proteins. Not only does each apo protein has a specific function, but each lipoprotein is comprised of characteristic apo proteins. The apo proteins illustrated here are the basic classifications. Each apo protein has several isoforms, not illustrated or explained here.
Image
Apo Protein
Lipoprotein Content
Function
apo A
Chylomicrons
VLDL
LDL
HDL
Co-factor for LCAT and/or binding of phospholipids
apo B
Chylomicrons
VLDL
LDL
HDL
Allows individual cells to recognize the LDL molecule so that the cholesterol contents can be taken into the cell to regulate cellular cholesterol metabolism.
apo C
Chylomicrons
VLDL
LDL
HDL
Allows LPL to recognize the cholesterol molecule so that it's triglyceride contents can be transported to individual cells.
apo E
Chylomicrons
VLDL
LDL
HDL
Allows the liver to recognize the cholesterol molecule so that the liver can metabolize the remnant cholesterol molecule
EXOGENOUS CHOLESTEROL TRANSPORT
Exogenous cholesterol transport begins the picture of cholesterol transport.
Click on the radial dials to see an explanation of the basic parts.
Diets rich in saturated fats and cholesterol are a common cause of the mild hypercholesterolemia seen in our society
Alcohol excess and weight gain can explain much of the tendency toward hypertriglyceridemia
Anorexia nervosa has long been associated with severe but reversible hypercholesterolemia
Drugs
Glucocorticoids elevate triglycerides and raise levels of HDL-c.
Estrogens elevate triglycerides and raise levels of HDL-c.
Anabolic steroids taken orally markedly reduce l HDL-c in contrast to injectable testosterone, which does not adversely affect the LDL-to-HDL ratio.
Oral contraceptives affect atherosclerotic risk depending on the kind and doses of progestin/estrogen.
Antihypertensives have variable effects on lipids and lipoproteins.
Although short-term thiazide usage raises cholesterol, triglycerides, and LDL-c, long-term usage is not necessarily associated with significant alterations in lipid levels.
Alpha blockers may cause an increase in HDL-c, whereas beta blockers raise triglycerides and lower HDL-c.
Sympatholytics, angiotensin converting enzyme inhibitors, and calcium channel blockers are essentially lipid neutral.
Retinoids can be associated with increased LDL-to-HDL ratios and occasionally striking elevations in triglycerides.
Cyclosporine raises LDL-c and lipoprotein(a).
Classes of drugs that may raise HDL-c include cimetidine, antiepileptic drugs, and tamoxifen, but the effect may be seen primarily in women.
Obesity
Hypothyroidism is the most common secondary cause of hyperlipidemia after dietary causes are considered.
Oxidation of LDL is a primary contributor to atherosclerosis. Oxidized LDL may directly cause an injury to the endothelium. In addition, oxidized LDL activates the immune response. In the immune response, the oxidized LDL is taken up by macrophage leading to the development of foam cells. In addition, the oxidized LDL cannot be recognized by the LDL receptor on the cell surface, thus contributing to elevated LDL.
There are five familial hyperlipidemias:
Genetic Disorder
Lipoprotein
Lipid
Defect
Name
Type 1 (rare)
Chylomicrons
Triglycerides
LPL Deficiency
Familial lipoprotein lipase defficiency
Type 2a
LDL
Cholesterol
LDL receptor deficiency
Familial hypercholesterolemia
Type 2b
LDL & VLDL
Cholesterol & Triglycerides
Decreased LDL receptors
Familial dysbeta-lipoproteinemia
Type 3 (rare)
Remnants
Cholesterol & Triglycerides
Defect in Apo E synthesis
Combined Hyperlipidemia
Type 4
VLDL
Triglycerides
increased VLDL production with decrease in elimination
Epidemiological evidence for exercise and hyperlipidemia is illustrated by one study by Wood and Haskell.
In this study, the cholesterol fractions of runners were compared to sedentary controls for both men and women. Although the total cholesterol was similar, the subfractions of HDL were significantly higher, LDL were significantly lower, and VLDL were significantly lower for runners than controls.
In a meta-analytical review article by Tran, modest reductions in lipids were in most lipids were reported, although not all subjects made changes.
When reviewing experimental trials, Dufaux and colleagues categorized the lipid and exercise studies into those that reported
Increase
Decrease
No Change
for the studies to that date. The results are illustrated in the next few slides.
Dufaux, B, G Assmann, W Hollmann. Plasma lipoproteins and physical activity: a review, International Journal of Sports Medicine 3(3):123-36, 1982
For triglycerides, there were more studies showing a decrease in triglycerides than no change or an increase. In fact, exercise may be most effective in decreasing triglycerides than any other form of lipid. Triglycerides are used as a fuel source and can be decreased with one bout of exercise. The mechanism by which triglycerides are reduced is through an increase of LPL.
The LDL response to training also appears to be mixed, although more studies report a decrease than report no change.
Cholesterol, on the other hand, is not as simple. There appears to be just as many studies that report an decrease in cholesterol as report no change in cholesterol
For HDL, more studies reported increases than decreases or no change.
Why are these results so mixed? Why are the reductions in cholesterol and cholesterol fractions moderate?
Mitch Whaley illustrates the point that the initial values affect the outcome very well in his 1992 study of the Adult Fitness Participants at Ball State. When all the subjects were combined, he found very little change in total cholesterol. However, when the subjects were divided into normal, borderline and high cholesterol subgroups, the subjects in the high category responded the best from exercise treatment.
The most responsive group was the high cholesterol group. Borderline group did not change. Diet may be the best intervention for the borderline group. Even though there appears to be an increase in the normal cholesterol group, the cholesterol remained normal.
Results for children are not as definite as for adults.
Traditionally, aerobic training has been used to change lipids. Resistance exercise appears to be successful, however, most studies are poorly controlled.
What is the significance of cholesterol reduction? The Lipid Research Clinics completed the largest prevention trial in the early 1980's.
The reduction is cardiovascular risk based on the reduction in cholesterol is illustrated in the figure to the left.
So, the average reduction of 10 mg/dL found in Tran's study, represents a signficant decrease in the risk.
When observing several cholesterol reduction programs and relating the risk to a standard reduction in total cholesterol of 20.7 mg/dL, the risk reduction ranges from -9 to -33.
What happens to the lipoprotein subfractions with exercise?
Kraus and colleages observe the subfractions with eight months of jogging 20 miles/week at 65-80% of VO2max. Their results are illustrated below.
The figure on the left illustrates little change in total LDL and HDL with traning. Whereas the figure on the right illustrates more dramatic changes of small and larger particle size. Thus, it it possible to change the concentration of particle size without dramatic changes in total lipids.
Kraus, W.E., J.A. Houmard, B.D. Duscha, KJ knetzger, MB. Wharton, JS. Mc Cartney, C.W. Bales, S Henes, G.P. Samsa, J.D. Otvos, K.R. Kulkarni, and CA Slentz. Effects of the amount and intensity of exercise on plasma lipoproteins. New England Journal of Medicine 347:1483-1492, 2002.
What are the mechanism of these subfractions change with exercise?
Grandjean and colleagues exercised 13 men with hyperlipdemia and 12 men with normal lipids on a treadmill at 70% of peak VO2max. They exhibited a signficant decrease in triglycerides with the exercise.
Along with the drop in triglycerides was an increase in lipoprotein lipase activity. Thus, a decrease in VLDL with exercise is associated with an increase in LPL.
Lopez and colleagues found the classic increase in HDL with three month exercise program. Associated with the increase in HDL was an increase in LCAT activity as illustrated in the figure to the right.
Lopez, A., R. Vial, L Balart, and G Arroyave. Effect of exercise and physical fitness on serum lipids and lipoproteins. Atherosclerosis 20:1-9, 1974.
On those same lines, Seip and colleagues found the same increase in HDL with 9-12 months of aerobic training. Along with the increase in HDL was a decrease in CETP activity as pictured in the figure to the left.
