K562

EXERCISE PRESCRIPTION

IN

HEALTH & DISEASE

DEFINITIONS

Cholesterol is an essential lipid:

  • cell membranes
  • steriod hormones
  • lipid rafts
    • cell surface to separate and concentrate surface proteins

The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.

JAMA 285:2486-2497, 2002

The full report can be found on the http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm

 

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.


Definitions Cholesterol Transport Etiology Pathophysiology Pharmacology Exercise Effectiveness Top

 


Cholesterol Transport

     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.

 


The different lipids are named based on their separation in centrifugation or electrophoresis.

Electrophoresis
motion of dispersed particles relative to a fluid under the influence of an electric field

Fraction
Centrifugation
The layering of particles in the test tube following centrifugation
Chylomicron
Top - largest
Lowest density
pre-beta
VLDL
IDL
beta
LDL
alpha
HDL
Bottom - smallest
Highest density

THE COMPOSITION OF LIPOPROTEINS

     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.

    Apo Proteins

         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

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    Exogenous cholesterol transport begins the picture of cholesterol transport.

    Click on the radial dials to see an explanation of the basic parts.

    or continue on to

    Endogenous Cholesterol Transport

    Reverse Cholesterol Transport

    LDL Uptake


    ENDOGENOUS CHOLESTEROL METABOLISM

    This is the process of endogenous cholesterol transport.

    Click here to see

    Exogenous Cholesterol Transport

    Reverse Cholesterol Transport

    LDL Uptake

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    REVERSE CHOLESTEROL TRANSPORT

     

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    HDL also enters the intimal wall to remove cholesterol from the oxidized LDL.

    LDL UPTAKE

     

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    Definitions Cholesterol Transport Etiology Pathophysiology Pharmacology Exercise Effectiveness Top

    Etiology

    • 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.
    Definitions Cholesterol Transport Etiology Pathophysiology Pharmacology Exercise Effectiveness Top

    Pathophysiology

    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 Familial hypertriglyceridemia
    Type 5 VLDL & Chylomicrons Cholesterol & Triglycerides Unknown

    Multiple lipoprotien-type hyperlipidemia

    or

    Familial combined hyperlipidemia

    Definitions Cholesterol Transport Etiology Pathophysiology Pharmacology Exercise Effectiveness Top

     


    PHARMACOLOGY

    The classes of antihyperlipidemic agents are:

    • HMG-CoA Reductase Inhibitors
    • Fibric Acids
    • Bile Acid Binding Resins
    • Nicotinic Acid
    Medications Mechanism of Action Targeted Lipids Side-Effects
    HMG-CoA Reductase Inhibitors
    • Lovastatin (Mevacor)
    • Simvastatin (Zocor)
    • Mevastatin (Compactin)
    • Pravastatin

    Blocks the synthesis of cholesterol in the liver by inhibiting the rate limiting enzyme HMG CoA Reducatase

    • LDL
    • VLDL
    • TG
    • Flatulence & Diarrhea
    • Dysepsia (indigestion)
    • Headache
    • hepatoxic - Elevated Liver enzymes
      • CPK
      • LDH
      • AST
    Fibric Acids
    • Gemfibrozil (Lopid)
    • Clofibrate (Atromide-S)
    • Decrease TG synthesis
    • decrease liver lipoprotein synthesis
    • Decrease excretion of lipoproteins from liver; primarily VLDL
    • Decrease synthesis of cholesterol
    • increase production of sterols
    • increases HDL
    • TG
    • VLDL
    • LDL
    • Cardioprotective
    • Diarrhea
    • Nausea
    • Vomiting
    • Alopecia (loss of hair)
    • decrease testosterone - impotence
    • Gall stone
    • hepatoxic
      • LDH
      • CPK
      • AST
    Bile Acid Binding Resins
    • Cholestyramine (Questran)
    • Cholestipol (Colestid)
    • Bind bile salts in gut
    • Cholesterol eliminated in the feces
    • Liver uses other sources of cholesterol (LDL) for more bile
    • LDL
    • nausea
    • vomiting
    • flatulence
    • constipation
    • binds to other meds
    Nicotinic Acid
     
    • inhibits liver secretion of VLDL
    • reduced serum LDL
    • inhibits removal of HDL
    • increases excretion of sterols in the feces
    • HDL
    • Hot Flush on empty stomach
    Most antihyperlipidemic meds act through the liver and GI system.

     

    Definitions Cholesterol Transport Etiology Pathophysiology Pharmacology Exercise Effectiveness Top

    EXERCISE EFFECTIVENESS

    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.

     


    Who Benefits?

    From the work of Tran and others, the responder exercise training for hyperlipidemia can be identified by:

    • Higher Initial Values
    • Older
    • Lower Exercise Intensities
    • Lower VO2max
    • Body Fat Loss
    • Not Familial Hyperlipidemia

     

    Definitions Cholesterol Transport Etiology Pathophysiology Pharmacology Exercise Effectiveness Top

     


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