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Encyclopedia of Physical Science and Technology EN008C-380 June 29, 2001 16:42

658 Lipoprotein/Cholesterol Metabolism

TABLE VIII Major Lipoprotein Disorders
Principal plasma
Disorder abnormality Clinical features a Estimated frequency
Heterozygous familial ↑LDL Tendinous xanthomas, cornial arcus, 0.2% of general population; 5% of MI
hypercholesterolemia premature CAD; family history survivors under age 60
of hypercholesterolemia
Familial combined ↑1/3 LDL only, ↑1/3 VLDL Patients usually over age 30, 0.5% of general population; 15% of MI
hyperlipidemia only, ↑1/3 LDL & VLDL, often overweight, usually survivors under age 60
apoB overproduction no xanthomas or premature
common CAD
Polygenic hypercholesterolemia ↑LDL Premature CAD, no xanthomas Unknown
Familial hypertriglyceridemia ↑VLDL only Patients often overweight, 1% of general population; 5% of MI
(200–500 mg/dl) usually do not have xanthomas survivors under age 60
or premature CAD
Severe hypertriglyceridemia ↑Chylomicrons & Patients usually middle Unknown
(>1000 mg/dl) ↑VLDL age, obese, hyperuricemic,
diabetic, at risk for
pancreatitis
Familial hypoalphalipoproteinemia ↓HDL Premature CAD ∼40% of patients with premature CAD
a CAD, Coronary artery disease; MI, myocardial infarction.

XV. Apo-E AND ALZHEIMER’S DISEASE LDL. The basic defect appears to involve overproduction
of apo-B100. In some cases, this is accompanied by over-
Epidemiological studies have revealed a correlation production of triglyceride. However, the molecular basis
between the apo-E4 allele and risk of developing for the defect and the responsible gene(s) have not been
Alzheimer’s disease. About 80% of familial and 64% of elucidated.
sporadic Alzheimer’s disease late-onset cases have at least Hypertriglyceridemia is commonly associated with
one apo-E4 allele, compared to 31% of control subjects. obesity and both Type I and Type II diabetes mellitus.
The apparent risk is dose dependent. In one study, 91% of (Note that fasting hypertriglyceridemia is synonymous
E4/E4 homozygous individuals from families with diag- with increased VLDL levels.) This disorder is almost in-
nosed Alzheimer’s disease were affected, while only 48% variably accompanied by low HDL levels (Fig. 11) and
of E3/E4 patients and approximately 20% of E2/E3 or for this reason is a risk factor for premature heart disease.
E3/E3 patients were affected. Three hypotheses are being (Whether high VLDL by itself is a cardiovascular risk
considered to explain this correlation. One suggests that factor is controversial.)
apo-E4 associates more readily than the other apoE iso- In Type I diabetes mellitus, there is a severe deficiency
forms with the amyloid protein to form deposits. Another (or total absence) of insulin due to an autoimmune attack
hypothesis states that apoE4 does not associate properly on the cells that produce insulin, pancreatic β-cells. The
with a microtubule associated protein termed tau. A third absence of insulin produces a deficiency in adipose tis-
hypothesis is that the different forms of apoE have distinct sue lipoprotein lipase. This causes sluggish catabolism of
effects on the growth and extension of axons after nerve VLDL and leads to hypertriglyceridemia. Another mech-
injury. anism by which insulin deficiency promotes increased
VLDL levels is the failure to inhibit the activity of adi-
pose tissue hormone-sensitive lipase. This enzyme hy-
XVI. FAMILIAL COMBINED drolyzes cytoplasmic triglyceride droplets. The fatty acids
HYPERLIPIDEMIA AND then go to the liver, where they are re-esterified to form
HYPERTRIGLYCERIDEMIA triglycerides. These triglycerides are exported on VLDL
particles. Since adipose tissue-derived fatty acids are an
A very common disorder frequently associated with ele- important substrate for hepatic VLDL triglycerides, the
vated VLDL and LDL or elevated VLDL only is termed failure to suppress adipose tissue lipolysis is an important
familial combined hyperlipidemia (FCHL) (Table VIII). contributor to the enhanced rate of VLDL triglyceride
In order to make a diagnosis, the family of the patient must secretion.
be screened. Some family members will display increases Obesity is almost invariably associated with insulin re-
in VLDL, others in LDL, and some in both VLDL and sistance, a poor response of insulin’s target tissues to an