Chemistry Reference
In-Depth Information
then gone on to prove that reduction in total plasma cholesterol levels in patients with
primary hypercholesterolemia can lower the incidence of coronary thrombosis.
5
Various drugs have been developed to regulate cholesterol metabolism based on
our current understanding of the key enzymes, receptors, and transporters in choles-
terol biosynthesis and transfer.
6
In addition, current dietary strategies for prevention
of CHD include low fat/low saturated fat diets.
7
Although these diets seem effec-
tive, they are difficult to maintain on a long-term basis and their efficacy diminishes
over time. Alternative dietary interventions include the use of soluble fibers, soy
protein, plant sterols, probiotic bacteria, and prebiotic compounds.
8
The effect of
prebiotics on lipid metabolism in animal and human studies has been the subject
of various reviews.
9-12
Indeed, a study in which inulin was added to a moderately
high carbohydrate/low fat diet was shown to decrease hepatic lipogenesis and plasma
triacylglyceride concentrations.
13
More to the point, a study of the effects of inulin on
atherosclerotic plaque formation in male apo E deficient mice revealed the prebiotic
group to have 32 to 25 percent less atherosclerotic lesion area than controls.
14
10.2 CholEsTErol METAbolIsM
Cholesterol is important in cell membranes, as well as acting as a precursor mol-
ecule for the synthesis of steroid hormones, vitamin D, and bile salts. It is derived
from the diet or synthesized within the body. The typical human diet contains 200
to 500 mg of cholesterol. Cholesterol also enters the intestine via bile (800 to 1,200
mg/day) and desquamated intestinal epithelial cells (300 mg/day). Between 30 and
60 percent of intestinal cholesterol is absorbed, with losses occurring through unab-
sorbed bile salts or dietary cholesterol, as well as through sebum. Approximately
900 mg of cholesterol needs to be synthesized daily to balance out losses.
15
The prin-
cipal sites of cholesterol synthesis are in the liver and central nervous system.
The principal plasma lipoproteins are the chylomicrons, very low density lipo-
proteins (VLDL), LDL, and HDL. Chylomicrons are rich in triglycerides and are
secreted by enterocytes into the lacteals of the intestine and enter the blood from
lymph. Triglyceride is the principal fat in the diet and is absorbed from mixed micelles
formed in the intestinal lumen as fatty acids and monoglycerides after hydrolysis by
intestinal and pancreatic lipases. In the enterocyte, triglyceride is resynthesized and
complexed with Apo B
48
to form chylomicrons. Short-chain fatty acids escape this
process and enter the portal vein directly. Free cholesterol is largely reesterified and
packaged with the triglyceride to form the core of the chylomicron.
Once chylomicrons enter the circulation they come in contact with lipoprotein
lipase on the luminal surface of the vascular epithelium of skeletal muscle, adipose
tissue, and lactating breast. This enzyme hydrolyzes the triglyceride in the chylomi-
cron which then becomes smaller, cholesterol-rich chylomicron remnants. The fatty
acids and monoglycerides released are then taken up by local adiposites, myosites,
or hepatocytes. The remnants are also taken up by the liver.
The liver also exports cholesterol to the tissue via secreted VLDL and to a lesser
degree as HDL. Triglycerides that cannot be accommodated in VLDL accumulate in
