Food Lipids: Chemistry, Nutrition, and Biotechnology

fibroblasts [42,43]. In general, cells outside the liver and intestine obtain cholesterol
from the plasma rather than by synthesizing them de novo. LDL, the primary source
of cholesterol, is first bound to a specific high affinity receptor on the cell surface;
endocytosis then transfers it to internal lysosomes, where the LDL cholesteryl ester
and protein are hydrolyzed. The released cholesterol suppresses the transcription of
the gene from HMG-CoA reductase, hence blocking de novo synthesis of cholesterol.
In the meantime, the LDL receptor itself is subject to feedback regulation. The raised
cholesterol concentration also suppresses new LDL receptor synthesis. So the uptake
of additional cholesterol from plasma LDL is blocked. After the drop of HMG-CoA
reductase activity, there is a reciprocal increase in the microsomal acyl CoA-cholesterol
acyltransferase (ACAT), with the result that the excess free cholesterol is reesterified
for storage. Also, the reduction in the rate of cholesterol biosynthesis, which
is attributed to uptake of LDL cholesterol by cells, may in fact be due to the presence
of a small amount of oxygenated sterol in the LDL [44]. Hydroxylated sterols are
known to be far more potent inhibitors of cholesterol biosynthesis and microsomal
HMG-CoA reductase activity than is pure cholesterol [45,46]. The development of
the hypothesis that oxysterols are regulators of cholesterol biosynthesis has attracted
much attention. A comprehensive review has been published by George Schroepfer,
Jr. [47a]. This work could lead to the development of new drugs for the treatment
of hypocholesterol diseases [47b].
D. Cholesterol Metabolism
In mammals, cholesterol is metabolized into three major classes of metabolic products:
(a) the C18, C19, and C21 steroid hormones and vitamin D; (b) the fecal neutral
sterols, such as 5�-cholestan-3�-ol and 5�-cholestan-3�-ol; and (c) the C 24 bile
acids. Only small amounts of cholesterol are metabolized to steroid hormones and
vitamin D. These metabolites are very important physiologically. A detailed discussion
of steroid hormones is beyond the scope of this chapter. Vitamin D, also considered
a steroid hormone, is discussed individually (see Sec. II.E). The neutral
sterols and bile acids are quantitatively the most important excretory metabolites of
cholesterol.
The fecal excretion of neutral sterols in humans is estimated to range from 0.5
to 0.7 g/day. These sterols are complex mixtures of cholesterol, 5�-cholestan-3�-ol,
5�-cholestan-3�-ol, cholest-4-en-3-one, and a number of cholesterol precursor sterols.
The major sterol, 5�-cholestan-3�-ol, is found in the feces as a microbial
transformation product of cholesterol.
The principal C24 bile acids are cholic acid and chenodeoxycholic acid. The
conversion of cholesterol to bile acids takes place in the liver. These bile acids are
conjugated with either glycine or taurine to produce bile salts. The bile salts produced
in the liver are secreted into the bile and enter the small intestine, where they facilitate
lipid and fat absorption. Most bile acids are reabsorbed from the intestine and
pass back to the liver and the enterohepatic circulation. The excretion of bile acids
in the feces is estimated to range from 0.4 to 0.6 g/day.
The metabolic pathway of cholesterol to bile acids has been studied for many
years. Recent advances in oxysterol syntheses have aided the study of this metabolic
pathway [48a–c]. Several reviews are available describing the formation of bile acids
from cholesterol [49a,49b]. There are three general stages in the biotransformation
Copyright 2002 by Marcel Dekker, Inc. All Rights Reserved.