Regulation of Organic Metabolism and Energy Balance
581
cells that produce steroid hormones from cholesterol. Thus,
most cells
remove
cholesterol from the blood. In contrast, the
liver and cells lining the gastrointestinal tract can produce
large amounts of cholesterol, most of which
enters
the blood.
Now for the other side of cholesterol balance—the
pathways, all involving the liver, for net cholesterol loss
from the body. First, some plasma cholesterol is picked up
by liver cells and secreted into the bile, which carries it to
the intestinal tract. Here it is treated much like ingested
cholesterol, some being absorbed back into the blood and the
remainder being excreted in the feces. Second, much of the
cholesterol picked up by the liver cells is metabolized into bile
salts (Chapter 15). After their production by the liver, these
bile salts, like secreted cholesterol, fl ow through the bile duct
into the small intestine. (As described in Chapter 15, many of
these bile salts are then reclaimed by absorption back into the
blood across the wall of the lower small intestine.)
The liver is clearly the major organ that controls
cholesterol homeostasis, for it can add newly synthesized
cholesterol to the blood and it can remove cholesterol from
the blood, secreting it into the bile or metabolizing it to bile
salts. The homeostatic control mechanisms that keep plasma
cholesterol concentrations within a normal range operate on
all of these hepatic processes, but the single most important
response involves cholesterol production. The liver’s synthesis
of cholesterol is inhibited whenever dietary—and therefore
plasma—cholesterol is increased. This is because cholesterol
inhibits the enzyme (called HMG-CoA reductase) critical for
cholesterol synthesis by the liver.
Thus, as soon as the plasma cholesterol level starts
increasing because of increased cholesterol ingestion,
hepatic synthesis of cholesterol is inhibited, and the plasma
concentration of cholesterol remains close to its original
value. Conversely, when dietary cholesterol is reduced
and plasma cholesterol begins to fall, hepatic synthesis
is stimulated (released from inhibition). This increased
production opposes any further decrease in plasma
cholesterol. The sensitivity of this negative feedback control
of cholesterol synthesis differs greatly from person to person,
but it is the major reason why, for most people, it is diffi
cult
to change plasma cholesterol very much in either direction by
altering only dietary cholesterol.
Thus far, the relative constancy of plasma cholesterol
has been emphasized. There are, however, environmental
and physiological factors that can signifi cantly alter plasma
cholesterol concentrations. Perhaps the most important of
these factors are the quantity and type of dietary fatty acids.
Ingesting saturated fatty acids, the dominant fatty acids of
animal fat (particularly high in red meats, most cheeses, and
whole milk), increases plasma cholesterol. In contrast, eating
either polyunsaturated fatty acids (the predominant plant
fatty acids) or monounsaturated fatty acids such as those in
olive or peanut oil, decreases plasma cholesterol. The various
fatty acids exert their effects on plasma cholesterol by altering
cholesterol synthesis, excretion, and metabolism to bile salts.
A variety of drugs now in common use are also capable
of lowering plasma cholesterol by infl uencing one or more of
the metabolic pathways for cholesterol—for example, inhibiting
the critical enzyme for hepatic cholesterol synthesis—or by
interfering with intestinal absorption of bile salts.
The story is more complicated than this, however,
because not all plasma cholesterol has the same function or
signifi cance for disease. Like most other lipids, cholesterol
circulates in the plasma as part of various lipoprotein
complexes. These include chylomicrons (Chapter 15), VLDL
(this chapter),
low-density lipoproteins (LDL),
and
high-
density lipoproteins (HDL).
LDL are the main cholesterol
carriers, and they
deliver
cholesterol to cells throughout the
body. LDL bind to plasma membrane receptors specifi c for
a protein component of the LDL, and the LDL are taken
up by the cells by endocytosis. In contrast to LDL, HDL
remove
excess cholesterol from blood and tissue, including the
cholesterol-loaded cells of atherosclerotic plaques (Chapter
12). They then deliver this cholesterol to the liver, which
secretes it into the bile or converts it to bile salts. HDL also
delivers cholesterol to steroid-producing endocrine cells.
Various cells
Incorporation into membranes,
steroid hormones, etc.
Excretion in feces
GI tract
Dietary cholesterol
Plasma cholesterol
(in lipoproteins)
Liver, GI tract, other cells
Synthesis of cholesterol
Liver
Secretion into bile,
catabolism to bile salts
Figure 16–13
Cholesterol balance. Most of the cholesterol that is converted to bile salts, stored in the gallbladder, and secreted into the intestine gets
recycled back to the liver. Changes in dietary cholesterol can modify plasma cholesterol concentration, but not usually dramatically. Cholesterol
synthesis by the liver is up-regulated when dietary cholesterol is reduced, and vice versa.
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