Page 92 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioChemistry

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

Lipoprotein/Cholesterol Metabolism 659

appropriate physiological dose of insulin. To prevent di-
abetes, the pancreatic β-cells must secrete additional in-
sulin to compensate for the poor insulin response. Thus,
insulin resistance is commonly associated with chronic
hyperinsulinemia. The poor response to insulin in insulin
resistance is selective for some of insulin’s actions. For
example, people with insulin resistance have a poor stim-
ulation of glucose transport into muscle and adipose tis-
sue in response to insulin. However, they retain the ability
to stimulate lipogenesis in response to insulin. Thus, the
hyperinsulinemia associated with insulin resistance can
promote excessive lipogenesis. This can lead to increased
hepatic triglyceride synthesis and secretion. In Type II di-
abetes mellitus, the pancreas fails to adequately compen-
sate for insulin resistance. Thus Type II diabetics can still
have high insulin levels but not high enough to achieve eu-
glycemia (normal glucose levels) or they can have below-
normal insulin levels due to loss of β-cells.
The hypertriglyceridemia of Type II diabetes, unlike
that which is found with Type I diabetes, is not due to
FIGURE 14 Sites of action of three common lipid-lowering drugs.
excessive adipocyte lipolysis. This is because only a small
Statins inhibit hepatic cholesterol synthesis. Bile acid seques-
level of insulin action is required to suppress excessive
trants increase cholesterol catabolism to bile acids. Both agents
adipose tissue hormone-sensitive lipase activity. In Type decrease hepatic cholesterol levels, leading to an upregulation
II diabetes, there is insufficient adipose tissue lipoprotein of the LDL receptor. This leads to increased LDL clearance from
lipase and excessive hepatic triglyceride synthesis. Thus, the circulation. In addition, LDLreceptor upregulation decreases
inefficient VLDL triglyceride catabolism and excessive VLDL secretion. Fibrates and nicotinic acid decrease VLDL triglyc-
eride secretion. Agents that lower VLDL tend to raise HDL through
VLDL triglyceride secretion both contribute to the excess
the mechanisms described in Fig. 13.
VLDL in Type II diabetes.
The dearth of cholesterol in the liver leads to upregulation
of the LDL receptor (see Fig. 14). In most patients who
XVII. TREATMENT OF LIPOPROTEIN respond to statins, LDL production is decreased. In addi-
DISORDERS tion, there is often an increase in LDL clearance. These
drugs are widely used and have made a significant impact
Treatment of lipoprotein disorders is primarily aimed at on cardiovascular disease in several nations.
achieving relatively low VLDL and LDL levels and rel- Nicotinic acid, an over-the-counter coenzyme, when
atively high HDL levels. Since obesity and insulin resis- used at very high doses (1–3 g/day), lowers triglycerides
tance are often associated with elevated VLDL, weight and can achieve a significant increase in HDL. In many
loss and exercise are often effective in reducing VLDL. individuals, this agent causes an unpleasant skin flushing.
Exercise has an insulin-sensitizing effect on muscle; thus Bile acid sequestrants are charged resins that are in-
regular exercise can have long-term effects on plasma gested in a liquid suspension. They bind to bile acids in the
lipoproteins. Exercise also tends to raise HDL levels. For intestine and prevent their reabsorption. Since bile acids
some people, a reduction in carbohydrate intake (replacing normally feed back on their own synthesis from choles-
the calories with monounsaturated fat) can lower triglyc- terol, these agents evoke a compensatory increase in bile
eride levels, presumably by decreasing the rate of de novo acid synthesis. The diversion of liver cholesterol for bile
lipogenesis in the liver and adipose tissue. acid production leads to an upregulation of the LDL recep-
Drugs derived from fibric acid (p-chlorophenoxyiso- tor and thus a reduction in LDL levels. Because bile acid
butyrate) are widely used to lower triglycerides when diet sequestrants increase cholesterol catabolism and statins
and exercise fail. These agents increase fatty acid oxi- decrease cholesterol synthesis, the two agents together act
dation and decrease VLDL triglyceride secretion. Occa- synergistically.
sionally, they increase LDL cholesterol and must be used The majority of people with low HDL have high triglyc-
together with an LDL-lowering drug. erides. Their HDL levels usually rise if their triglyceride
Statins are a family of drugs that specifically reduce levels are reduced. However, a significant number of
cholesterol synthesis by inhibiting HMG-CoA reductase. people have low HDL and normal triglycerides; they have