Treatment of lipoprotein disorders is primarily aimed at
achieving relatively low VLDL and LDL levels and relatively
high HDL levels. Since obesity and insulin resistance
are often associated with elevated VLDL, weight
loss and exercise are often effective in reducing VLDL.
Exercise has an insulin-sensitizing effect on muscle; thus
regular exercise can have long-term effects on plasma
lipoproteins. Exercise also tends to raise HDL levels. For
some people, a reduction in carbohydrate intake (replacing
the calories with monounsaturated fat) can lower triglyceride
levels, presumably by decreasing the rate of de novo
lipogenesis in the liver and adipose tissue.
Drugs derived from fibric acid
are widely used to lower triglycerides when diet
and exercise fail. These agents increase fatty acid oxidation
and decrease VLDL triglyceride secretion. Occasionally,
they increase LDL cholesterol and must be used
together with an LDL-lowering drug.
are a family of drugs that specifically reduce
cholesterol synthesis by inhibiting HMG-CoA reductase.
The dearth of cholesterol in the liver leads to upregulation
of the LDL receptor (see Fig. 14). In most patients who
respond to statins, LDL production is decreased. In addition,
there is often an increase in LDL clearance. These
drugs are widely used and have made a significant impact
on cardiovascular disease in several nations.
|Figure 14 Sites of action of three
common lipid-lowering drugs.
inhibit hepatic cholesterol synthesis. Bile
catabolism to bile acids. Both agents
decrease hepatic cholesterol levels,
leading to an upregulation
of the LDL
receptor. This leads to increased LDL
the circulation. In addition,
LDLreceptor upregulation decreases
VLDL secretion. Fibrates and nicotinic
acid decrease VLDL triglyceride
secretion. Agents that lower VLDL tend
to raise HDL through
described in Fig. 13.
, an over-the-counter coenzyme, when
used at very high doses (1–3 g/day), lowers triglycerides
and can achieve a significant increase in HDL. In many
individuals, this agent causes an unpleasant skin flushing.
Bile acid sequestrants
are charged resins that are ingested
in a liquid suspension. They bind to bile acids in the
intestine and prevent their reabsorption. Since bile acids
normally feed back on their own synthesis from cholesterol,
these agents evoke a compensatory increase in bile
acid synthesis. The diversion of liver cholesterol for bile
acid production leads to an upregulation of the LDL receptor
and thus a reduction in LDL levels. Because bile acid
sequestrants increase cholesterol catabolism and statins
decrease cholesterol synthesis, the two agents together act
The majority of people with low HDL have high triglycerides.
Their HDL levels usually rise if their triglyceride
levels are reduced. However, a significant number of
people have low HDL and normal triglycerides; they have primary hypoalphalipoproteinemia
. The treatment options
for these individuals are limited. Thus, the next frontier
in drug development is to develop treatments for low
HDL or ones that enhance the catabolism of cholesterol.
The discovery of lipid transport proteins such as ABCA1
provides potential new targets for drug development.