Physiological Study of Human Cholesterol Metabolism and Excretion
| Status: | Completed |
|---|---|
| Conditions: | High Cholesterol, Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 80 |
| Updated: | 5/7/2016 |
| Start Date: | January 2014 |
| End Date: | June 2015 |
Reverse Cholesterol Transport in Humans
The underlying hypothesis is that whole body cholesterol - including cholesterol present in
tissues that cannot be measured by standard blood tests - is related to heart disease risk.
Endogenous cholesterol will be labeled with an intravenous infusion of one type of
cholesterol tracer and dietary cholesterol will be labeled with another. These tracers will
be used to measure how fast cholesterol is synthesized and excreted using mass spectrometry
to distinguish the tracers. Data will be related to circulating biomarkers (blood tests) and
to the thickness of the lining of the carotid artery. The effect of the drug ezetimibe on
these processes will also be determined. Successful completion of this study will give us
more knowledge about cholesterol metabolism that may be useful in designing new drugs and
treatments for patients with heart disease, especially those that are already receiving
maximum amounts of current medications.
tissues that cannot be measured by standard blood tests - is related to heart disease risk.
Endogenous cholesterol will be labeled with an intravenous infusion of one type of
cholesterol tracer and dietary cholesterol will be labeled with another. These tracers will
be used to measure how fast cholesterol is synthesized and excreted using mass spectrometry
to distinguish the tracers. Data will be related to circulating biomarkers (blood tests) and
to the thickness of the lining of the carotid artery. The effect of the drug ezetimibe on
these processes will also be determined. Successful completion of this study will give us
more knowledge about cholesterol metabolism that may be useful in designing new drugs and
treatments for patients with heart disease, especially those that are already receiving
maximum amounts of current medications.
The central hypothesis of this proposal is that reverse cholesterol transport is related to
coronary heart disease (CHD) risk. It is complementary to the concept that reduction of
cholesterol biosynthesis with statin drugs prevents CHD, but it focuses on whole body
cholesterol metabolism and kinetic cholesterol transport rather than on static levels of
circulating lipoproteins. Although this is an old idea, it has not been adequately tested in
humans because of lack of suitable methods. In this proposal we will apply innovative stable
isotope and mass spectroscopic technology to study reverse cholesterol transport in human
subjects. The first specific aim is to improve the preparation of intravenous deuterated
cholesterol tracer, a critical limiting element in the study of whole body cholesterol
metabolism. The second aim is to use that intravenous tracer, along with a different oral
tracer, to partition fecal cholesterol into excreted endogenous cholesterol, unabsorbed
dietary cholesterol and newly-synthesized cholesterol derived from the liver and intestine.
Measurements will be made during consumption of a controlled diet provided by the metabolic
kitchen. The pool size of the rapidly-mixing body cholesterol pool will be measured along
with the fractional rate of cholesterol catabolism. These direct measures of reverse
cholesterol transport will be correlated with plasma biomarkers and with metabolic
covariates. The relation of reverse cholesterol transport to carotid intima-media thickness
will be determined. The third specific aim will use similar methods to study the mechanism
of action for the widely-used drug ezetimibe. The fractional rate of endogenous cholesterol
excretion and the rate of plasma cholesterol turnover will be determined in two periods, one
with drug and one with placebo treatment. This work represents a new direction for
cholesterol research with the potential to develop new and complementary methods of reducing
CHD risk that can be added to diet and statin drug treatment.
coronary heart disease (CHD) risk. It is complementary to the concept that reduction of
cholesterol biosynthesis with statin drugs prevents CHD, but it focuses on whole body
cholesterol metabolism and kinetic cholesterol transport rather than on static levels of
circulating lipoproteins. Although this is an old idea, it has not been adequately tested in
humans because of lack of suitable methods. In this proposal we will apply innovative stable
isotope and mass spectroscopic technology to study reverse cholesterol transport in human
subjects. The first specific aim is to improve the preparation of intravenous deuterated
cholesterol tracer, a critical limiting element in the study of whole body cholesterol
metabolism. The second aim is to use that intravenous tracer, along with a different oral
tracer, to partition fecal cholesterol into excreted endogenous cholesterol, unabsorbed
dietary cholesterol and newly-synthesized cholesterol derived from the liver and intestine.
Measurements will be made during consumption of a controlled diet provided by the metabolic
kitchen. The pool size of the rapidly-mixing body cholesterol pool will be measured along
with the fractional rate of cholesterol catabolism. These direct measures of reverse
cholesterol transport will be correlated with plasma biomarkers and with metabolic
covariates. The relation of reverse cholesterol transport to carotid intima-media thickness
will be determined. The third specific aim will use similar methods to study the mechanism
of action for the widely-used drug ezetimibe. The fractional rate of endogenous cholesterol
excretion and the rate of plasma cholesterol turnover will be determined in two periods, one
with drug and one with placebo treatment. This work represents a new direction for
cholesterol research with the potential to develop new and complementary methods of reducing
CHD risk that can be added to diet and statin drug treatment.
Inclusion Criteria:
- Aim II. 100 subjects aged 30-80 with stable medical and/or surgical illnesses.
- Aim III. 30 subjects age 18-80 with LDL cholesterol <190, fasting triglycerides<250
and stable medical or surgical illnesses.
Exclusion Criteria:
- Aim II. Subjects taking ezetimibe, bile acid sequestrants or with gastrointestinal or
liver disease will be excluded since these may affect whole body cholesterol
metabolism.
- Subjects with coronary heart disease or other medical illnesses will not be excluded
if medically stable.
- Adults under age 30 and children will be excluded because in our current database
there is no relation between carotid intima-media thickness and cardiovascular risk
factors in this younger group.
- Aim III. Individuals have risk factors for coronary heart disease that mandate drug
treatment according to the National Cholesterol Education Program guidelines will be
excluded.
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