Abstract 20016: Direct Measurement of the Long Term Contribution of De novo Cholesterol Synthesis to Plasma and Tissue Cholesterol Pools in Animals and Humans
De novo cholesterol synthesis (DNCS) is a well studied process in rodents and humans. Many methods have been applied to assess whole body cholesterol synthesis rates, directly measured with isotopes, sterol balance and steady state feeding. Here we sought to determine the contribution of DNCS to tissue cholesterol pools directly over longer periods of time. Deuterated water is a safe, non radioactive label that can be easily administered to animals and humans for months or years. This allows the direct measurement of the contribution of de novo cholesterol synthesis (DNCS) to tissue and plasma cholesterol pools in long term studies. We examined the contribution of DNCS to plasma cholesterols and tissue free cholesterol in humans labeled for 6 weeks and mice labeled for up to 52 weeks. In 16 human subjects, DNCS accounted for 61 +/- 13 % of plasma free cholesterol and 58 +/- 13% of cholesterol-ester (CE). In every subject the contribution of DNCS to CE was modestly but significantly lower than FC (3+/- 1%). In skeletal muscle obtained from 8 of these 16 subjects, DNCS accounted for 36 +/- 7%; which was 18% lower than plasma values in the same subjects. In a separate study, DNCS contribution to plasma cholesterol was measured on multiple occasions for up to 60 days. Modeling these results suggested that plasma DNCS does not increase linearly, but is more closely approximated by a mono-exponential rise to plateau. In mice labeled for 52 weeks, nearly complete turnover of liver and cardiac free cholesterol was observed by 8 weeks where plasma reached a pseudo-plateau at 8 weeks then continued to rise over the remaining period. Brain cholesterol, in contrast, increased in a nearly linear fashion. These studies demonstrate the utility of long term labeling studies to assess the net contribution of de novo cholesterol synthesis to the study of whole body and tissue specific cholesterol metabolism and illustrate differential turnover rates of brain cholesterol in the mouse. Tissue DNCS has also been proposed as a method to assess reverse cholesterol transport, or centripetal cholesterol flux but this has previously been difficult in humans. This approach can be used to assess dietary and pharmacological interventions on cholesterol metabolism in specific tissues in animals and humans.
- © 2010 by American Heart Association, Inc.