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It is well established that high plasma cholesterol levels play a key role in the development of atherosclerosis, a form of coronary heart disease (CHD). Data from numerous laboratory experiments, genetic and epidemiological studies as well as extensive clinical trials have shown that reducing plasma cholesterol concentrations leads to a decreased risk for the development of CHD. Among the recommended strategies for achieving and maintaining lower plasma cholesterol levels is the use of pharmacological agents. While there are many different classes of lipid-lowering drugs currently available with varying degrees of safety and efficacy, the HMG-CoA reductase inhibitors (statins) are the most widely prescribed for lowering plasma total and LDL-cholesterol levels. HMG-CoA reductase inhibitors, however, are not effective in all individuals and there are safety concerns over the long-term administration of the high doses of these drugs that are often required to achieve target cholesterol levels. FM-VP4 is a novel phytostanol analogue which has been shown to lower plasma cholesterol levels in a variety of animals models. Additionally, FM-VP4 has also demonstrated the ability to reduce the formation of athersclerotic lesions. The purpose of this study was to measure the cholesterol-lowering and lesion-reduction properties of FMVP4 as well as to try to ascertain its molecular mechanism of action in LDL-dominant animal models. From our studies in the rabbit model we were unable to make any significant conclusions due to the great variability in response to both dietary cholesterol and FM-VP4 treatment in the different groups of animals over the 10-week treatment period. In the apo B-100 mouse model, however, we demonstrated a 61% decrease in plasma total cholesterol levels as well as a 34% decrease in plasma apolipoprotein B levels compared to control animals on the same high fat, high cholesterol diet. We also showed a small, but significant, decrease in fatty lesion area in the aortic arch of the treated mice compared to controls. In examining the expression of genes involved in cellular cholesterol control (ABCA1, ABCG5, ABCG8 and LDL receptor) we demonstrated a significant decrease in the expression of ABCG5 in the liver of treated animals. Additionally, we showed a trend towards lowering of ABCA1 and ABCG8 in the liver and small intestine of FM-VP4-treated animals. The expression of the LDL receptor in the liver of the mice was unchanged subsequent to FM-VP4 treatment while there was a trend towards increased expression of this gene in the small intestine. These results have led us to propose that the effect of FMVP4 on the expression of these genes is secondary to its lipid-lowering capabilities.

Measuring the hypolipidemic, atheroprotective and mechanistic properties of FM-VP4 in LDL-dominant animal models