The Effect of Dietary Sitosterol on Blood Sugar and Cholesterol

The relative distribution of the various amounts of lipids in the membranes of the adipocytes plays an important role in lipid metabolism and energy homeostasis. Sitosterolemia, a rare genetic disease is caused by a defective ABC transporter in the gut and biliary tract, which results in increased absorption and decreased excretion of plant sterols, ultimately leading to accelerated atherosclerosis and premature death.

Very recently, a mutation of the ABCG8 gene, very rare in the general population, has been described in 4% of the Old Order Amish, a well-characterized founder population in Lancaster County, Pennsylvania. Preliminary data indicate that otherwise healthy carriers (heterozygotes) of the mutation showed, as compared to controls, reduced body mass index, more large buoyant LDL cholesterol, decreased carotid intima media thickness (IMT), and a trend toward lower insulin and glucose levels, consistent with an improved metabolic syndrome profile. These data suggest that a mild excess in plant sterols could play a role in the modulation of the energy metabolism, and that dietary sitosterol may improve lipid profile and other aspects of the metabolic syndrome in genetically normal subjects.

In order to characterize mechanistically the effects of sitosterol, the most abundant plant sterol in the diet, on the development of the metabolic syndrome, we propose to study in greater detail the carriers of the ABCG8 gene mutation; that will provide the opportunity to analyze new insights into dietary sitosterol and its role in lipid and energy metabolism. We hypothesize that sitosterol in the diet will affect metabolic syndrome indices differentially in carriers of the mutation as compared to non-carriers.

We will perform a nutrigenomics intervention on 15 ABCG8 mutation carriers and sex-matched unaffected persons (age +/- 5 years). They will be treated with high-, low- sitosterol iso-caloric diets. Study subjects will be then evaluated in the NIH Clinical Center for changes in the following parameters: circulating lipids and free fatty acids, glucose disposal, resting energy expenditure and RQ, and endothelial vascular function. The Division of Endocrinology, Diabetes and Nutrition at the University Of Maryland School of Medicine will carry out the genotyping, study volunteer recruitment, cell membrane lipid content analysis, and ex-vivo adipocyte analysis.

We hypothesize that carriers of the ABCG8 gene mutation will further improve metabolic syndrome indices when challenged with a high-sitosterol diet, and will regress toward the non-carrier controls when treated with a low-sitosterol diet. Non-carrier controls will remain unchanged or show modest improvement in metabolic syndrome indices when challenged with a high-sitosterol diet, which will worsen, compared to baseline and carrier sibs, when treated with a low-sitosterol diet.

These clinical data, combined with the in vitro analysis of the effects of sitosterol on cell membranes and adipocyte metabolism will advance knowledge in the field of lipid metabolism on the relation of lipid composition to common disorders such as the metabolic syndrome. Data obtained from this project could then potentially be translated into nutritional and therapeutic interventions in the general population.