Efectos de los esteroles y estanoles vegetales en el metabolismo enterohepático del colesterol y los triglicéridos

Abstract

Plant sterols are cholesterol analogs in plants. They share its same structure, only differing in their side chains. Plant stanols derive from the saturation of the double bond in the ring. Since the 90s, both sterols and plant stanols are approved as functional foods to lower total and LDL cholesterol. Although their mechanism of action is not yet fully known, it is estimated that 2g/day of plant sterols lower LDL cholesterol levels by approximately 10%. However, new forms and combinations are being developed in order to increase this effectiveness. The first work of this thesis studies the behavior and action of one of them, the so-called FM-VP4. FM-VP4 is a synthetic derivative of sitostanol and campestanol which showed greater hypocholesterolemic action than their isolated components. However, its mechanism of action is still unknown. In this work, the ability of FM-VP4 to alter cholesterol homeostasis in mice was studied. In conclusion, it was found that FM-VP4 effectively reduced the intestinal cholesterol absorption as well as plasma and liver cholesterol. FM-VP4 also affected bile acid homeostasis by inducing bile acid intestinal reabsorption and changed the liver expression of genes that play an essential role in cholesterol homeostasis. This is the first phytosterol or stanol that affects bile acid metabolism and lowers plasma cholesterol in normocholesterolaemic mice. On the other hand, the safety of plant sterols is still controversial. Patients suffering from a rare autosomal recessively inherited disease, called sitosterolemia, accumulate large amounts of plant sterols in plasma and tissues, and develop a massive and early atherosclerosis despite their cholesterol levels are usually normal. It has been proven that certain plant sterols can activate LXR, a nuclear receptor that regulates fatty acid metabolism and leads to increased plasma triglyceride levels. This action could contribute to the development of atherosclerosis by sitosterolemic patients. In the second paper of this thesis we studied the triglyceride metabolism in ABCG5/G8 deficient mice, an animal model of sitosterolemia. In conclusion, it was found that ABCG5/G8 deficiency markedly raises plasma triglyceride levels through multiple pathways. The massive accumulation of plant sterols increased liver and intestinal triglyceride secretion and decreased triglyceride peripheral catabolism. Moreover, it caused a degree of insulin resistance. Moreover, many of these effects are also seen in heterozygous mice, in which plant sterol accumulation is significantly lower.

Date of Award	14 Jun 2013
Original language	Spanish
Awarding Institution	Department of Biochemistry and Molecular Biology
Supervisor	Francisco Blanco Vaca (Director) & Joan Carles Escolà Gil (Director)