Proposed mechanisms of action of serum triglyceride lowering by plant sterols and stanols
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Plant sterols and their saturated derivates called stanols (PS) are structurally very similar to cholesterol. Due to this similarity, PS compete with dietary cholesterol for absorption in the small intestine. Consequently, a daily intake of 2 gram PS causes an average reduction of 9% in serum LDL-cholesterol. Recently, it has been recognized that PS also lower fasting serum triglycerides (TG) by 6% on average. Moreover, it was shown that PS lowering of TG is higher in metabolic syndrome patients with high baseline TG levels. However, the mechanism by which PS lower fasting serum TG is currently unknown and in this thesis, a number of potential mechanisms are proposed. To that end, cholesterol and TG homeostasis were reviewed. Given the stronger TG lowering by PS in metabolic syndrome patients, the role of insulin resistance (IR) was reviewed as well. TG and cholesterol are assembled and secreted into the circulation by the liver in very-low-density lipoprotein particles (VLDL). It has been suggested that fasting serum TG lowering by PS is associated with reduced numbers of circulating VLDL particles. Hepatic VLDL assembly and secretion depends on hepatic cholesterol and TG content. The latter is determined by free fatty acid (FA) flux, dietary fat intake and de novo lipogenesis (DNL). IR causes increased VLDL secretion. Here, the following hypotheses on the mechanism of fasting serum TG lowering by PS are proposed: 1) PS reduce intestinal absorption of dietary FA, 2) PS reduce hepatic uptake of chylomicron remnants and/or reduce DNL, 3) Reduced VLDL secretion is an indirect effect of cholesterol lowering by PS, 4) PS reduce levels of proteins involved in assembly and secretion of VLDL, 5) PS have an anti-inflammatory effect on activated Kupffer cells, reducing the expression of TNFα and IL-6 and alleviating IR-induced hypersecretion of VLDL. In vitro experiments to test these hypotheses are proposed.