Regulation of biliary cholesterol secretion and reverse cholesterol transport

According to the World Health Organization the number one cause of death throughout the world is cardiovascular disease. Therefore, there is an urgent need for new therapeutic strategies to prevent and treat cardiovascular disease. One possible way is to target the HDL-driven reverse cholesterol transport pathway. Cholesterol levels need to be tightly regulated as the accumulation of excessive cholesterol within the body can promote the development of cardiovascular disease. In this thesis we describe research carried out on different parts of the reverse cholesterol transport pathway, in our quest to provide improved insights. Biliary cholesterol secretion is a critical step in reverse cholesterol transport. Two receptors involved in biliary cholesterol secretion are SR-BI and ABCG5/G8. We show that SR-BI contributes significantly to reverse cholesterol transport and therefore is a possible therapeutic target for cardiovascular disease. ABCG5/G8 seems to be of minor importance to reverse cholesterol transport. The transintestinal cholesterol excretion pathway is increasingly gaining interest. The experiments described in this thesis indicate that the intestine contributes to reverse cholesterol transport in two different ways. By (1) reabsorption of cholesterol secreted via the bile, and (2) possibly by excreting cholesterol that is secreted by hepatocytes within VLDL via the transintestinal cholesterol excretion pathway. We estimate that around 75% of cholesterol relevant for reverse cholesterol transport is entering the intestinal lumen via the biliary route, while around 25% is derived from transintestinal cholesterol excretion.