University of Groningen, Netherlands
Reverse cholesterol transport (RCT) is defined as the transport of excess cholesterol from the periphery via the liver into the feces. It is generally assumed that defects in RCT play an important role in the etiology of atherosclerosis. The role of bile acid signaling in regulation of RCT is ill understood. Recently, we have shown that direct secretion of cholesterol from blood to the intestinal lumen is an active pathway for cholesterol removal from the body. In mouse models the capacity of this transintestinal cholesterol secretory pathway (TICE) is twofold higher than the hepatobiliary route and can be stimulated via diet. We now show that pharmacological stimulation can drive this pathway to very high activity. By a combination of Farnesoid X Receptor (FXR/NR1H4) activation and inhibition of the intestinal cholesterol transporter NPC1L1, this pathway can be stimulated to such an extent that mice excrete up to 60% of their total cholesterol pool daily. Using a panel of knock-out and transgenic mice as well as pharmacological manipulation we elucidated the underlying regulatory mechanism. We show that TICE is regulated via the concerted action of NPC1L1, intestinal FXR and the sterol exporting heterodimer Abcg5/g8. Biliary bile acid concentration but in particular and, unexpectedly, bile acid hydrophobicity plays a crucial role in the stimulation of the TICE pathway. Clearly this pathway provides an attractive target for therapy aiming at reduction of atherosclerosis.
Hosts: Prof. Bruno Lemaitre (EPFL), Prof. Lluis Fajas (UNIL) and Prof. Kristina Schoonjans (EPFL)
For those who would like to see Prof. Schrauwen, please contact Prof. Kristina Schoonjans.