| It is generally assumed that hepatobiliary cholesterol excretion is the only way to excrete substantial amounts of cholesterol from the body. We have investigated the validity of this paradigm. Cholesterol balance studies in various mouse models demonstrated, that more neutral sterols are present in feces, than can be derived from hepatobiliary excretion. To investigate the origin of the non-biliary derived cholesterol in the intestinal lumen an isolated intestinal perfusion procedure was developed. After canulation of the gallbladder to divert bile, segments of the intestine were perfused in situ with buffers in the presence and absence of cholesterol acceptors. Substantial secretion of cholesterol in the intestinal lumen was observed primarily in the first 10 cm of the small intestine. A highly surprising result in view of the fact that cholesterol absorption in the gut also takes place primarily in the proximal part. Direct intestinal cholesterol secretion was strongly stimulated by the presence of mixed bile salt/phospholipid (10mM/2mM) micelles in the perfusate. To further characterize the contribution of known cholesterol transporters experiments with SR-BI and Abcg8 knock-out mice were carried out. In both mouse models unaltered intestinal cholesterol secretion was found indicating that SR-BI and Abcg5/g8 are not involved. Apparently, the efflux mechanism in the enterocytes is highly specific and novel transporters are involved. Pharmacologic activation of neutral sterol excretion by means of a PPARdelta agonist induced direct intestinal cholesterol secretion twofold indicating that the pathway provides a new drug target to increase cholesterol excretion from the body. |
