Inhibiting intestinal NPC1L1 activity prevents diet-induced increase in biliary cholesterol in Golden Syrian hamsters

Abstract

Niemann-Pick C1-like 1 (NPC1L1) facilitates the uptake of sterols into the enterocyte and is the target of the novel cholesterol absorption inhibitor, ezetimibe. These studies used the Golden Syrian hamster as a model to delineate the changes in the relative mRNA expression of NPC1L1 and other proteins that regulate sterol homeostasis in the enterocyte during and following cessation of ezetimibe treatment and also to address the clinically important question of whether the marked inhibition of cholesterol absorption alters biliary lipid composition. In hamsters fed a low-cholesterol, low-fat basal diet, the abundance of mRNA for NPC1L1 in the small intestine far exceeded that in other regions of the gastrointestinal tract, liver, and gallbladder. In the first study, female hamsters were fed the basal diet containing ezetimibe at doses up to 2.0 mg.day(-1).kg body wt(-1). At this dose, cholesterol absorption fell by 82%, fecal neutral sterol excretion increased by 5.3-fold, and hepatic and intestinal cholesterol synthesis increased more than twofold, but there were no significant changes in either fecal bile acid excretion or biliary lipid composition. The ezetimibe-induced changes in intestinal cholesterol handling were reversed when treatment was withdrawn. In a second study, male hamsters were given a diet enriched in cholesterol and safflower oil without or with ezetimibe. The lipid-rich diet raised the absolute and relative cholesterol levels in bile more than fourfold. This increase was largely prevented by ezetimibe. These data are consistent with the recent finding that ezetimibe treatment significantly reduced biliary cholesterol saturation in patients with gallstones.

Blockade of cholesterol absorption by ezetimibe reveals a complex homeostatic network in enterocytes

“…The current studies confi rm and extend prior studies that report increased LDLR and HMGR mRNAs in the intestines of miniature pigs, hamsters, and mice in response to ezetimibe, as well other reports that in vivo sterol synthesis rates in the intestine are increased by ezetimibe in hamsters and mice ( 39,47,54 ). Ezetimibe has also been shown to increase whole-body fractional LDL clearance as estimated by apoB kinetics in miniature pigs and humans ( 54,55 ).…”

“…This fi nding agrees with prior studies that reported decreases in the intestinal expression of ABCA1, ABCG5, and ABCG8 in response to ezetimibe in multiple species ( 47,48 ). Although the mechanism for this effect is unclear, the reduced sterol fl ux associated with NPC1L1 blockade may reduce the availability of endogenous LXR ligands.…”

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men

“…The pathways explored in animal studies are very similar to those operating in man and undoubtedly help in understanding the compensatory processes in man (19)(20)(21). These studies indicate that there is an increase in cholesterol synthesis in the liver and perhaps more importantly, in the intestinal tract.…”

“…These studies indicate that there is an increase in cholesterol synthesis in the liver and perhaps more importantly, in the intestinal tract. In addition, there is an upregulation of hepatic LDL receptors (19)(20)(21).…”

La Respuesta Terapéutica a Ezetimiba en Ratones C57BL/6 es Mediada por Cambios en la Expresión de NPC1L1, ABCG5 y ABCG8 en el Enterocito

“…Por el contrario, los niveles de ARNm de ABCG5 y ABCG8 cayeron significativamente en respuesta al tratamiento, retornando rápidamente a la normalidad una vez que fue cesada la administración de ezetimiba. En este estudio, además se constató un incremento en la expresión de la HMG-CoA reductasa como mecanismo compensatorio ante la disminución de colesterol (Valasek et al, 2008).…”