Ezetimibe stimulates faecal neutral sterol excretion depending on abcg8 function in mice

Abstract 

Ezetimibe stimulates faecal neutral sterol (FNS) excretion in mice, which cannot be explained by cholesterol absorption inhibition alone. We investigated whether these effects are mediated via the sterol exporter ATP binding cassette transporter G8 (abcg8). Ezetimibe increased FNS excretion 2.7-fold in WT mice and 1.5-fold in abcg8^−/− mice, without affecting biliary cholesterol secretion. Daily FNS excretion exceeded the sum of dietary cholesterol intake and biliary secretion by about 60%. Ezetimibe enhanced this ‘extra’ FNS excretion by 3.5-fold and 1.5-fold in wildtype (WT) and abcg8^−/− mice, respectively. Ezetimibe stimulates fecal sterol excretion of non-biliary and non-dietary origin, probably through stimulation of trans-intestinal cholesterol excretion. We show that this effect depends on intact abcg8 function.

Abbreviations: Abcg8, ATP binding cassette transporter G8, BW, body weight, FNS, faecal neutral sterols, LXR, liver X receptor, NPC1L1, Niemann-Pick C1 Like 1, PPARd, peroxisome proliferator activated receptor delta, RCT, reverse cholesterol transport, TICE, trans-intestinal cholesterol excretion, WT, wildtype

Keywords: Reverse cholesterol transport, Ezetimibe, abcg5/g8, NPC1L1