Liver X receptor agonist modulation of cholesterol efflux in mice with intestine-specific deletion of microsomal triglyceride transfer protein.

OBJECTIVE: Previous work demonstrated that intestinal cholesterol absorption and regulated expression of intestinal Niemann-Pick C1-like 1 and ATP-binding cassette protein A1 are required for liver X receptor (LXR) agonist-mediated increases in high-density lipoprotein biogenesis. We re-examined those conclusions in mice with intestine-specific deletion of the microsomal triglyceride transfer protein (MTTP-IKO), where chylomicron formation is eliminated. METHODS AND
RESULTS: MTTP-IKO mice demonstrated sustained ≈90% reduction in cholesterol absorption and >80% reduction in Niemann-Pick C1-like 1 expression, yet LXR agonist treatment increased serum high-density lipoprotein and upregulated intestinal ATP-binding cassette protein A1 expression. Hepatic lipogenesis and triglyceride content increased with LXR agonist treatment in both genotypes. Biliary cholesterol secretion was increased in MTTP-IKO mice without further increase upon LXR agonist administration. LXR agonist treatment caused a paradoxical increase in cholesterol absorption in MTTP-IKO mice and decreased fecal neutral sterol excretion, but to levels that still exceeded fecal neutral sterol excretion in LXR agonist-treated control mice. Finally, MTTP-IKO mice demonstrated indistinguishable patterns of increased cholesterol turnover and efflux after intravenous radiolabeled cholesterol administration, with or without LXR agonist treatment.
CONCLUSIONS: Both intestinal and hepatic cholesterol efflux pathways are basally upregulated in MTTP-IKO mice. Moreover, LXR-dependent pathways modulate intestinal cholesterol absorption, transport, efflux, and high-density lipoprotein production independent of chylomicron assembly and secretion.