We investigated whether: (1)
liver X receptor (LXR)-driven induction of
high-density lipoprotein cholesterol (HDL-C) and other LXR-mediated effects on
cholesterol metabolism depend on intestinal
cholesterol absorption; and (2) combined treatment with the LXR agonist
GW3965 and the
cholesterol absorption inhibitor
ezetimibe results in synergistic effects on
cholesterol metabolism that could be beneficial for treatment of
atherosclerosis. Mice were fed 0.2 %
cholesterol and treated with GW3965+ezetimibe,
GW3965 or
ezetimibe. GW3965+ezetimibe treatment elevated serum HDL-C and
Apolipoprotein (
Apo) AI, effectively reduced the intestinal
cholesterol absorption and increased the excretion of faecal neutral
sterols. No changes in intestinal
ATP-binding cassette (ABC) A1 or
ABCG5 protein expression were observed, despite increased
mRNA expression, while hepatic ABCA1 was slightly reduced. The combined treatment caused a pronounced down-regulation of intestinal Niemann-Pick C1-like 1 (NPC1L1) and reduced hepatic and intestinal
cholesterol levels.
GW3965 did not affect the intestinal
cholesterol absorption, but increased serum HDL-C and ApoAI levels.
GW3965 also increased Apoa1
mRNA levels in primary mouse hepatocytes and HEPA1-6 cells.
Ezetimibe reduced the intestinal
cholesterol absorption, ABCA1 and ABCG5, but did not affect the serum HDL-C or ApoAI levels. Thus, the LXR-driven induction of HDL-C and ApoAI was independent of the intestinal
cholesterol absorption and increased expression of intestinal or hepatic ABCA1 was not required. Inhibited influx of
cholesterol via NPC1L1 and/or low levels of intracellular
cholesterol prevented post-transcriptional expression of intestinal ABCA1 and ABCG5, despite increased
mRNA levels. Combined LXR activation and blocked intestinal
cholesterol absorption induced effective faecal elimination of
cholesterol.