Intestinal specific LXR activation stimulates reverse cholesterol transport and protects from atherosclerosis.
Several steps of the HDL-mediated reverse cholesterol transport (RCT) are transcriptionally regulated by the nuclear receptors LXRs in the macrophages, liver, and intestine. Systemic LXR activation via synthetic ligands induces RCT but also causes increased hepatic fatty acid synthesis and steatosis, limiting the potential therapeutic use of LXR agonists. During the last few years, the participation of the intestine in the control of RCT has appeared more evident. Here we show that while hepatic-specific LXR activation does not contribute to RCT, intestinal-specific LXR activation leads to decreased intestinal cholesterol absorption, improved lipoprotein profile, and increased RCT in vivo in the absence of hepatic steatosis. These events protect against atherosclerosis in the background of the LDLR-deficient mice. Our study fully characterizes the molecular and metabolic scenario that elects the intestine as a key player in the LXR-driven protective environment against cardiovascular disease.
Lo Sasso
Giuseppe
G
Laboratory of Lipid Metabolism and Cancer, Department of Translational Pharmacology, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Chieti, Italy.
Murzilli
Stefania
S
Salvatore
Lorena
L
D'Errico
Ilenia
I
Petruzzelli
Michele
M
Conca
Paola
P
Jiang
Zhao-Yan
ZY
Calabresi
Laura
L
Parini
Paolo
P
Moschetta
Antonio
A
D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D002784:Cholesterol