LXRβ activation increases intestinal cholesterol absorption, leading to an atherogenic lipoprotein profile

Hu X, Steffensen KR, Jiang Z-Y, Parini P, Gustafsson J-A, Gafvels M, Eggertsen G (Karolinska Institutet, Huddinge, Stockholm, Sweden; Karolinska Institutet, Huddinge, Stockholm, Sweden; Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and University of Houston, Houston, TX, USA). LXR beta activation increases intestinal cholesterol absorption, leading to an atherogenic lipoprotein profile. J Intern Med 2012; 272: 452464. Objectives. Liver X receptors (LXRs) are essential for the regulation of intestinal cholesterol absorption. Because two isoforms exist, LXRa and LXR beta, with overlapping but not identical functions, we investigated whether LXRa and LXR beta exert different effects on intestinal cholesterol absorption. Design. Wild-type (WT), LXRa-/- and LXR beta-/- mice were fed control diet, 0.2% cholesterol-enriched diet or 0.2% cholesterol-enriched diet plus the LXR agonist GW3965. Results. When fed a control diet, all three genotypes showed similar levels of cholesterol absorption. Of interest, a significant increase in cholesterol absorption was found in the LXRa-/- mice, but not in the WT or LXR beta-/- animals, when fed a diet enriched with 0.2% cholesterol or 0.2% cholesterol + GW3965. Reduced faecal neutral sterol excretion and a hydrophobic bile acid profile were also observed in LXRa-/- mice. Greater increases in the apolipoprotein (apo)B-containing lipoproteins in serum were seen in the LXRa-/- mice. A 0.2% cholesterol + GW3965 diet suppressed intestinal Npc1l1 protein expression to the same extent for all genotypes, while Abca1 and Abcg5 were elevated to the same degree. Conclusions. In the intestine, LXRa and LXR beta seem to exert similar effects on expression of cholesterol-transporting proteins such as Npc1l1. Selective activation of LXR beta may generate effects such as increased cholesterol absorption and elevated serum levels of apoB-containing lipoproteins, which seem to be counteracted by LXRa. Therefore, an intestinal LXR beta-specific pathway might exist in terms of cholesterol transportation in addition to the main pathway.