Resveratrol enhances trans-intestinal cholesterol excretion through selective activation of intestinal liver X receptor alpha

[Display omitted] Resveratrol (RSV) is a dietary polyphenol with well-documented cardio-protective activity, but its effects on blood cholesterol levels remain to be established. Due to its poor bioavailability, tissue accumulation of RSV is extremely low except for that in the small intestine. In the present study, we aimed to investigate the dose-dependent effects of RSV on blood cholesterol levels and the involvement of small intestine in the cholesterol-lowering impacts of RSV. Mice were administrated with RSV at various doses with high-fat diet (HFD) or high-fat and high-cholesterol diet (HCD) for 12 weeks. The fecal neutral sterol contents were analyzed, and intestinal perfusion test was performed. An enteric barrier model using Caco-2 cells was established. We observed that RSV reduced blood cholesterol levels in a dose-dependent manner in mice fed with HFD or HCD. Further investigation revealed that RSV administration increased the bile acid pool size but did not affect cholesterol consumption or de novo cholesterol synthesis. Interestingly, RSV promoted trans-intestinal cholesterol excretion (TICE) by 2-fold in the intestinal perfusion test. In addition, RSV upregulated the expressions of ATP-binding cassette sub-family G member 5 or 8 (Abcg5/8) and ATP-binding cassette sub-family B member 1a or 1b (Abcb1a/b) by up to 8 times in the duodenum mucosa but not in the liver. RSV also significantly downregulated the expression of intestinal Niemann-Pick C1-Like 1 (Npc1l1). Knock-down of liver X receptor alpha (LXRα) but not Sirt1 by siRNA significantly blocked RSV-induced cholesterol excretion in Caco-2 cells. In conclusion, RSV could decrease circulating cholesterol levels through enhancing TICE and limiting cholesterol absorption via selective activation of intestinal LXRα.