Background: Dietary phytosterols are a recommended therapeutic option for decreasing plasma cholesterol. The increased activity of ATP-binding cassette (ABC) transporters ABCA1, ABCG5 and ABCG8, or, alternatively, a decrease in Niemann-Pick C1 Like 1 (NPC1L1) could mediate the reduction in intestinal cholesterol absorption caused by phytosterols. Other biological properties such as a direct immune modulatory activity have recently been ascribed to these plant compounds.
Methods: To gain insight into the molecular effects of phytosterols, global genome-wide gene profiling and real-time RT-PCR studies were conducted in small intestines and livers of phytosterol-treated apolipoprotein E-deficient (apoE(-/-)) mice. Re-testing of the main results was performed in C57BL/6J and LDL receptor-deficient (LDLR(-/-)) mice.
Results: Intestinal cholesterol absorption was decreased in all mouse models but plasma cholesterol was only decreased in apoE(-/-) and LDLR(-/-) mice. ABCA1, ABCG5, ABCG8 and NPC1L1 mRNA levels were slightly reduced in the intestine of phytosterol-treated apoE(-/-) and LDLR(-/-) mice, but increased in C57BL/6J-treated mice. Phytosterols changed genes involved in immune regulation in apoE(-/-) mice. However, these changes were less extensive in LDLR(-/-) mice and were not found in C57BL/6J mice.
Conclusions: Inhibition of intestinal cholesterol absorption by phytosterols is not mediated via transcriptional changes in ABCA1, ABCG5, ABCG8 or NPC1L1. Changes suggestive of immunomodulation are associated with the hypocholesterolemic effect of phytosterols and with apoE deficiency.