43(P-1) Phytosterol Derivatives Acting on the Sterol-Sensing Nuclear Receptor LXR
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The nuclear receptors liver X receptor (LXR) α and LXRβ serve as oxysterol receptors and regulate the expression of genes involved in lipid metabolism. LXR activation induces the expression of ATP-binding cassette (ABC) transporters, such as ABCG5 and ABCG8, which inhibit intestinal absorption of cholesterol and phytosterols. Although several synthetic LXR agonists have been generated, these compounds have limited clinical application because they cause hypertriglycemia by inducing the expression of lipogenic genes in the liver. We synthesized derivatives of phytosterols and found some of them to act as LXR agonists. Among them, YT-32 [(22E)-ergost-22-ene-1α,3β-diol], which is related to ergosterol and brassicasterol, is the most potent LXR agonist. YT-32 directly bound to LXRα and LXRβ and induced the interaction of LXRα with cofactors, such as SRC-1, as effectively as the natural ligands, 22(R)-hydroxycholesterol and 24(S),25-epoxycholesterol. YT-32 is a sterol compound with a saturated cholesterol structure and the same side chain as ergosterol and brassicasterol. YT-33, which differs from YT-32 only in the absence of the 1α-hydroxyl group, completely lacks LXRα agonist activity. To further examine the structure-function relationship between YT-32 and LXRα, we synthesized several YT-32 derivatives containing the 1α-hydroxyl group. The data indicate that the 1α-hydroxyl group and saturated ring structure are important for LXRα and LXRβ activation. These structures are also important for induction of the LXR target gene in intestinal cells. YT-32 selectively activated intestinal ABC transporters in mice and inhibited intestinal cholesterol absorption without increasing plasma triglyceride levels. The phytosterol-derived LXR agonist YT-32 might selectively modulate intestinal cholesterol metabolism.
