Selective activation of liver X receptor alpha by 6α-hydroxy bile acids and analogs

We have found that certain natural 6 alpha-hydroxylated bile acids are receptor-specific activators of nuclear liver X receptor alpha (LXR alpha) (NR1H3), a nuclear receptor regulating the expression of the cholesterol 7 alpha-hydroxylase gene, coding for the rate-limiting enzyme in the major pathway of bile acid synthesis. The LXR homolog, ubiquitous nuclear receptor (UR/LXR beta) (NR1H2), was also activated by these bile acids, but at higher concentrations than for LXR alpha. Synthetic 6 alpha-hydroxylated bile acid analogs were synthesized with LXR alpha-selective agonistic activity, with potential to modulate cholesterol catabolism in hypercholesterolemia. (C) 2000 Elsevier Science Inc. All rights reserved.