Human NR1H2 blocking peptide

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.

The liver X receptors, LXR alpha (NR1H3) and LXR beta (NR1H2), are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. LXRs play a critical role in cholesterol homeostasis and bile acid metabolism. In addition, oral administration of LXR agonists to mice results in elevated hepatic fatty acid synthesis and steatosis and increased secretion of triglyceride-rich very low density lipoprotein resulting in hypertriglyceridemia. This increased hepatic lipogenesis has been largely attributed to the LXR-dependent upregulation of sterol regulatory element-binding protein 1c (SREBP-1c) expression. However, it has been reported that treating Srebp-1c null mice with the synthetic LXR agonist T0901317 still results in enhanced expression of many lipogenic genes, suggesting additional mechanisms by which LXR can enhance hepatic lipogenesis. In this report, we identify the carbohydrate response element-binding protein (ChREBP) as an LXR target that independently enhances the up-regulation of select lipogenic genes. The ChREBP promoter contains functional LXR-binding sites that confer receptor-dependent binding and transactivation. We show that T0901317 treatment of mice is associated with up-regulation of the ChREBP target gene, liver-type pyruvate kinase. Therefore, activation of LXR not only increases ChREBP mRNA via enhanced transcription but also modulates ChREBP activity. This establishes LXR as a master lipogenic transcription factor, as it directly regulates both SREBP-1c and ChREBP to enhance hepatic fatty acid synthesis.