PubMed · 11436260
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M R Walters, K R Lees. 2001. Transient ischaemic attacks: a GP guide.. https://pubmed.ncbi.nlm.nih.gov/11436260/
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The x-ray crystal structures of the human liver X receptor beta ligand binding domain complexed to sterol and nonsterol agonists revealed a perpendicular histidinetryptophan switch that holds the receptor in its active conformation. Hydrogen bonding interactions with the ligand act to position the His-435 imidazole ring against the Trp-457 indole ring, allowing an electrostatic interaction that holds the AF2 helix in the active position. The neutral oxysterol 24(S),25-epoxycholesterol accepts a hydrogen bond from His-435 that positions the imidazole ring of the histidine above the pyrrole ring of the tryptophan. In contrast, the acidic T0901317 hydroxyl group makes a shorter hydrogen bond with His-435 that pulls the imidazole over the electron-rich benzene ring of the tryptophan, possibly strengthening the electrostatic interaction. Point mutagenesis of Trp-457 supports the observation that the ligand-histidine-tryptophan coupling is different between the two ligands. The lipophilic liver X receptor ligand-binding pocket is larger than the corresponding steroid hormone receptors, which allows T0901317 to adopt two distinct conformations. These results provide a molecular basis for liver X receptor activation by a wide range of endogenous neutral and acidic ligands.
BACKGROUND: Despite the established efficacy of statins, many patients do not achieve recommended LDL cholesterol (LDL-C) goals. Contributing factors may be inadequate dosing, increased risk for adverse effects with high-dose monotherapy, and increased potential for intolerance and adverse effects with combinations of available agents. METHODS AND RESULTS: In a double-blind study, 628 patients with baseline LDL-C 145 to 250 mg/dL and triglycerides < or =350 mg/dL were randomly assigned to receive 1 of the following for 12 weeks: ezetimibe (10 mg/d); atorvastatin (10, 20, 40, or 80 mg/d); ezetimibe (10 mg) plus atorvastatin (10, 20, 40, or 80 mg/d); or placebo. The primary efficacy end point was percentage reduction in LDL-C for pooled ezetimibe plus atorvastatin versus pooled atorvastatin treatment groups. Ezetimibe plus atorvastatin significantly improved LDL-C, HDL cholesterol (HDL-C), triglycerides, total cholesterol:HDL-C, and high-sensitivity C-reactive protein (hs-CRP) compared with atorvastatin alone (P<0.01). Coadministration of ezetimibe provided a significant additional 12% LDL-C reduction, 3% HDL-C increase, 8% triglyceride reduction, and 10% hs-CRP reduction versus atorvastatin alone. Ezetimibe plus atorvastatin provided LDL-C reductions of 50% to 60%, triglyceride reductions of 30% to 40%, and HDL-C increases of 5% to 9%, depending on atorvastatin dose. LDL-C reductions with ezetimibe plus 10 mg atorvastatin (50%) and 80 mg atorvastatin alone (51%) were similar. CONCLUSIONS: Ezetimibe plus atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone and to placebo. When coadministered with atorvastatin, ezetimibe provided significant incremental reductions in LDL-C and triglycerides and increases in HDL-C. Coadministration of ezetimibe and atorvastatin offers a well-tolerated and highly efficacious new treatment option for patients with hypercholesterolemia.