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Targeting liver X receptors in human health: deadlock or promising trail?
Emilie Viennois1, Aurélien J C Pommier, Kévin Mouzat
1Clermont Université, Université Blaise Pascal, Génétique Reproduction et Développement, BP 10448, F-63000 Clermont-Ferrand, France.
Introduction:
Liver X receptors (LXR) are transcription factors that belong to the nuclear receptor superfamily. Natural derivatives of cholesterol, known as oxysterols, have been identified as agonistic ligands of LXR. They are thus mainly considered to be intracellular cholesterol 'sensors' whose activation leads to decreased plasma cholesterol. Their implication in other physiologic processes currently prevents their use as therapeutic targets, because of potentially deleterious side effects.
Areas Covered:
The various LXR agonists and antagonists, along with the physiological functions of LXR. Putative clinical targets including atherosclerosis, diabetes, Alzheimer's disease, skin disorders, reproductive disorders and cancer.
Expert Opinion:
LXR are promising pharmacological targets because of the high potential to develop ligands owing to the variety of natural or synthetic agonists. Three aspects should be developed to select a LXR-ligand for treatment of human disease: bio-availability; isoform specificity; tissue specificity. This will allow the development of selective liver X modulators (SLiMs). The challenge is to overcome deleterious side effects to establish LXR as new pharmacological targets.
Insights
Liver X receptors (LXR) are cholesterol sensors with therapeutic potential. Developing specific LXR modulators requires addressing bioavailability, isoform, and tissue specificity to minimize side effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Liver X receptors (LXR) are nuclear receptors activated by oxysterols, cholesterol derivatives.
- LXR activation influences intracellular cholesterol levels and other physiological processes.
- Current understanding limits LXR therapeutic applications due to potential side effects.
Purpose of the Study:
- To review the physiological functions of LXR.
- To explore LXR as a therapeutic target for various diseases.
- To discuss the development of selective LXR modulators.
Main Methods:
- Review of LXR agonists and antagonists.
- Analysis of LXR physiological functions.
- Identification of potential clinical applications and challenges.
Main Results:
- LXR agonists and antagonists modulate cholesterol metabolism.
- LXR plays roles in atherosclerosis, diabetes, Alzheimer's disease, and cancer.
- Development of selective liver X modulators (SLiMs) is proposed.
Conclusions:
- LXR represents a promising pharmacological target due to diverse ligand availability.
- Key factors for LXR ligand development include bioavailability, isoform, and tissue specificity.
- Overcoming side effects is crucial for establishing LXR as a viable therapeutic target.
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