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The liver X receptor: control of cellular lipid homeostasis and beyond Implications for drug design

Maaike H Oosterveer1, Aldo Grefhorst, Albert K Groen

  • 1Department of Pediatrics, Center for Liver Digestive and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. m.h.oosterveer@med.umcg.nl

Progress in Lipid Research
|April 6, 2010
PubMed

Insights

Liver X receptors (LXRs) regulate metabolism and show promise for treating atherosclerosis and diabetes. However, side effects like fatty liver necessitate targeted therapies for safe clinical use.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Liver X receptors (LXRs) α and β are nuclear receptors crucial for regulating cellular cholesterol and lipid metabolism.
  • LXRs respond to cellular cholesterol levels, making them key targets for treating metabolic diseases like atherosclerosis.
  • Previous studies in rodents show LXR agonists can halt atherosclerosis but cause adverse effects like hepatic steatosis.

Purpose of the Study:

  • To explore the multifaceted roles of LXRs beyond cholesterol homeostasis, including implications for obesity, Alzheimer's disease, and type 2 diabetes.
  • To identify strategies for developing novel LXR agonists that maximize therapeutic benefits while minimizing adverse effects.
  • To establish tissue- and isotype-specific effects of LXR action for targeted therapeutic development.

Main Methods:

  • Review of existing literature on LXR function and pharmacological activation.
  • Analysis of LXR's role in cholesterol efflux, transport, and excretion in preclinical models.
  • Investigation of LXR's impact on hepatic lipid metabolism, glucose control, and other physiological processes.

Main Results:

  • LXR activation effectively promotes cholesterol efflux and halts atherosclerosis progression in rodents.
  • Pharmacological LXR activation can lead to undesirable hepatic steatosis and increased secretion of atherogenic VLDL particles.
  • Emerging evidence suggests LXRs play roles in fat tissue, pituitary, and brain, with potential therapeutic implications for obesity and Alzheimer's disease.
  • LXR activation demonstrates beneficial effects on glucose control in mouse models of type 2 diabetes.

Conclusions:

  • Targeting specific LXR-mediated processes is essential for developing effective therapies for metabolic diseases.
  • Understanding tissue- and isotype-specific LXR actions is critical for circumventing adverse effects.
  • Combinatorial drug approaches and identification of co-regulatory networks can lead to novel LXR agonists with improved therapeutic profiles.
  • Pathway analyses of LXR actions offer valuable tools for optimizing novel therapeutic strategies for metabolic disorders.

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