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Cell signaling and nuclear receptors: new opportunities for molecular pharmaceuticals in liver disease

Jeff L Staudinger1, Kristin Lichti

  • 1University of Kansas, Department of Pharmacology and Toxicology, 1251 Wescoe Hall Dr, 5038 Malott Hall, Lawrence, Kansas 66045, USA. stauding@ku.edu

Molecular Pharmaceutics
|December 28, 2007
PubMed

Insights

Liver-enriched nuclear receptors (NRs) act as sensors for metabolism and toxins. Their function is modulated by signal transduction pathways, offering new therapeutic targets for liver diseases.

Area of Science:

  • Molecular biology
  • Hepatology
  • Endocrinology

Background:

  • Liver-enriched nuclear receptors (NRs) are crucial regulators of hepatic gene expression.
  • NRs control the uptake, metabolism, and excretion of key metabolic substrates and xenobiotics.
  • NRs play a vital role in maintaining energy homeostasis in mammals.

Purpose of the Study:

  • To review recent insights into the molecular mechanisms at the interface of signal transduction pathways and liver-enriched NRs.
  • To explore how disease-mediated activation of signaling pathways impacts NR function in the liver.
  • To highlight opportunities for developing novel therapeutic strategies targeting these interactions.

Main Methods:

  • Review of current scientific literature on nuclear receptor signaling and hepatic physiology.
  • Analysis of molecular mechanisms involving post-translational modifications (e.g., phosphorylation) of NRs.
  • Integration of knowledge on the interplay between signaling pathways and NRs in the context of metabolic diseases.

Main Results:

  • Ligand-binding is not the sole activator of NRs; signal transduction pathways significantly modulate their function.
  • Phosphorylation of hepatic NRs affects their transactivation, DNA binding, localization, cofactor interaction, and stability.
  • Pathological conditions like obesity, diabetes, and inflammation alter hepatic signaling pathways, impacting NR activity.

Conclusions:

  • The interface between signal transduction pathways and liver-enriched NRs is a critical determinant of hepatic function.
  • Dysregulation of this interface contributes to the pathogenesis of prevalent metabolic and inflammatory liver diseases.
  • Understanding these molecular mechanisms opens avenues for novel therapeutic interventions for liver-related disorders.

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