Nuclear Receptors Resolve Endoplasmic Reticulum Stress to Improve Hepatic Insulin Resistance

Jae Man Lee1,2

  • 1Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu, Korea.

Insights

Chronic endoplasmic reticulum (ER) stress drives insulin resistance and type 2 diabetes. Nuclear receptors offer potential treatments by resolving ER stress and improving liver insulin sensitivity.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Cellular Biology

Background:

  • Chronic endoplasmic reticulum (ER) stress and subsequent proteotoxicity are key factors in insulin resistance.
  • Insulin resistance is a major precursor to type 2 diabetes mellitus.
  • Pharmacologic targeting of nuclear receptors is a promising therapeutic strategy for insulin resistance.

Purpose of the Study:

  • To review recent advances linking ER stress to insulin resistance.
  • To explore the role of nuclear receptors in resolving ER stress.
  • To elucidate how nuclear receptors improve hepatic insulin resistance.

Main Methods:

  • Literature review of recent scientific publications.
  • Analysis of studies on ER stress, insulin resistance, and nuclear receptors.
  • Synthesis of findings on the mechanistic basis of therapeutic effects.

Main Results:

  • ER stress is strongly associated with the development of insulin resistance.
  • Nuclear receptors exhibit multifaceted metabolic and inflammatory functions.
  • These receptors play a crucial role in ER stress resolution and enhancing insulin sensitivity.

Conclusions:

  • Targeting ER stress through nuclear receptors represents a viable therapeutic approach for insulin resistance.
  • Understanding the interplay between ER stress and nuclear receptors is vital for diabetes treatment.
  • Further research into nuclear receptor mechanisms can lead to novel antidiabetic therapies.

Related Concept Videos

Transducer Mechanism: Nuclear Receptors01:31

Transducer Mechanism: Nuclear Receptors

Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
About 48 different soluble family members of nuclear receptors are identified that can be divided into two main classes:
4.2K
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
3.1K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
6.6K
Insulin: The Receptor and Signaling Pathways01:28

Insulin: The Receptor and Signaling Pathways

Insulin action is mediated through a receptor tyrosine kinase, akin to the IGF-1 receptor. The number of receptors per cell varies significantly, from 40 on erythrocytes to 300,000 on adipocytes and hepatocytes. The insulin receptor consists of linked α/β subunit dimers, forming a heterotetramer glycoprotein with two extracellular α subunits and two β subunits spanning the membrane. The α subunits inhibit the inherent tyrosine kinase activity of the β subunits, but...
5.4K
Role of ER in the Secretory Pathway01:17

Role of ER in the Secretory Pathway

Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
7.6K
Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
3.4K