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Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
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The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
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Inhibiting IP6K1 confers atheroprotection by elevating circulating apolipoprotein A-I.

Xiaoqi Liu1, Zixuan Zhang1, Tim Aguirre2

  • 1Tianjin Key Laboratory of Metabolic Diseases, Department of Physiology and Pathophysiology, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, 22 Qixiangtai Road, Tianjin 300070, China.

Metabolism: Clinical and Experimental
|December 6, 2024
PubMed
Summary

Blocking IP6K1 increases apolipoprotein A-I (apoA-I) production by preventing its degradation. This strategy elevates circulating apoA-I, reducing atherosclerosis and offering a potential therapeutic approach for cardiovascular disease.

Keywords:
AtherosclerosisCholesterol effluxHDLHepatocyteIP6KInositol pyrophosphateUBE4A

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Atherosclerotic cardiovascular diseases are a leading cause of mortality worldwide.
  • Apolipoprotein A-I (apoA-I) plays a crucial role in cholesterol efflux, mediating protection against atherosclerosis.
  • Regulatory mechanisms governing apoA-I levels remain incompletely understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms controlling apolipoprotein A-I (apoA-I) production.
  • To investigate the role of IP6K1 in apoA-I degradation and its potential as a therapeutic target.

Main Methods:

  • Co-immunoprecipitation assays to study protein-protein interactions.
  • Chemical biology tools to identify binding partners and functions of 5PP-InsP5.
  • A mouse model of atherosclerosis induced by AAV-PCSK9 and Western diet, with plaque analysis via Oil Red O and H&E staining.

Main Results:

  • Inhibition of IP6K1 activity enhances apoA-I production in hepatocytes.
  • IP6K1 product 5PP-InsP5 mediates apoA-I degradation through ubiquitination involving UBE4A.
  • Hepatocyte-specific IP6K1 deletion increases circulating apoA-I, augments cholesterol efflux, and reduces atherosclerotic burden.
  • Atheroprotection by IP6K1 deletion is dependent on apoA-I.

Conclusions:

  • Blocking IP6K1 activity provides a novel mechanism to increase apoA-I production.
  • Targeting IP6K1 is a promising therapeutic strategy for elevating apoA-I and achieving atheroprotection.