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A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
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Genetic variation in ANGPTL4 provides insights into protein processing and function.

Wu Yin1, Stefano Romeo, Shurong Chang

  • 1Eugene McDermott Center for Human Growth and Development, Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-8591, USA.

The Journal of Biological Chemistry
|March 10, 2009
PubMed
Summary

Oligomerization of Angiopoietin-like protein 4 (ANGPTL4) is essential for inhibiting lipoprotein lipase (LPL) and lowering triglycerides. The E40K variant prevents ANGPTL4 oligomerization, abolishing its LPL inhibitory function.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Angiopoietin-like protein 4 (ANGPTL4) regulates circulating triglyceride levels by inhibiting lipoprotein lipase (LPL).
  • A human sequence variant, E40K, is linked to reduced plasma triglyceride levels.

Purpose of the Study:

  • To investigate the synthesis and post-translational processing of ANGPTL4.
  • To determine the role of ANGPTL4 oligomerization and cleavage in its function.
  • To elucidate the mechanism by which the E40K variant affects ANGPTL4 activity.

Main Methods:

  • Expression of wild-type and mutant ANGPTL4 in HEK-293A cells.
  • Analysis of protein oligomerization, secretion, and cleavage.
  • In vitro assessment of ANGPTL4's ability to inhibit LPL activity.
  • In vivo validation in a mouse model.

Main Results:

  • ANGPTL4 forms dimers and tetramers before secretion and cleavage.
  • Cleavage at RRKR site releases C-terminal monomers but retains N-terminal oligomers.
  • Oligomerization, not cleavage, is critical for LPL inhibition.
  • The E40K variant prevents extracellular ANGPTL4 oligomer accumulation and LPL inhibition.

Conclusions:

  • ANGPTL4 oligomerization is necessary for its function in inhibiting LPL.
  • Cleavage of ANGPTL4 is not required for LPL inhibition.
  • The E40K substitution destabilizes secreted ANGPTL4, impairing its triglyceride-lowering function.