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Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion

  1. Xin Rong
  2. Bo Wang
  3. Merlow M Dunham
  4. Per Niklas Hedde
  5. Jinny S Wong
  6. Enrico Gratton
  7. Stephen G Young
  8. David A Ford
  9. Peter Tontonoz  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, Los Angeles, United States
  2. Saint Louis University, United States
  3. University of California, Irvine, United States
  4. Gladstone Institute of Cardiovascular Disease, United States
  5. University of California, Los Angeles, United States
Research Article
  • Cited 70
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Cite this article as: eLife 2015;4:e06557 doi: 10.7554/eLife.06557

Abstract

The role of specific phospholipids in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo. Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma triglycerides. Mice lacking Lpcat3 in the liver show reduced plasma triglycerides, hepatosteatosis, and secrete lipid-poor VLDL lacking arachidonoyl phospholipids. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl phospholipids in lipidating lipoprotein particles. These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways.

Article and author information

Author details

  1. Xin Rong

    Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  2. Bo Wang

    Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.

  3. Merlow M Dunham

    Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, United States
    Competing interests
    No competing interests declared.

  4. Per Niklas Hedde

    Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  5. Jinny S Wong

    Electron Microscopy Core, Gladstone Institute of Cardiovascular Disease, San Francisco, United States
    Competing interests
    No competing interests declared.

  6. Enrico Gratton

    Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  7. Stephen G Young

    Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    Stephen G Young, Reviewing Editor, eLife.

  8. David A Ford

    Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, United States
    Competing interests
    No competing interests declared.

  9. Peter Tontonoz

    Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    ptontonoz@mednet.ucla.edu
    Competing interests
    Peter Tontonoz, Reviewing editor, eLife.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (99-131 and 2003-166) of the University of California Los Angeles

Reviewing Editor

  1. Tobias C Walther, Harvard School of Public Health, United States

Publication history

  1. Received: January 18, 2015
  2. Accepted: March 24, 2015
  3. Accepted Manuscript published: March 25, 2015 (version 1)
  4. Version of Record published: April 17, 2015 (version 2)

Copyright

© 2015, Rong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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