Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis
Peixiang Zhang, … , Stephen G. Young, Karen Reue
Peixiang Zhang, … , Stephen G. Young, Karen Reue
Published January 2, 2019; First published December 3, 2018
Citation Information: J Clin Invest. 2019;129(1):281-295. https://doi.org/10.1172/JCI122595.
View: Text | PDF
Categories: Research Article Metabolism

Lipin 2/3 phosphatidic acid phosphatases maintain phospholipid homeostasis to regulate chylomicron synthesis

  • Text
  • PDF
Abstract

The lipin phosphatidic acid phosphatase (PAP) enzymes are required for triacylglycerol (TAG) synthesis from glycerol 3-phosphate in most mammalian tissues. The 3 lipin proteins (lipin 1, lipin 2, and lipin 3) each have PAP activity, but have distinct tissue distributions, with lipin 1 being the predominant PAP enzyme in many metabolic tissues. One exception is the small intestine, which is unique in expressing exclusively lipin 2 and lipin 3. TAG synthesis in small intestinal enterocytes utilizes 2-monoacylglycerol and does not require the PAP reaction, making the role of lipin proteins in enterocytes unclear. Enterocyte TAGs are stored transiently as cytosolic lipid droplets or incorporated into lipoproteins (chylomicrons) for secretion. We determined that lipin enzymes are critical for chylomicron biogenesis, through regulation of membrane phospholipid composition and association of apolipoprotein B48 with nascent chylomicron particles. Lipin 2/3 deficiency caused phosphatidic acid accumulation and mammalian target of rapamycin complex 1 (mTORC1) activation, which were associated with enhanced protein levels of a key phospholipid biosynthetic enzyme (CTP:phosphocholine cytidylyltransferase α) and altered membrane phospholipid composition. Impaired chylomicron synthesis in lipin 2/3 deficiency could be rescued by normalizing phospholipid synthesis levels. These data implicate lipin 2/3 as a control point for enterocyte phospholipid homeostasis and chylomicron biogenesis.

Authors

Peixiang Zhang, Lauren S. Csaki, Emilio Ronquillo, Lynn J. Baufeld, Jason Y. Lin, Alexis Gutierrez, Jennifer R. Dwyer, David N. Brindley, Loren G. Fong, Peter Tontonoz, Stephen G. Young, Karen Reue

×

Figure 1

Lipin 2 and lipin 3 in mouse small intestine.

Options: View larger image (or click on image) Download as PowerPoint
Lipin 2 and lipin 3 in mouse small intestine.
(A) Immunoblot analysis of...
(A) Immunoblot analysis of lipins 1, 2, and 3 in proximal small intestine (duodenum). Mice were fasted for 16 hours or were fasted 16 hours and refed 4 hours with a chow or high-fat diet (HFD), as indicated. Recombinant protein controls are shown in the right column (+). Lanes were all on the same blot, but noncontiguous, as indicated by vertical lines. This experiment is representative of 3 studies of lipin protein levels in small intestine from fasted mice, and 1 experiment in mice that were refed chow or HFD. (B) Localization of endogenous lipin 2 (green) and lipin 3 (red) in mouse duodenum shown by confocal fluorescence microscopy. Duodenum was collected from mice fasted for 5 hours. (C and D) Lpin2/3-KO mice (Lpin2–/– Lpin3–/–) have reduced body weight (shown for 3 weeks and 5 months of age), increased intestinal circumference, and normal intestinal length compared with WT, Lpin2-KO, or Lpin3-KO mice. Data shown are average ± SD, n = 6–9/group. (E) Body-weight change in mice fed HFD for 6 days. Average ± SD, n = 4–6/genotype. **P < 0.01, ***P < 0.001 vs. other groups by ANOVA.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts