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.
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Research Article Metabolism

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

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

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Figure 1

Lipin 2 and lipin 3 in mouse small intestine.

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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.