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 4

Aberrant lipid compartmentalization in response to an acute fat load in Lpin2/3-KO intestine.

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Aberrant lipid compartmentalization in response to an acute fat load in ...
(A) Distribution of fluorescence in proximal small intestine of mice 2 hours after oral gavage of oil containing BODIPY-labeled fatty acids. Upper: Fluorescence image of lipid droplet (LD) distribution. Middle: Overlay of fluorescence image and bright field with DAPI nuclear stain (blue). Lower: Enlarged image of single villus tip showing LD localization to both apical (A) and basolateral (B) regions of enterocytes in WT enterocytes (left) and primarily to the apical region in Lpin2/3-KO enterocytes (right). Representative of 2 experiments. (B) LDs marked by BODIPY (green) associate with the ER protein calnexin in the proximal small intestine of WT but not Lpin2/3-KO mice. The image was taken 2 hours after oil gavage with BODIPY-labeled fatty acids. Nuclei are stained blue with DAPI. (C) ApoB associates with LDs in WT but not in Lpin2/3-KO enterocytes. Image taken 2 hours after oil gavage with BODIPY-labeled fatty acids. (D) Partial colocalization of lipin 2 and apoB proteins on the surface of LDs in the proximal small intestine of WT mice. The image was taken 2 hours after oil gavage with BODIPY-labeled fatty acids.