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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 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

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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 7

Proposed role of lipins 2 and 3 in intestinal chylomicron (CM) production.

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Proposed role of lipins 2 and 3 in intestinal chylomicron (CM) productio...
Left: In WT enterocytes, TAG synthesized in the ER membrane may bud into the cytosol for storage as lipid droplets (LDs) or into the ER lumen to associate with apoB48 through the action of microsomal TAG transfer protein. The resulting prechylomicron particles (PreCMs) ultimately bud from the ER. In steps not shown, these lipoproteins subsequently mature in the Golgi and are released from enterocytes as mature CMs. Right: In the absence of lipin 2/3 PAP activity, the lipin substrate phosphatidic acid (PA) accumulates at membrane sites in the ER (and possibly additional cell membranes). Elevated PA may activate mTORC1, which enhances CCTα levels by increasing protein stability or translation. Increased CCTα contributes to elevated PC levels and altered membrane phospholipid composition and impaired PreCM formation. TAG-rich lipid droplets accumulate in the cytoplasm rather than contribute to CM formation.
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