Fatty acyl-chain remodeling by LPCAT3 enriches arachidonate in phospholipid membranes and regulates triglyceride transport

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Abstract

Polyunsaturated fatty acids (PUFAs) in phospholipids affect the physical properties of membranes, but it is unclear which biological processes are influenced by their regulation. For example, the functions of membrane arachidonate that are independent of a precursor role for eicosanoid synthesis remain largely unknown. Here, we show that the lack of lysophosphatidylcholine acyltransferase 3 (LPCAT3) leads to drastic reductions in membrane arachidonate levels, and that LPCAT3-deficient mice are neonatally lethal due to an extensive triacylglycerol (TG) accumulation and dysfunction in enterocytes. We found that high levels of PUFAs in membranes enable TGs to locally cluster in high density, and that this clustering promotes efficient TG transfer. We propose a model of local arachidonate enrichment by LPCAT3 to generate a distinct pool of TG in membranes, which is required for normal directionality of TG transfer and lipoprotein assembly in the liver and enterocytes.

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Tomomi Hashidate-Yoshida

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
No competing interests declared.
Takeshi Harayama

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Switzerland

Competing interests
No competing interests declared.
Daisuke Hishikawa

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
No competing interests declared.
Ryo Morimoto

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
Ryo Morimoto, Department of Lipidomics, the University of Tokyo is financially supported by Shimadzu Co., and ONO Phamraceutical Col. Ltd..
Fumie Hamano

Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Competing interests
Fumie Hamano, Department of Lipidomics, the University of Tokyo is financially supported by Shimadzu Co., and ONO Phamraceutical Col. Ltd..
Suzumi M Tokuoka

Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Competing interests
Suzumi M Tokuoka, Department of Lipidomics, the University of Tokyo is financially supported by Shimadzu Co., and ONO Phamraceutical Col. Ltd..
Miki Eto

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
Miki Eto, Department of Lipidomics, the University of Tokyo is financially supported by Shimadzu Co., and ONO Phamraceutical Col. Ltd..
Miwa Tamura-Nakano

Communal Laboratory, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
No competing interests declared.
Rieko Yanobu-Takanashi

Department of Laboratory Animal Medicine, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
No competing interests declared.
Yoshiko Mukumoto

Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan

Competing interests
No competing interests declared.
Hiroshi Kiyonari

Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan

Competing interests
No competing interests declared.
Tadashi Okamura

Department of Laboratory Animal Medicine, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
No competing interests declared.
Yoshihiro Kita

Department of Lipidomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Competing interests
Yoshihiro Kita, Department of Lipidomics, the University of Tokyo is financially supported by Shimadzu Co., and ONO Phamraceutical Col. Ltd..
Hideo Shindou

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan

Competing interests
No competing interests declared.
Takao Shimizu

Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan

For correspondence
tshimizu@ri.ncgm.go.jp

Competing interests
Takao Shimizu, Department of Lipidomics, the University of Tokyo is financially supported by Shimadzu Co., and ONO Phamraceutical Col. Ltd..

Ethics

Animal experimentation: All animal experiments were approved by and performed in accordance with the guidelines of the Animal Research Committee of National Center for Global Health and Medicine (12053, 13009, 14045), and the animal experimentation committee of the University of Tokyo (H09-144, P08-042).

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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.