Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity

Hishikawa, Daisuke; Shindou, Hideo; Kobayashi, Saori; Nakanishi, Hiroki; Taguchi, Ryo; Shimizu, Takao

doi:10.1073/pnas.0712245105

Cited by 291 publications

(317 citation statements)

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“…Moreover, we showed that LPCAT4 (originally called MBOAT2) possesses LPCAT and LPEAT activities, whereas LPEAT1 (called MBOAT1) exhibits LPEAT and LPSAT activities (54). Thus, these results demonstrate that the MBOAT family is a novel LPLAT family.…”

Section: Acyltransferases In the Remodeling Pathway (Lands' Cycle)mentioning

confidence: 67%

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Acyl-CoA:Lysophospholipid Acyltransferases

Shindou

Shimizu

2009

Journal of Biological Chemistry

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Cell membranes contain several classes of glycerophospholipids, which have numerous structural and functional roles in the cells. Polyunsaturated fatty acids, including arachidonic acid and eicosapentaenoic acid, are located at the sn-2 (but not sn-1)-position of glycerophospholipids in an asymmetrical manner. Using acyl-CoAs as donors, glycerophospholipids are formed by a de novo pathway (Kennedy pathway) and modified by a remodeling pathway (Lands' cycle) to generate membrane asymmetry and diversity. Both pathways were reported in the 1950s. Whereas enzymes involved in the Kennedy pathway have been well characterized, including enzymes in the 1-acylglycerol-3-phosphate O-acyltransferase family, little is known about enzymes involved in the Lands' cycle. Recently, several laboratories, including ours, isolated enzymes working in the remodeling pathway. These enzymes were discovered not only in the 1-acylglycerol-3-phosphate O-acyltransferase family but also in the membrane-bound O-acyltransferase family. In this review, we summarize recent studies on cloning and characterization of lysophospholipid acyltransferases that contribute to membrane asymmetry and diversity.

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Section: Acyltransferases In the Remodeling Pathway (Lands' Cycle)mentioning

confidence: 67%

“…Using 20:4-CoA as a donor, endogenous LPCAT, LPEAT, and LPSAT activities were found to be decreased in B16 melanoma cells transfected with LPCAT3 small interfering RNA. Thus, LPCAT3 appears to be a key enzyme exhibiting LPCAT, LPEAT, and LPSAT activities in B16 cells (54).…”

Section: Acyltransferases In the Remodeling Pathway (Lands' Cycle)mentioning

confidence: 91%

Acyl-CoA:Lysophospholipid Acyltransferases

Shindou

Shimizu

2009

Journal of Biological Chemistry

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352

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“…In mouse, LPCAT2 (53) and LPCAT3 (49) have been suggested to show a preference for AA. In human cells, it is LPCAT3 the form that appears to exhibit preference for AA, although also by linoleic acid (50,52).…”

Section: Discussionmentioning

confidence: 99%

“…Four isoforms of LPCAT exist in mammalian cells, termed LPCAT1, LPCAT2, LPCAT3, and LPCAT4 (45-51), but only two of them, LPCAT2 and LPCAT3, have been documented to participate in AA reacylation reactions (49)(50)(51)(52)(53). Human peripheral blood monocytes express both LPCAT2 and LPCAT3 (data not shown).…”

Section: Lpcat3 Regulates Pl Aa Incorporation In Activated Cellsmentioning

confidence: 99%

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Pérez-Chacón

Astudillo²,

Ruipérez³

et al. 2009

The Journal of Immunology

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Cellular availability of free arachidonic acid (AA) is an important step in the production of pro- and anti-inflammatory eicosanoids. Control of free AA levels in cells is carried out by the action of phospholipase A2s and lysophospholipid acyltransferases, which are responsible for the reactions of deacylation and incorporation of AA from and into the sn-2 position of phospholipids, respectively. In this work, we have examined the pathways for AA incorporation into phospholipids in human monocytes stimulated by zymosan. Our data show that stimulated cells exhibit an enhanced incorporation of AA into phospholipids that is not secondary to an increased availability of lysophospholipid acceptors due to phospholipase A2 activation but rather reflects the receptor-regulated nature of the AA reacylation pathway. In vitro activity measurements indicate that the receptor-sensitive step of the AA reacylation pathway is the acyltransferase using lysophosphatidylcholine (lysoPC) as acceptor, and inhibition of the enzyme lysoPC acyltransferase 3 by specific small interfering RNA results in inhibition of the stimulated incorporation of AA into phospholipids. Collectively, these results define lysoPC acyltransferase 3 as a novel-signal–regulated enzyme that is centrally implicated in limiting free AA levels in activated cells.

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“…One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).…”

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confidence: 99%

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

Kabir

Bui

et al. 2016

Journal of Biological Chemistry

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Lysophosphatidylcholine acyltransferase 3 (Lpcat3) is involved in phosphatidylcholine remodeling in the small intestine and liver. We investigated lipid metabolism in inducible intestine-specific and liver-specific Lpcat3 gene knock-out mice. We produced Lpcat3-Flox/villin-Cre-ER T2 mice, which were treated with tamoxifen (at days 1, 3, 5, and 7), to delete Lpcat3 specifically in the small intestine. At day 9 after the treatment, we found that Lpcat3 deficiency in enterocytes significantly reduced polyunsaturated phosphatidylcholines in the enterocyte plasma membrane and reduced Niemann-Pick C1-like 1 (NPC1L1), CD36, ATP-binding cassette transporter 1 (ABCA1), and ABCG8 levels on the membrane, thus significantly reducing lipid absorption, cholesterol secretion through apoB-dependent and apoB-independent pathways, and plasma triglyceride, cholesterol, and phospholipid levels, as well as body weight. Moreover, Lpcat3 deficiency does not cause significant lipid accumulation in the small intestine. We also utilized adenovirus-associated virus-Cre to deplete Lpcat3 in the liver. We found that liver deficiency only reduces plasma triglyceride levels but not other lipid levels. Furthermore, there is no significant lipid accumulation in the liver. Importantly, small intestine Lpcat3 deficiency has a much bigger effect on plasma lipid levels than that of liver deficiency. Thus, inhibition of small intestine Lpcat3 might constitute a novel approach for treating hyperlipidemia.The majority of lipids on the cell membrane as well as the plasma lipoproteins are phospholipids, in particular phosphatidylcholines (PCs) 2 (1, 2). Monounsaturated and saturated fatty acids are usually esterified at the sn-1 position of PCs, whereas polyunsaturated fatty acids are esterified at the sn-2 position (3). The asymmetric distribution of fatty acids at the sn-1 and sn-2 positions of PCs is maintained in part by a deacylationreacylation process known as the Lands cycle or PC remodeling (3, 4). One key enzyme in this remodeling is lysophosphatidylcholine acyltransferase (Lpcat), which utilizes lyso-PC and polyunsaturated acyl-CoA to produce sn-2 polyunsaturated PCs. There are four isoforms of this enzyme (5), and Lpcat3 is the major isoform in the small intestine and liver (6 -8).Lpcat3 is one of the downstream targets of liver X receptor (8) and peroxisome proliferator-activated receptor ␣ (6). Acute knockdown of Lpcat3 expression in the liver of genetically obese mice exacerbates lipid-induced endoplasmic reticulum (ER) stress (8). Moreover, global Lpcat3 knock-out (KO) mice exhibit neonatal lethality and have an abnormal small intestine (9, 10). Liver-specific deletion of Lpcat3 has no effect on ER stress but results in a reduction of plasma triglycerides and induction of hepatosteatosis under high fat feeding conditions (9). Because of neonatal lethality (non-inducible approach was utilized), only 1-week-old newborns were analyzed for the impact of intestine-specific Lpcat3 deficiency on lipid metabolism (9). Very recently, we found that...

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Discovery of a lysophospholipid acyltransferase family essential for membrane asymmetry and diversity

Cited by 291 publications

References 55 publications

Acyl-CoA:Lysophospholipid Acyltransferases

Acyl-CoA:Lysophospholipid Acyltransferases

Signaling Role for Lysophosphatidylcholine Acyltransferase 3 in Receptor-Regulated Arachidonic Acid Reacylation Reactions in Human Monocytes

Small Intestine but Not Liver Lysophosphatidylcholine Acyltransferase 3 (Lpcat3) Deficiency Has a Dominant Effect on Plasma Lipid Metabolism

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