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1 Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan
2 CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan
3 Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo 162-8666, Japan
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Abstract |
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 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
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Introduction |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
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In the remodeling reaction, fatty acyl chains at the sn-2 position of glycerol backbone are hydrolyzed by a specific phospholipase A2 family member to produce 1-acyl lysophospholipids which is then reacylated by lysophospholipid acyltransferase. In fact, lysophospholipid acyltransferase activity such as lysophosphatidylcholine (LPC) acyltransferase (LPCAT), lysosphosphatidylserine (LPS) acyltransferase (LPSAT) and lysophosphatidylinositol (LPI) acyltransferase (LPIAT) have been detected in the microsomal fractions of tissues and cells (Keenan & Hokin 1962, 1964; Holub 1980; Lands et al. 1982; Inoue et al. 1984). Partial purification and characterization of these enzymes have led to the hypothesis that they exist in multiple forms in different tissues and cells. Attempts to purify the enzymes have not been successful historically largely because of their very labile nature in their detergent-solubilized states. It has also been clear that the enzymes that acylate glycerol phosphate (glycerol-3-phosphate acyltransferase: GPAT) and 1-acyl glycerol phosphate [lysophosphatidic acid (LPA) acyltransferase (LPAAT)] do not catalyze the acylation of membrane phospholipids such as phosphatidylcholine (PC) and phosphatidylinositol (PI). Recently, however, two LPCATs have been cloned by extensive genomic data base search; LPCAT1 is specifically expressed in lung alveolar type II cells and prefers saturated fatty acids as an acyl donor (Chen et al. 2006; Nakanishi et al. 2006), suggesting that LPCAT1 is involved in the synthesis of pulmonary surfactant phospholipids. A second LPCAT (LPCAT2) was also reported to act as an acetyl-CoA:lyso-platelet-activating factor (PAF) acetyltransferase (Shindou et al. 2006). These two LPCATs belong to the GPAT family of glycerolipid acyltransferases that contain four conserved motifs, which were identified by a bioinformatical approach (Coleman & Lee 2004). The GPAT family includes acyltransferases for GPAT, dihydroxyacetone-phosphate acyltransferase, LPAAT, lysophosphatidylglycerol acyltransferase and monocardiolipin acyltransferase. Neither LPCAT1 nor LPCAT2 appears to participate in the fatty acyl chain remodeling of membrane phospholipids, as both enzymes appear to catalyze the synthesis of secretory phospholipids such as PAF and the pulmonary surfactant dipalmitoyl-PC. Another acyltransferase family is called the membrane-bound O-acyltransferase (MBOAT) family (Hofmann 2000). Recently, a member of this family has been shown to exhibit lysophospholipid acyltransferase activity in yeast (Riekhof et al. 2007a; Benghezal et al. 2007; Jain et al. 2007; Tamaki et al. 2007). Interestingly, deletion of this gene in yeast results in strong reductions of the activities of various lysophospholipid acyltransferases such as LPCAT, LPSAT, LPIAT, lysophosphatidylethanolamine (LPE) acyltransferase (LPEAT) and LPAAT, suggesting this acyltransferase is involved in the metabolism of a variety of lysophospholipids in yeast. Independent of this study, we identified another member of the MBOAT family, which we named mboa-7, as a LPIAT with a preference for PUFAs as acyl donors, by establishing a screening system to identify genes required for use of exogenous PUFAs in Caenorhabditis elegans. The product of a human mboa-7 orthologue showed the same enzymatic properties when expressed in C. elegans mboa-7 mutants (Lee et al. 2008). All MBOAT proteins have several (typically eight to ten) membrane-spanning regions, and they share regions of detectable sequence similarity. Biochemically characterized members of the family include acyl-CoA:cholesterol acyltransferase (ACAT), diacylglycerol acyltransferase 1 (DGAT1) and acyltransferases for specific secretory proteins such as Wnt (Takada et al. 2006), Hedgehog (Chamoun et al. 2001; Lee & Treisman 2001) and Ghrelin (Yang et al. 2008). The C. elegans genome possesses 10 MBOAT genes, some of which have not been characterized yet (Lee et al. 2008). Since mboa-7 was found to be required for use of exogenous PUFAs, we examined whether other members of this family are involved in incorporation of PUFA into membrane phospholipids. As a result, we found that C. elegans mboa-6 is involved in incorporation of PUFAs into PC, PS and PE. We also found that the human homologue of mboa-6 encodes an acyltransferase that acts on LPC, LPS and LPE but not on LPI.
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Results |
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We first knocked down the expression of MBOAT family members in C. elegans (mboa-3, -4, -5 and -6, Table 1, Lee et al. 2008) by feeding RNAi and examined incorporation of radiolabeled arachidonic acid (AA) into the lipid fraction of these RNAi-treated worms. Synchronized first-stage larvae were cultured under [14C]AA-supplemented conditions until they reached the young adult stage, and the lipids extracted from the worms were analyzed for uptake of AA into phospholipids. [14C]AA was incorporated into all the major membrane phospholipids such as PC, PE, PI and PS (Fig. 1A; mock). In mboa-6 RNAi worms, incorporation of [14C]AA into PC was reduced to about 60% of the control (Fig. 1A), indicating that mboa-6 is involved in incorporation of AA into PC in C. elegans. Uptake of [14C]AA into PS and PE was also reduced significantly, while uptake of [14C]AA into PI was rather increased in mboa-6 RNAi worms (Fig. 1A). The effect of mboa-6 RNAi on the incorporation of [14C]AA into PS and PE was found to be more prominent in the fat-3 (
6 desaturase) mutant background in which endogenous PUFAs such as AA and eicosapentaenoic acid (EPA) are absent (Fig. 1B; Watts & Browse 2002). In contrast to mboa-6, knockdown of each of other MBOAT members, mboa-3, mboa-4, or mboa-5 did not affect the incorporation of [14C]AA into phospholipids (data not shown). Knockdown of mboa-6 caused several developmental defects such as early larval arrest, slow growth, and a dumpy morphology during post-embryonic development in C. elegans (Fig. 1C). These data indicate that mboa-6 contributes to the incorporation of AA into PC, PE and PS in living worms and is required for normal larval growth and morphology.
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A database search for C. elegans mboa-6 revealed that an MBOAT family member C3F is the closest homologue of mboa-6 (Fig. 2A, Ansari-Lari et al. 1997). C3F was identified as a gene, the over-expression of which results in the disruption of Golgi and endosome integrity using a strategy for rapid and unbiased functional annotation of uncharacterized human proteins (Hodges et al. 2005). mboa-6/C3F is evolutionarily conserved in a variety of species ranging from C. elegans, zebrafish to mammals. Human C3F, also referred to as MBOAT5 (Accession number: NP_005759 [GenBank] ), consists of 487 amino acid residues and shows a 33% identity with C. elegans mboa-6 at the amino acid level (Fig. 2A). The histidine residues, the predicted active site of the membrane-bound O-acyltransferase family, were conserved in all the mboa-6 homologues (Fig. 2A, asterisk). Hereafter, we will refer to C3F as MBOAT5.
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[14C]AA and [14C]LA added to the culture were incorporated into PC, PE, PI and PS of control HeLa cells time-dependently for at least 3 h (Fig. 2C–F). Incorporation of [14C]AA and [14C]LA into cellular PC was reduced to more than 40% and 70% of the control in the siMBOAT5–1-treated cells, respectively (Fig. 2G,H). Uptake into PS and PE fractions was also reduced significantly in the MBOAT5 knockdown cells, and incorporation of [14C]AA and [14C]LA into the PI fraction was increased in a complementary manner. We observed that LPIAT was not up-regulated in these MBOAT5 knockdown conditions (data not shown). Thus, the increased incorporation of PUFA into PI is due to the increase of availability of radioactive PUFA for LPIAT. In the MBOAT5 knockdown cells, incorporation of radiolabeled monounsaturated fatty acid such as oleic acid into PC was slightly reduced, but incorporation of saturated fatty acids into cellular phospholipids was not affected (data not shown), suggesting that MBOAT5 primarily contributes to the incorporation of PUFA into lysophospholipids in living cells.
We next measured arachidonoyl-CoA:lysophospholipid acyltransferase activities of the membranes of MBOAT5 knockdown cells using various lysophospholipids as acyl acceptors (Fig. 3A–E). Incorporation of [14C]arachidonoyl-CoA was elevated with increasing concentrations of lysophospholipids and reached plateau in the membranes treated with control siRNA. Incorporation of [14C]arachidonoyl-CoA into LPA and LPI was not affected in the membranes of MBOAT5 knockdown cells (Fig. 3D,E); however, incorporation into LPC and LPS was remarkably reduced at any concentration of these lysophospholipids (Fig. 3A,B). We also found that [14C]arachidonoyl-CoA transferase activity toward LPE was significantly reduced in the membranes of MBOAT5 knockdown cells, though the LPEAT activity was substantially lower than those against other lysophospholipids in HeLa cells (Fig. 3C). These data indicate that, at least in the membranes of HeLa cells, MBOAT5, a human homologue of C. elegans mboa-6, is primarily responsible for incorporation of AA into LPC, LPS and LPE, but not into LPI or LPA.
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Next we expressed the c-myc-tagged MBOAT5 in human embryonic kidney (HEK) 293 cells and measured acyltransferase activity using membrane fractions of the cells. Consistent with the results described above, the membranes of MBOAT5-over-expressing cells showed remarkably increased acyltransferase activity against LPC, LPS and LPE with [14C]arachidonoyl-CoA as an acyl donor (Fig. 4A–C). On the other hand, MBOAT5 did not show any detectable activity against LPA and LPI (data not shown). These results indicate that human MBOAT5 encodes an acyltransferase against LPC, LPS and LPE.
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Discussion |
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LPCAT and LPSAT activities preferring PUFAs as acyl donors have been reported in mammalian tissues and cells (Holub 1980; Lands et al. 1982; Yamashita et al. 1997). LPEAT activity has also been reported in rat brain microsomes, although oleoyl-CoA (18:1-CoA) was a preferred acyl donor to arachidonoyl-CoA (Masuzawa et al. 1989). At least in HeLa cells, MBOAT5 is primarily responsible for LPSAT and LPEAT activities since these activities with [14C]arachidonoyl-CoA as an acyl donor were remarkably reduced to approximately 20% of the control in the membranes of MBOAT5 knockdown cells (Fig. 3B,C). For LPCAT activity, MBOAT5 seems to be responsible for at least 50% of total LPCAT activity in HeLa cells (Fig. 3A). Oleoyl-CoA acyltransferase activity toward LPC can be separated chromatographically from oleoyl-CoA acyltransferase activity toward LPE or LPS when bovine heart microsomes were used as an enzyme source (Sanjanwala et al. 1988), suggesting that other LPCATs with a broad acyl donor specificity exist in mammalian tissues and cells.
In HeLa cells, knockdown of MBOAT5 caused reduced incorporation of PUFAs into PC, PS and PE at the cellular level, though the incorporation of PUFAs into cellular PE was less affected than the incorporation of PUFAs into PC and PS (Fig. 2G,H). On the other hand, in an in vitro assay using the microsomes of MBOAT5 knockdown cells, LPEAT activity with arachidonoyl-CoA as an acyl donor was remarkably reduced in a similar manner to LPSAT activity (Fig. 3B,C). These results suggest that LPEAT activity of MBOAT5 does not mainly contribute to the incorporation of exogenous PUFAs into PE in HeLa cells under the present conditions, and that other acyl transfer systems such as transacylation (Irvine & Dawson 1979; Kramer et al. 1984; Sugiura et al. 1988) are responsible for PUFAs transfer to PE at the cellular level.
In C. elegans, mboa-6 also contributes significantly to the incorporation of exogenous PUFAs into PC, PS and PE based on the data that incorporation of [14C]AA into PC, PS or PE was reduced to about 50%–60% of the control in mboa-6 knockdown worms (Fig. 1B; PUFA-depleted condition). It may be possible that other MBOAT family members, such as mboa-3, mboa-4, or mboa-5, contribute redundantly to the uptake of PUFAs into these phospholipids. Further biochemical analyses using null mutants of mboa genes will reveal the precise contributions to the incorporation of PUFAs into membrane phospholipids.
It has been suggested that mammalian tissues and cells have several PUFA-preferring acyltransferases toward LPC, LPE, LPS and LPI (Yamashita et al. 1997). Our previous and present studies suggest that both human and worms possess at least two PUFA-transferring acyltransferases which belong to MBOAT family; one is a LPI-specific acyltransferase, mboa-7/human LPIAT, and the other is mboa-6/MBOAT5 which utilizes LPC, LPE and LPS, but not LPI as an acyl acceptor. From an evolutionary point of view, it is interesting to note that in yeast, one MBOAT family member (referred to as ALE1, SLC4, or LPT1) catalyzes all the lysophospholipid acyltransferase activities such as LPEAT, LPCAT, LPSAT, LPIAT and LPAAT activities (Benghezal et al. 2007; Chen et al. 2007; Jain et al. 2007; Riekhof et al. 2007a; Tamaki et al. 2007). This enzyme is involved in the acylation of lysophospholipids added to the culture in yeast (Riekhof et al. 2007a,b) and also in the acylation of endogenous LPA during de novo phospholipids synthesis (Benghezal et al. 2007; Jain et al. 2007; Tamaki et al. 2007).
The physiologic role of mboa-6/MBOAT5 remains to be fully elucidated, as appropriate animal models deficient of these genes have not been established. In HeLa cells, over-expression of human MBOAT5 disrupts Golgi and endosome integrity (Hodges et al. 2005), while in Drosophila, an MBOAT5 homologue (nessy) is regulated by homeobox genes at the transcriptional level (Maurel-Zaffran et al. 1999). In this study, we showed that mboa-6 is required for normal larval growth and morphology in C. elegans, suggesting that acyltransferase activities toward LPC, LPS or LPE are essential for larval development in C. elegans. We are planning to analyze the physiological function of mboa-6 by using mboa-6 knockout worms, and genetically elucidate the molecular mechanism how MBOAT5 acts in cells and tissues.
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Experimental procedures |
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[1-14C]Arachidonoyl-CoA (55 mCi/mmol), [1-14C]linoleic acid (55 mCi/mmol), and [1-14C]arachidonic acid (55 mCi/mmol) were purchased from American Radiolabeled Chemicals (St. Louis, MO). LPC from egg yolk, LPS from porcine brain, LPE from porcine liver, and 1-oleoyl-glycerophosphate were obtained from Avanti Polar Lipids (Alabaster, AL). LPI from porcine liver was obtained from Serdary Research Laboratories (London, Ontario, Canada). Dulbecco's modified Eagle's medium and arachidonoyl-CoA were obtained from Sigma. TLC silica gel plates were purchased from Merck (Darmstadt, Germany).
Plasmid construction
Full-length mboa-6 was amplified by polymerase chain reaction (PCR) from C. elegans cDNA with primers mboa-6-F, 5'-AGC CTT CTA GAA TGG GCG TAG TCG GAG CAC-3' and mboa-6-R, 5'-TGC AAG GAT CCT TAG AGC TCT TTC TTG ACT TC-3'. The PCR amplified product was cloned into pPD129.36 vector at the XbaI and BamHI sites and sequenced. Full-length human MBOAT5 was amplified by PCR from a HeLa cell cDNA with primers hMBOAT5-F, 5'-CCG GAG GTA CCA TGG CGT CCT CAG CGG AGG G-3' and hMBOAT5-R, 5'-GAA ATC TCG AGT TCC ATC TTC TTT AAC TTC-3', and was cloned into pcDNA3-myc vector (C-terminal Myc tag) at the KpnI and SalI sites.
General methods and strains
General methods for maintaining C. elegans are described by Brenner (Brenner 1974). The C. elegans wild-type strain was Bristol N2, and E. coli HT115 was used as the sole food source. Feeding RNAi was performed as described previously (Kamath et al. 2001). For phenotypic analysis of mboa-6 RNAi worms, adult wild-type worms were allowed to lay eggs for 2–3 h on RNAi plates, and the progeny were observed for growth and morphology. For growth rate analysis, first larval stage worms were incubated on RNAi plates at 20 °C and the growth rate was scored by counting adult worms under a stereomicroscope.
Cell culture and transfection
HEK 293 and HeLa cells were maintained in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal calf serum, penicillin (100 units/mL), streptomycin (100 mg/mL), and L-glutamine (2 mM). Transfection of the plasmid DNA and siRNA into cells was performed using LipofectAMINE 2000 (Invitrogen, San Diego, CA) according to the manufacturer's protocol.
Quantitative real-time RT-PCR
Total RNA from cells was extracted using ISOGEN (Nippongene, Toyama, Japan) and reverse-transcripted using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA). Oligonucleotide primers for PCR were designed using Primer Express Software (Applied Biosystems). The sequences of the oligonucleotides for human MBOAT5 were the following primers: forward primer, 5'-TGG GCC GCA CCA TCA C-3'; reverse primer, 5'-TAG TTG CCG GTG GCA GTG TA-3'. As an internal control for RT-PCR analysis, glyceraldehydes-3-phosphate dehydrogenase (GAPDH) transcripts were amplified and expression of each sample was normalized on the basis of GAPDH content.
Acyltransferase assay
HeLa cells and HEK 293 cells were harvested, washed with ice-cold PBS, then sonicated three times on ice for 3 s in 50 mM potassium phosphate buffer (pH 7.0) containing 0.15 M KCl, 0.25 M sucrose, 1 mM EDTA, 1 mM dithiothreitol and 5 µg/mL pepstatin, leupeptin and aprotinin (homogenizing buffer). After centrifugations at 1000 g for 5 min, the supernatant was collected and centrifuged at 100 000 g for 1 h. The resulting pellet was resuspended in homogenizing buffer (without EDTA, dithiothreitol, and protease inhibitor cocktail) and immediately used for the enzyme assay described below. Reaction mixtures contained the indicated concentrations of an acyl-CoA and a lysophospholipid, and 0.08 mg of microsomal protein in a total volume of 0.8 mL assay buffer [0.15 M KCl, 0.25 M sucrose, 50 mM potassium phosphate buffer (pH 6.8)]. After incubation at 37 °C for 5 min, reactions were stopped by the addition of 2 mL of methanol. Total lipid was extracted by the method of Bligh and Dyer (Bligh & Dyer 1959), and separated by one-dimensional TLC on silica gel 60 plates (Merck) in chloroform/ethanol/water/triethylamine (30/35/7/35, v/v). The radioactivities of separated bands on TLC were quantified using a BAS 1500 bio-imaging analyzer.
In vivo incorporation of exogenous fatty acids into Caenorhabditis elegans and HeLa cells
For incorporation of exogenous fatty acids into C. elegans, synchronized first-stage larvae (800–1200 animals) were cultured with 1 µCi of [14C]AA on nematode growth medium plates at 20 °C until they reached the young adult stage. Lipids of young adult worms were extracted by the method of Bligh and Dyer (Bligh & Dyer 1959) and separated by one-dimensional TLC on silica gel 60 plates (Merck) in chloroform/ethanol/water/triethylamine (30/35/7/35, v/v). Incorporation of [14C]fatty acid into individual phospholipids was expressed as the percentage of radioactivity incorporated into total lipids.
HeLa cells (1.5 x 105) were plated in 6-well plates and incubated for 24 h. siRNAs for human MBOAT5 (siMBOAT5-1, see text) were then transfected into HeLa cells with LipofectAMINE 2000 reagent (Invitrogen) according to the manufacturer's protocol. The final concentration of siRNA was 40 nM. After incubation for 48 h, the cells were washed and incubated in DMEM containing 0.1% bovine serum albumin for 24 h. Then, 1.82 nmol per well of [14C]LA or [14C]AA (0.1 µCi) was added to the medium as an albumin complex. After 1 h incubation, the cell lipids were extracted and separated by TLC as described above. Incorporation of [14C]fatty acid into individual phospholipids was expressed as the percentage of radioactivity incorporated into total lipids.
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Acknowledgements |
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Footnotes |
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As we were preparing this manuscript for publication, the molecular characterization of MBOAT5, which was named LPCAT3, was reported (Hishikawa et al. 2008; Zhao et al. 2008).
* Correspondence: harai{at}mol.f.u-tokyo.ac.jp
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Accepted: 14 May 2008
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