Lysophosphatidylcholine Acyltransferase 3 Knockdown-mediated Liver Lysophosphatidylcholine Accumulation Promotes Very Low Density Lipoprotein Production by Enhancing Microsomal Triglyceride Transfer Protein Expression

Li, Zhiqiang; Ding, Tonghai; Pan, Xiaoyue; Li, Yan; Li, Ruohan; Sanders, P.; Kuo, Ming‐Shang; Hussain, M. Mahmood; Cao, Guoqing; Jiang, Xian‐Cheng

doi:10.1074/jbc.m111.334664

Cited by 46 publications

(48 citation statements)

References 53 publications

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“…Noticeably, LPCAT3 silencing did not induce an accumulation of lysophospholipids in the cells, although this was observed after LPCAT3 inhibition in the liver. 25 The picture was totally different in LXR agonist-treated macrophages because LXR activation induced an increase in LPCAT activity that was directly related to the upregulation of LPCAT3 (Figure 3). In these conditions, LPCAT3 contributed to the alterations in cellular lipid composition induced by LXR and was specifically responsible for the increase in the AA content of PLs.…”

Section: Discussionmentioning

confidence: 97%

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Ishibashi

Varin

Filomenko

et al. 2013

ATVB

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L iver X receptor-α (LXRα) and LXRβ (Nr1h3 and Nr1h2, respectively) are oxysterol-activated nuclear receptors that regulate the expression of genes involved in different pathways, such as cholesterol and fatty acid (FA) metabolism or inflammation.1 LXRs are attractive targets in the field of atherosclerosis because LXR activation improves cholesterol homeostasis and promotes cholesterol removal from macrophages through the coordinate regulation of apolipoprotein E and the cholesterol transporters ATP-binding cassette transporter A1 and and ATP-binding cassette transporter G1. LXR also stimulates lipogenesis and the production of monounsaturated FAs through induction of prolipogenic genes, including sterol regulatory element-binding protein 1c, FA synthase, and stearoyl CoA desaturase.1 In addition, a specific role for LXR in cellular phospholipid (PL) metabolism was recently described because LXR activation was shown to reduce the biosynthesis of phosphatidylethanolamines by inhibiting the CTP:phosphoethanolamine cytidylyltransferase, an enzyme involved in the Kennedy pathway. 2 Besides cholesterol and FA metabolism, a major function for LXR in macrophages is the control of innate immunity. Treatment of murine macrophages with synthetic LXR agonists attenuates the inflammatory response to lipopolysaccharide (LPS) 3 and it has been demonstrated that LXR ligands can induce the sumoylation of LXR, which subsequently forms complexes with nuclear receptor corepressor 1 and SMRT that inhibit NF-κB-mediated and AP-1-mediated inflammatory response. 4,5 In contrast to mouse macrophages, treatment of human macrophages with © 2013 American Heart Association, Inc. Objective-Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that are highly expressed in macrophages and regulate lipid homeostasis and inflammation. Among putative LXR target genes, lysophosphatidylcholine acyltransferase 3 (LPCAT3) involved in the Lands cycle controls the fatty acid composition at the sn-2 position of glycerophospholipids and, therefore, the availability of fatty acids, such as arachidonic acid (AA), used for eicosanoid synthesis. The aim of our study was to determine whether LXRs could regulate the Lands cycle in human macrophages, to assess the consequences in terms of lipid composition and inflammatory response, and to work out the relative contribution of LPCAT3 to the observed changes. Approach and Results-Transcriptomic analysis revealed that LPCAT3 was upregulated by LXR agonists in human macrophages. Accordingly, LXR stimulation significantly increased lysophospholipid acyltransferase activity catalyzed by LPCAT3. Lipidomic analysis demonstrated that LXR activation increased the AA content in the polar lipid fraction, specifically in phosphatidylcholines. The LXR-mediated effects on AA distribution were abolished by LPCAT3 silencing, and a redistribution of AA toward the neutral lipid fraction was observed in this context. Finally, we observed that preconditioning of human macrophages by LXR agonist treatment increased...

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Section: Discussionmentioning

confidence: 97%

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Ishibashi

Varin

Filomenko

et al. 2013

ATVB

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“…Lipoprotein/Apolipoprotein Analysis and Lipid AbsorptionLipoproteins and apolipoproteins (apoA-I, apoB, and apoE) in mice (both sexes) were measured as described (7). Cholesterol absorption studies were performed with male mice using the conventional fecal dual-isotope ratio method (14).…”

Section: Methodsmentioning

confidence: 99%

“…Measuring Total Lpcat Activity and PC Subspecies-Total Lpcat activity was measured as described (7). PC subspecies were measured with liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) as described (7).…”

Section: Methodsmentioning

confidence: 99%

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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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“…The unfolded protein response was also enhanced in those cells. In vivo, shRNA-mediated reduction in mouse hepatic LPCAT3 expression increased very LDL secretion ( 19 ).…”

Section: In Vitro Microsomal Lpcat Assaysmentioning

confidence: 99%

Saccharomyces cerevisiae lysophospholipid acyltransferase, Lpt1, requires Asp146 and Glu297 for catalysis

Renauer

Nasiri

Oelkers

2015

Journal of Lipid Research

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The esterifi cation of lysophospholipids contributes to phospholipid synthesis, remodeling, and scavenging. Acyl-CoA-dependent lysophospholipid acyltransferase activity with broad substrate use is mediated by Saccharomyces cerevisiae Lpt1p. We sought to identify Lpt1p active site amino acids besides the histidine conserved among homologs and repeatedly found to be required for catalysis. In vitro Lpt1p assays with amino acid modifying agents implicated aspartate, glutamate, and lysine as active site residues. Threonine and tyrosine were not ruled out. Aligning the primary structures of functionally characterized LPT1 homologs from fungi, plants, and animals identifi ed 11 conserved aspartate, glutamate, lysine, threonine, and tyrosine residues. Site-directed mutagenesis of the respective codons showed that changing D146 and E297 abolished activity without abolishing protein expression. The mechanism of Lpt1p was further analyzed using monounsaturated acyl-CoA species with different double bond positions. Delta 6 species showed the highest catalytic effi ciency. We propose that D146 and E297 act in conjunction with H382 as nucleophiles that attack the hydroxyl group in lysophospholipids in a general acid/base mechanism. This sequential mechanism provides a precedent for other members of the membrane bound O-acyltransferase family. Also, Lpt1p optimally orients acyl-CoA substrates with 7.5 Å between a double bond and the thioester bond. -Renauer, P., N. Nasiri, and P. Oelkers.

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Lysophosphatidylcholine Acyltransferase 3 Knockdown-mediated Liver Lysophosphatidylcholine Accumulation Promotes Very Low Density Lipoprotein Production by Enhancing Microsomal Triglyceride Transfer Protein Expression

Cited by 46 publications

References 53 publications

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

Liver X Receptor Regulates Arachidonic Acid Distribution and Eicosanoid Release in Human Macrophages

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

Saccharomyces cerevisiae lysophospholipid acyltransferase, Lpt1, requires Asp146 and Glu297 for catalysis

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