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BBA - Molecular and Cell Biology of Lipids (v.1761, #12)

Editorial Board (pp. ii).

Effects of FXR in foam-cell formation and atherosclerosis development by Grace L. Guo; Silvia Santamarina-Fojo; Taro E. Akiyama; Marcelo J.A. Amar; Beverly J. Paigen; Bryan Brewer Jr.; Frank J. Gonzalez (pp. 1401-1409).
Farnesoid X receptor (FXR), a bile-acid-activated member of the nuclear receptor superfamily, is essential in regulating bile-acid, cholesterol, and triglyceride homeostasis. Disruption of the FXR gene in mice results in a proatherosclerotic lipid profile with increased serum cholesterols and triglycerides. However, the role of FXR in foam-cell formation and atherosclerosis development remains unclear. The current study showed that the peritoneal macrophages isolated from FXR-null mice took up less oxidized LDL-cholesterol (oxLDL-C), which was accompanied by a marked reduction in CD36 expression in these cells. This result appears to be FXR-independent, as FXR was not detected in the peritoneal macrophages. To assess to what extent FXR modulates atherosclerosis development, FXR/ApoE double-null mice were generated. Female mice were used for atherosclerosis analysis. Compared to ApoE-null mice, the FXR/ApoE double-null mice were found to have less atherosclerotic lesion area in the aorta, despite a further increase in the serum cholesterols and triglycerides. Our results indicate that disruption of the FXR gene could attenuate atherosclerosis development, most likely resulting from reduced oxLDL-C uptake by macrophages. Our study cautions the use of serum lipid levels as a surrogate marker to determine the efficiency of FXR modulators in treating hyperlipidemia.

Keywords: Abbreviations; ACAT; acyl coenzyme A: acylcholesterol transferase; FXR; farnesoid X receptor; FAS; fatty-acid synthase; LOX-1; oxidized LDL receptor-1; LPL; lipoprotein lipase; LPS; lipopolysaccharide; LXR; liver X receptor; oxLDL-C; oxidized LDL cholesterol; PLTP; phospholipid transfer protein; PPARγ; peroxisome proliferator-activated receptor γ; SR; scavenger receptors; SREBP1c; sterol-response-element-binding protein 1c; VCAM-1; vascular cell adhesion molecule-1FXR; Nuclear receptor; Atherosclerosis; Cholesterol; Cytokine


Purification and characterization of lysophospholipase D from rat brain by Sayaka Sugimoto; Hiroyuki Sugimoto; Chieko Aoyama; Chizu Aso; Masatomo Mori; Takashi Izumi (pp. 1410-1418).
A lysophospholipase D (lysoPLD) was purified to apparent homogeneity from rat brain nuclear fractions using 1-[14C]palmitoyl-glycerophosphorylcholine as a substrate. The abundance of autotaxin (ATX), a secretory lysoPLD, was also estimated for each fraction. The nuclear fraction had relatively high levels of lysoPLD activity but weak immunoreactivity with an anti-ATX antibody. LysoPLD activity was further purified 5550-fold by sequential chromatography. The final preparation migrated as a single band with a molecular weight of 35,000. Anti-ATX antibodies did not cross-react with the purified enzyme. Moreover, enzyme activity was highest at pH 7.0–7.5 and requires Mg2+. The Km and Vmax values for 1-palmitoyl-glycerophosphorylcholine were 176 μM and 0.3 μmol/min/mg, respectively. The purified enzyme hydrolyzed saturated forms of LPC more robustly than unsaturated forms. The enzyme could hydrolyze platelet-activating factor (PAF) to the same extent as 16:0-LPC, and showed a higher activity toward lysoPAF (1- O-hexadecyl-2-lyso-glycerophosphorylcholine). These results suggested that the lysoPLD purified from rat brain nuclear fractions in this work is a novel enzyme that hydrolyzes lysoPAF, PAF, and LPC to liberate choline.

Keywords: Abbreviations; ATX; autotaxin; CHAPS; 3-[(3-Cholamidopropyl)dimethylammonio]propanesulfonic acid; DTT; Dithiothreitol; EDTA; ethylenediaminetetraacetic acid; EDG; endothelial differentiation genes; GPC; glycerophosphorylcholine; GP; glycerophosphate; LPA; lysophosphatidic acid; LPC; lysophosphatidylcholine; lysoPLC; lysophospholipase C; lysoPLD; lysophospholipase D; lysoPAF; 1-; O; -hexadecyl-2-lyso-GPC (lyso-platelet activating factor); PA; phosphatidic acid; PC; phosphatidylcholine; PLA; phospholipase A; PLD; phospholipase D; PAF; 1-; O; -hexadecyl-2-acetyl-GPC (platelet activating factor); PMSF; phenylmethylsulfonyl fluoride; SPC; sphingosylphosphorylcholine; SDS-PAGE; SDS-polyacrylamide gel electrophoresisLysophospholipase D; Lysophosphatidylcholine; Lysophosphatidic acid; Autotaxin; Rat brain; Lyso-platelet activating factor


Hydroperoxide lyases (CYP74C and CYP74B) catalyze the homolytic isomerization of fatty acid hydroperoxides into hemiacetals by Alexander N. Grechkin; Fredi Brühlmann; Lucia S. Mukhtarova; Yuri V. Gogolev; Mats Hamberg (pp. 1419-1428).
The conversion of linoleic acid 9-hydroperoxide (9-HPOD) by recombinant melon ( Cucumis melo L.) hydroperoxide lyase (HPL, CYP74C subfamily) was studied. Short (5 s–1 min) incubations at 0 °C followed by rapid extraction and trimethylsilylation made it possible to trap a new unstable ( t1/2 <30 s) product, i.e. the hemiacetal (1′ E,3′ Z)-9-hydroxy-9-(1′,3′-nonadienyloxy)-nonanoic acid. Identification was performed by GC-MS analysis and substantiated by the formation of trimethylsilyl 9-trimethylsilyloxy-9-nonyloxy-nonanoate upon catalytic hydrogenation and by2H-labelling experiments. Both18O atoms of [18O2-hydroperoxy]9-HPOD were incorporated into the hemiacetal. Along with the hemiacetal, three chain-cleavage products, i.e. the enol (1 E,3 Z)-nonadienol and the hydrates of 3( Z)-nonenal and 9-oxononanoic acid, were trapped as their trimethylsilyl derivatives. The kinetics of18O incorporation from [18O2]9-HPOD provided strong evidence that the cleavage products originated in the hemiacetal. Linolenic and linoleic acid 13-hydroperoxides served as substrates for recombinant HPLs of melon, alfalfa ( Medicago sativa) and guava ( Psidium guajava), and in each case hemiacetals and enols were detectable by the trapping technique. The data obtained demonstrated that CYP74C and CYP74B HPLs act as isomerases performing a homolytic rearrangement of fatty acid hydroperoxides into short-lived hemiacetals which upon decomposition produce 3( Z)-nonenal, 3( Z)-hexenal and other short chain aldehydes.

Keywords: Abbreviations; HPL; hydroperoxide lyase; CmHPL; melon (; Cucumis melo; ) hydroperoxide lyase; AOS; allene oxide synthase; DES; divinyl ether synthase; 9-HPOD; (9; S; ,10; E; ,12; Z; )-9-hydroperoxy-10,12-octadecadienoic acid; 13-HPOD; (9; Z; ,11; E; ,13; S; )-13-hydroperoxy-9,11-octadecadienoic acid; 13-HPOT; (9; Z; ,11; E; ,13; S; ,15; Z; )-13-hydroperoxy-9,11,15-octadecatrienoic acid; TMS; trimethylsilyl; HPLC; high performance liquid chromatography; GC-MS; gas chromatography-mass spectrometry; RT; retention timeHydroperoxide lyase; Linoleic acid 9-hydroperoxide; Hemiacetal; Oxylipin; Melon (; Cucumis melo; L.)


The differential regulation of phosphatidylinositol 4-phosphate 5-kinases and phospholipase D1 by ADP-ribosylation factors 1 and 6 by Borja Perez-Mansilla; Vi Luan Ha; Neil Justin; Andrew J. Wilkins; Christopher L. Carpenter; Geraint M.H. Thomas (pp. 1429-1442).
Phosphatidylinositol 4-phosphate 5-kinases [PtdIns4 P5Ks] synthesise the majority of cellular phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5) P2] and phospholipase D1 (PLD1) synthesises large amounts of phosphatidic acid (PtdOH). The activities of PtdIns4 P5Ks and PLDs are thought to be coupled during cell signalling in order to support large simultaneous increases in both PtdIns(4,5) P2 and PtdOH, since PtdOH activates PtdIns4 P5Ks and PLD1 requires PtdIns(4,5) P2 as a cofactor. However, little is known about the control of such a system. Membrane recruitment of ADP-ribosylation factors (Arfs) activates both PtdIns4 P5Ks and PLDs, but it is not known if each enzyme is controlled in series by different Arfs or in parallel by a single form. We show through pull-down and vesicle sedimentation interaction assays that PtdIns4 P5K activation may be facilitated by Arf-enhanced membrane association. However PtdIns4 P5Ks discriminate poorly between near homogeneously myristoylated Arf1 and Arf6 although examples of all three known active isoforms (mouse α>β, γ) respond to these G-proteins. Conversely PLD1 genuinely prefers Arf1 and so the two lipid metabolising enzymes are differentially controlled. We propose that isoform selective Arf/PLD interaction and not Arf/PtdIns4 P5K will be the critical trigger in the formation of distinct, optimal triples of Arf/PLDs/PtdIns4 P5Ks and be the principle regulator of any coupled increases in the signalling lipids PtdIns(4,5) P2 and PtdOH.

Keywords: Arf; ADP-ribosylation factor; Kinase; Phospholipase; Phosphatidylinositol; Membrane; GTPase; PtdIns4; P; PLDAbbreviations; PtdInsP; phosphatidylinositol phosphate; DAG; 1,2 diacylglycerol; Ins(1,4,5)P3; inositol 1,4,5-trisphosphate; PtdIns(3,4,5)P3; phosphatidylinositol 3,4,5-trisphosphate; GEF; guanine nucleotide exchange factor; GST; reduced glutathione; GST; glutathione-S-transferase; HA; haemagluttinin; HEPES; 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; PIPES; Piperrazine-; N; ,; N; ′-bis(2-ethanesulfonic acid); EDTA; ethyenediamine tetraacetic acid; GTPγS; guanosine 5′-O-(thio)triphosphate; DTT; dithiothreitol; Arf; ADP-ribosylation factor; PBS; phosphate buffered saline; PMSF; phenlymethysulphonylfluoride


Endothelial cell COX-2 expression and activity in hypoxia by Rebecca J. Cook-Johnson; Maryanne Demasi; Leslie G. Cleland; Jennifer R. Gamble; David A. Saint; Michael J. James (pp. 1443-1449).
The clinical experience with selective cyclooxygenase (COX)-2 inhibitors reveals there are important protective roles for COX-2 in the cardiovascular system. This study examined the response to hypoxia of endothelial cell eicosanoid synthesis with respect to the role of COX-2 and its molecular regulation in hypoxia. Human umbilical vein endothelial cells (HUVEC) were exposed to hypoxia and the effects on COX-2, prostacyclin (PGI2) and thromboxane (TXA2) synthesis were examined. COX-2 promoter constructs were used to examine the role of Hypoxia Inducible Factors (HIFs) in COX-2 responses to hypoxia. Hypoxia caused an increase in PGI2 synthesis, but not TXA2 synthesis. PGI2, but not TXA2 synthesis, was absolutely dependent on upregulation of COX-2 by hypoxia. Mutations of transcription factor binding sites in the promoter showed a lack of involvement of NFκB in the response to hypoxia, but suggested involvement of HIFs. Transfection of HUVEC with HIF expression vectors increased activity of the promoter construct and increased native COX-2 expression in normoxia. EMSA showed HIF binding in nuclear extracts of hypoxic HUVEC to a region of the COX-2 promoter. The endothelial cell response to hypoxia involves increased production of the anti-thrombotic eicosanoid, PGI2, which is dependent on COX-2 upregulation by a HIF-mediated process.

Keywords: Prostacyclin; Thromboxane; Prostaglandin; COX-2; Endothelial


Expression and characterization of Arabidopsis phospholipase Dγ2 by Chunbo Qin; Maoyin Li; Wensheng Qin; Sung Chul Bahn; Cunxi Wang; Xuemin Wang (pp. 1450-1458).
The phospholipase D (PLD) family of Arabidopsis thaliana has 12 identified members, including three highly homologous PLDγs. The enzymatic and molecular properties of PLDγ2 were characterized and compared with those of PLDγ1. Two variants of PLDγ2 cDNAs, designated PLDγ2a and PLDγ2b , were isolated, and they differ in the presence of a 96-nucleotide fragment at the beginning of the open reading frame. Catalytically active PLDγ2a was expressed in E. coli. PLDγ2a and γ1 both require phosphatidylinositol 4,5-bisphosphate (PIP2) and calcium for activity, but they differ in the effect of PIP2 and Triton X-100 on their activities. While Triton X-100 could greatly activate PLDγ1 activity and served only as a neutral diluent in the substrate vesicles, it totally abolished PLDγ2a activity and prohibited any stimulation effect from PIP2. PLDγ2a misses one of the basic, PIP2-interacting residues, which may weaken the binding of PIP2 to PLDγ2a. In addition, PLDγ2 and PLDγ1 displayed different patterns of expression in different tissues, and the transcript of PLDγ2a differs from that of PLDγ1 by having a longer 5′-UTR. These differences in biochemical and molecular properties suggest that the highly homologous PLDγs are subjected to unique regulations and might have distinguishable functions.

Keywords: Abbreviations; PLD; phospholipase D; EST; expressed sequence tag; PC; phosphatidylcholine; PIP; 2; phosphatidylinositol 4,5-bisphosphate; GST; glutathione S-transferase; SDS-PAGE; SDS-polyacrylamide gel electrophoresis; CMC; critical micelle concentration; UTR; untranslated regionArabidopsis; Phospholipase D; Phospholipid hydrolysis; Gene expression; Substrate composition; Membrane environment


Expression of mouse membrane-associated prostaglandin E2 synthase-2 (mPGES-2) along the urogenital tract by Guangrui Yang; Lihong Chen; Yahua Zhang; Xiaoyan Zhang; Jing Wu; Shuo Li; Mingfen Wei; Zhiwen Zhang; Matthew D. Breyer; Youfei Guan (pp. 1459-1468).
Prostaglandin E2 (PGE2) is the most common prostanoid and has a variety of bioactivities including a crucial role in urogenital function. Multiple enzymes are involved in its biosynthesis. Among 3 PGE2 terminal synthetic enzymes, membrane-associated PGE2 synthase-2 (mPGES-2) is the most recently identified, and its role remains uncharacterized. In previous studies, membrane-associated PGE2 synthase-1 (mPGES-1) and cytosolic PGE2 synthase (cPGES) were reported to be expressed along the urogenital tracts. Here we report the genomic structure and tissue distribution of mPGES-2 in the urogenital system. Analysis of several bioinformatic databases demonstrated that mouse mPGES-2 spans 7 kb and consists of 7 exons. The mPGES-2 promoter contains multiple Sp1 sites and a GC box without a TATA box motif. Real-time quantitative PCR revealed that constitutive mPGES-2 mRNA was most abundant in the heart, brain, kidney and small intestine. In the urogenital system, mPGES-2 was highly expressed in the renal cortex, followed by the renal medulla and ovary, with lower levels in the ureter, bladder and uterus. Immunohistochemistry studies indicated that mPGES-2 was ubiquitously expressed along the nephron, with much lower levels in the glomeruli. In the ureter and bladder, mPGES-2 was mainly localized to the urothelium. In the reproductive system, mPGES-2 was restricted to the epithelial cells of the testis, epididymis, vas deferens and seminal vesicle in males, and oocytes, stroma cells and corpus luteum of the ovary and epithelial cells of the oviduct and uterus in females. This expression pattern is consistent with an important role for mPGES-2-mediated PGE2 in urogenital function.

Keywords: Prostaglandin E; 2; Membrane-associated PGE; 2; synthase-2; PGES; Gene expression; Urogenital system


Genomic structure, alternative maturation and tissue expression of the human BBOX1 gene by Caroline Rigault; Françoise Le Borgne; Jean Demarquoy (pp. 1469-1481).
Gamma-butyrobetaine hydroxylase (BBOX1) is the enzyme responsible for the biosynthesis ofl-carnitine, a key molecule of fatty acid metabolism. This cytosolic dimeric protein belongs to the dioxygenase family. In human, enzyme activity has been detected in kidney, liver and brain. The human gene encoding gamma-butyrobetaine hydroxylase is located on chromosome 11. Although the protein structure and activity have been extensively described, little information is available concerning BBOX1 structure and expression. In this study, the organization of the human gene was determined. The structure and functions of the 5′- and 3′-untranslated regions of the human BBOX1 mRNA were characterized in kidney, liver and brain. Our experiments revealed that the transcription initiation of the human BBOX1 gene might occur at 3 different exons, and that the expression level of each type of transcript is organ-specific. We showed that the use of 3 different promoters is responsible for the 5′-end heterogeneity. Investigations on BBOX1 mRNA maturation highlighted an alternative polyadenylation mechanism that generates two 3′-untranslated regions differing by their length. This alternative polyadenylation exhibited a tissue specificity.

Keywords: Fatty acid oxidation; l; -carnitine; Gene expression; RNA maturation; Tissue-specificity


Cholesteryl ester transfer protein (CETP) expression enhances HDL cholesteryl ester liver delivery, which is independent of scavenger receptor BI, LDL receptor related protein and possibly LDL receptor by Hongwen Zhou; Zhiqiang Li; David L. Silver; Xian-Cheng Jiang (pp. 1482-1488).
Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that mediates the transfer and exchange of cholesteryl ester (CE) and triglyceride (TG) between plasma lipoproteins, and also plays an important role in HDL metabolism. Previous studies have indicated that, compared to wild type mice, human CETP transgenic mice had significantly lower plasma HDL CE levels, which was associated with enhancement of HDL CE uptake by the liver. However, the mechanism of this process is still unknown. To evaluate the possibility that this might be directly mediated by CETP, we utilized CETP transgenic (CETPTg) mice with liver scavenger receptor BI (SR-BI) deficiency [i.e., PDZK1 gene knockout (PDZK1O)], and with receptor associated protein (RAP) overexpression, to block LDL receptor-related protein (LRP) and LDL receptor (LDLR). We found that (1) CETPTg/PDZK1O mice have significantly lower HDL-C than that of PDZK1 KO mice (36%, p<0.01); (2) CETPTg and CETPTg/PDZK1O mice have same HDL-C levels; (3) CETPTg/PDZK1O/RAP mice had significant lower plasma HDL-C levels than that of PDZK1O/RAP ones (50%, p<0.001); (4) there is no incremental transfer of HDL CE radioactivity to the apoB-containing lipoprotein fraction in mice expressing CETP; and (5) CETPTg/PDZK1O/RAP mice had significant higher plasma and liver [3H]CEt-HDL turnover rates than that of PDZK1O/RAP ones (50% and 53%, p<0.01, respectively). These results suggest that CETP expression in mouse increases direct removal of HDL CE in the liver and this process is independent of SR-BI, LRP, and possibly LDLR.

Keywords: Abbreviations; CETP; cholesteryl ester transfer protein; Tg; transgene; WT; wild type; NFR; natural flanking region; SR-BI; scavenger receptor BI; RAP; receptor associate protein; LRP; LDL receptor related protein; LDLR; LDL receptor; HDL; high density lipoprotein; FCR; fractional catabolism rate; FPLC; fast protein liquid chromatography; TG; triglycerideCholesteryl ester transfer protein (CETP); Scavenger receptor BI (SR-BI); LDL receptor; LDL related protein (LRP); PDZK1 gene knockout mice; Cholesterol; High density lipoprotein (HDL)


Group V secretory phospholipase A2 amplifies the induction of cyclooxygenase 2 and delayed prostaglandin D2 generation in mouse bone marrow culture-derived mast cells in a strain-dependent manner by Bruno L. Diaz; Yoshiyuki Satake; Eriya Kikawada; Barbara Balestrieri; Jonathan P. Arm (pp. 1489-1497).
Activation of mouse bone marrow-derived mast cells (BMMC) with stem cell factor (SCF) or IgE and antigen elicits exocytosis and an immediate phase of prostaglandin (PG) D2 and leukotriene (LT) C4 generation. Activation of BMMC by SCF, IL-1β and IL-10 elicits a delayed phase of PGD2 generation dependent on cyclooxygenase (COX) 2 induction. Cytosolic phospholipase A2 α provides arachidonic acid in both phases and amplifies COX-2 induction. Pharmacological experiments implicate an amplifying role for secretory (s) PLA2. We used mice lacking the gene encoding group V sPLA2 ( Pla2g5−/−) to definitively test its role in eicosanoid generation by BMMC. Pla2g5−/− BMMC on a C57BL/6 genetic background showed a modest reduction in exocytosis and immediate PGD2 generation after activation with SCF or with IgE and antigen, while LTC4 generation was not modified. Delayed-phase PGD2 generation and COX-2 induction were reduced ∼35% in C57BL/6 Pla2g5−/− BMMC and were restored by exogenous PGE2. There was no deficit in either phase of eicosanoid generation by Pla2g5−/− BMMC on a BALB/c background. Thus, group V sPLA2 amplifies COX-2 expression and delayed phase PGD2 generation in a strain-dependent manner; it has at best a limited role in immediate eicosanoid generation by BMMC.

Keywords: Abbreviations; BMMC; bone marrow-derived mast cells; cPLA; 2; cytosolic phospholipase A; 2; COX; cyclooxygenase; HBA; Hanks' balanced salt solution without Mg; 2+; or CA; 2+; containing 0.1% BSA; LT; leukotriene; PG; prostaglandin; SCF; stem cell factor; sPLA; 2; secretory phospholipase A; 2Phospholipase A; 2; Secretory phospholipase A; 2; Mast cell; Leukotriene C; 4; Prostaglandin D; 2; Cyclooxygenase


Interaction of human 15-lipoxygenase-1 with phosphatidylinositol bisphosphates results in increased enzyme activity by Erik Andersson; Frida Schain; Märta Svedling; Hans-Erik Claesson; Pontus K.A. Forsell (pp. 1498-1505).
15-lipoxygenase-1 (15-LO-1) can oxygenate both free fatty acids and fatty acids bound to membrane phospholipids. The regulation of the activity of membrane associated 15-LO-1 is poorly understood. Here we demonstrate that calcium ionophore stimulates the translocation of 15-LO-1 to the plasma membrane in human dendritic cells. In a protein–lipid overlay assay, 15-LO-1 was capable of interacting with several phosphoinositides. In the presence of calcium, addition of phosphatidylinositol-4.5-bisphosphate (PI(4.5)P2) or PI(3.4)P2 to the vesicles containing arachidonic acid, led to the formation of approximately three times more 15-HETE than vesicles without phosphoinositides and up to seven times more 15-HETE than vesicles without both calcium and phosphoinositides. The Vmax was unchanged but the apparent Km of 15-LO-1 towards arachidonic acid was significantly lower in the presence of PI(4.5)P2 or PI(3.4)P2 in the vesicles in comparison to vesicles with PC only. Taken together, this report demonstrates that human 15-LO-1 binds to PI(4.5)P2 and PI(3.4)P2 and that these phospholipids stimulate enzyme activity in the presence of calcium in a vesicle based assay.

Keywords: Abbreviations; 15-LO-1; (human 15-lipoxygenase type 1); PI(4.5)P; 2; (phosphatidylinositol-4.5-bisphosphate); PI(3.4)P; 2; (phosphatidylinositol-3.4-bisphosphate); DC; (dendritic cell); 15-HETE; (15-hydroxyeicosa-5Z,8Z,11Z,13E-tetraenoic acid); 12-HETE; (12-hydroxyeicosa-5Z,8Z,10E,14Z-tetraenoic acid); (13-HODE); 13-hydroxyoctadeca-9Z,11E-dienoic acid15-lipoxygenase-1; Phospholipid; Arachidonic acid; Linoleic acid; Vesicle


Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: Inhibition of LPA GPCR and activation of PPARs by Karoly Liliom; Tamotsu Tsukahara; Ryoko Tsukahara; Monika Zelman-Femiak; Ewa Swiezewska; Gabor Tigyi (pp. 1506-1514).
Oligoprenyl phosphates are key metabolic intermediates for the biosynthesis of steroids, the side chain of ubiquinones, and dolichols and the posttranslational isoprenylation of proteins. Farnesyl phosphates are isoprenoid phosphates that resemble polyunsaturated fatty alcohol phosphates, which we have recently shown to be the minimal pharmacophores of lysophosphatidic acid (LPA) receptors. Here we examine whether farnesyl phosphates can interact with the cell surface and nuclear receptors for LPA. Both farnesyl phosphate and farnesyl diphosphate potently and specifically antagonized LPA-elicited intracellular Ca2+-mobilization mediated through the LPA3 receptor, while causing only modest inhibition at the LPA2 receptor and no measurable effect at the LPA1 receptor. Farnesol also inhibited LPA3 but was much less effective. The estimated dissociation constant of LPA3 for farnesyl phosphate is 48±12 nM and 155±30 nM for farnesyl diphosphate. The transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) binds to and is activated by LPA and its analogs including fatty alcohol phosphates. We found that both farnesyl phosphate and diphosphate, but not farnesol, compete with the binding of the synthetic PPARγ agonist [3H]rosiglitazone and activate the PPARγ-mediated gene transcription. Farnesyl monophosphate at 1 μM, but not diphosphate, activated PPARα and PPARβ/δ reporter gene expression. These results indicate new potential roles for the oligoprenyl phosphates as potential endogenous modulators of LPA targets and show that the polyisoprenoid chain is recognized by some LPA receptors.

Keywords: Abbreviations; ACox; acetylCoA oxidase; ACox-Rluc; acyl-coenzyme A oxidase-luciferase; AGP; alkyl-glycerophosphate; ATP; definition; [Ca; 2+; ]; i; intracellular Ca; 2+; concentration; FAP; fatty alcohol phosphate; FDP; farnesyl diphosphate; FMP; farnesyl phosphate; FR; farnesol; GPCR; G protein-coupled receptor; LDL; low-density lipoproteins; LPA; lysophosphatidic acid; PPAR; peroxisome proliferator-activated receptor; PPRE; PPAR response element; Rosi; rosiglitazone; SREBP; sterol regulatory element binding proteinFarnesyl phosphate; Isoprenoid; LPA; Lysophospholipid; GPCR; PPARγ


22-Hydroxycholesterols regulate lipid metabolism differently than T0901317 in human myotubes by Eili Tranheim Kase; Bård Andersen; Hilde I. Nebb; Arild C. Rustan; G. Hege Thoresen (pp. 1515-1522).
The nuclear liver X receptors (LXRα and β) are regulators of lipid and cholesterol metabolism. Oxysterols are known LXR ligands, but the functional role of hydroxycholesterols is at present unknown. In human myotubes, chronic exposure to the LXR ligand T0901317 promoted formation of diacylglycerol (DAG) and triacylglycerol (TAG), 22- R-hydroxycholesterol (22- R-HC) had no effect, and 22- S-hydroxycholesterol (22- S-HC) reduced the formation. In accordance with this, 22-HC and T0901317 regulated the expression of fatty acid transporter CD36, stearoyl-CoA desaturase-1, acyl-CoA synthetase long chain family member 1 and fatty acid synthase (FAS) differently; all genes were increased by T0901317, 22- R-HC did not change their expression level, while 22- S-HC reduced it. Transfection studies confirmed that the FAS promoter was activated by T0901317 and repressed by 22- S-HC through an LXR response element in the promoter. Both 22- R-HC and T0901317 increased gene expression of LXRα, sterol regulatory element-binding protein 1c and ATP-binding cassette transporter A1, while 22- S-HC had little effect. In summary, 22- R-HC regulated lipid metabolism and mRNA expression of some LXR target genes in human myotubes differently than T0901317. Moreover, 22- S-HC did not behave like an inactive ligand; it reduced synthesis of complex lipids and repressed certain genes involved in lipogenesis and lipid handling.

Keywords: Abbreviations; 22-; R; -HC; 22-; R; -hydroxycholesterol; 22-; S; -HC; 22-; S; -hydroxycholesterol; ACSL1; acyl-CoA synthetase long chain family member 1; ABCA1; ATP-binding cassette transporter A1; CD36; fatty acid transporter; DAG; diacylglycerol; FAS; fatty acid synthase; FFA; free fatty acids; GLUT4; glucose transporter 4; LXR; liver X receptor; LXRE; LXR responsive element; PPAR; peroxisome proliferator-activated receptor; SCD-1; stearoyl-CoA desaturase-1; SREBP1c; sterol regulatory element-binding protein 1c; TAG; triacylglycerolLXR; human myotubes; lipid metabolism; 22-hydroxycholesterol
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