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BBA - Molecular and Cell Biology of Lipids (v.1811, #7-8)

Editorial Board (pp. i).

Bis (monoacylglycero) phosphate interfacial properties and lipolysis by pancreatic lipase-related protein 2, an enzyme present in THP-1 human monocytes by Michel Record; Sawsan Amara; Caroline Subra; Guowei Jiang; Glenn D. Prestwich; Francine Ferrato; Carriere Frédéric Carrière (pp. 419-430).

The interfacial physical properties of bis(monoacylglycero)phosphate (BMP) and its derivatives with three oleoyl chains (hemi-BDP) and four oleoyl chains (bis(diacylglycero)phosphate, BDP) were investigated using Langmuir monomolecular films. The mean molecular area of BMP at the collapse surface pressure (45mN m−¹) was similar to those measured with other phospholipids bearing two acyl chains (66 and 59.6Å² molecule−¹ at pH 5.5 and 8.0, respectively). In Hemi-BDP and BDP, the mean molecular area increased by 26 and 35Å² molecule−¹ per additional acyl chain at pH 5.5 and 8.0, respectively. When BMP was added to a phospholipid mixture mimicking late endosome membrane composition at pH 8.0, the mean phospholipid molecular area increased by 7% regardless of the surface pressure. In contrast, the variation in molecular area was surface pressure-dependent at pH 5.5, a pH value close to that of intra-endosomal content. BMP and hemi-BDP, but not BDP, were hydrolyzed by pancreatic lipase-related protein 2 (PLRP2), which exhibits phospholipase A₁ activity. At pH 5.5, the maximum activities of PLRP2 on BMP were recorded at high surface pressures (25–35mN/m). At pH 8.0, the PLRP2 activity vs. surface pressure showed a bell-shaped curve with maximum activities at 15mN/m for both BMP and hemi-BDP. This is a new activity for this enzyme which could degrade cellular BMP since both human PLRP2 (HPLRP2) and BMP were localized in human monocytic THP-1 cells. This is the first report on the cellular localization of HPLRP2 in human monocytes.► Interfacial properties of bis (monoacylglycero) phosphate (BMP) and mixed monolayers. ► pH-dependent role of BMP in vesicle formation. ► Phospholipase A1 activity of pancreatic lipase related-protein 2 (PLRP2) on BMP. ► Cellular location of human PLRP2 and BMP in THP-1 monocytes.

Keywords: Lipase; Monomolecular film; Phospholipase A1; Phospholipid; PLRP2

Increased Δ5- and Δ6-desaturase, cyclooxygenase-2, and lipoxygenase-5 expression and activity are associated with fatty acid and eicosanoid changes in cystic fibrosis by Sarah W. Njoroge; Adam C. Seegmiller; Waddah Katrangi; Michael Laposata (pp. 431-440).

Patients with cystic fibrosis consistently demonstrate selective abnormalities in essential fatty acid concentrations, including decreased linoleate (LA) and docosahexaenoate (DHA), with variably increased arachidonate (AA). These changes appear important for the pathophysiology of the disease. However, the mechanisms of these changes are not clearly understood. The current study demonstrates that metabolism of LA and alpha linolenate (LNA) to AA and eicosapentaenoate (EPA), respectively, are significantly increased in two different cell culture models of cystic fibrosis. These changes correlated with increased expression of fatty acid Δ5- and Δ6-desaturases, key enzymes in this metabolic pathway. In contrast, cystic fibrosis cells showed decreased metabolism of AA and EPA to docosapentaenoate (DPA) and docosahexaenoate (DHA), respectively, although metabolism of 22:5n-3 to DHA was relatively unchanged. In addition, the expression and activity of both cyclooxygenase-2 and lipoxygenase-5 was markedly increased in these cells. Taken together, these findings are consistent with the conclusion that the diminished LA and increased AA in cystic fibrosis result from increased metabolism of LA, while the observed decrease in DHA is at least partly due to decreased elongation and desaturation beyond EPA.► CFTR-mutated cells show fatty acid changes similar to cystic fibrosis patients. ► These abnormalities are associated with increased 18:2n-6 and 18:3n-3 metabolism. ► However, the cells exhibit decreased production of 22:5n-6 and 22:6n-3. ► These changes correlate with increased expression of fatty acid metabolic enzymes.

Keywords: Cystic fibrosis; Fatty acid; Eicosanoid; Desaturase; Cyclooxygenase; Lipoxygenase

Differential effects of short- and long-term high-fat diet feeding on hepatic fatty acid metabolism in rats by Jolita Ciapaite; Nicole M. van den Broek; Heleen te Brinke; Klaas Nicolay; Jeroen A. Jeneson; Sander M. Houten; Jeanine J. Prompers (pp. 441-451).

Imbalance in the supply and utilization of fatty acids (FA) is thought to contribute to intrahepatic lipid (IHL) accumulation in obesity. The aim of this study was to determine the time course of changes in the liver capacity to oxidize and store FA in response to high-fat diet (HFD). Adult male Wistar rats were fed either normal chow or HFD for 2.5weeks (short-term) and 25weeks (long-term). Short-term HFD feeding led to a 10% higher palmitoyl-l-carnitine-driven ADP-stimulated (state 3) oxygen consumption rate in isolated liver mitochondria indicating up-regulation of β-oxidation. This adaptation was insufficient to cope with the dietary FA overload, as indicated by accumulation of long-chain acylcarnitines, depletion of free carnitine and increase in FA content in the liver, reflecting IHL accumulation. The latter was confirmed by in vivo^¹H magnetic resonance spectroscopy and Oil Red O staining. Long-term HFD feeding caused further up-regulation of mitochondrial β-oxidation (24% higher oxygen consumption rate in state 3 with palmitoyl-l-carnitine as substrate) and stimulation of mitochondrial biogenesis as indicated by 62% higher mitochondrial DNA copy number compared to controls. These adaptations were paralleled by a partial restoration of free carnitine levels and a decrease in long-chain acylcarnitine content. Nevertheless, there was a further increase in IHL content, accompanied by accumulation of lipid peroxidation and protein oxidation products. In conclusion, partially effective adaption of hepatic FA metabolism to long-term HFD feeding came at a price of increased oxidative stress, caused by a combination of higher FA oxidation capacity and oversupply of FA.► We study the time-course of changes in hepatic fatty acid metabolism in obesity. ► β-oxidation is up-regulated insufficiently causing accumulation of triacylglycerols. ► Obesity-induced adaptation of fatty acid metabolism results in oxidative stress.

Keywords: Abbreviations; ANOVA; analysis of variance; Ct; threshold cycle number; HFD; high-fat diet; IHL; intrahepatic lipids, MRS, magnetic resonance spectroscopy; mtDNA; mitochondrial DNA; MUFA; mono-unsaturated fatty acids; NAFLD; non-alcoholic fatty liver disease; NC; normal chow; PGC-1α; peroxisome proliferator-activated receptor-γ coactivator-1α; PPAR-α; peroxisome proliferator-activated receptor α; PUFA; poly-unsaturated fatty acids; ORO; Oil Red O; OXPHOS; oxidative phosphorylation; RCR; respiratory control ratio; ROS; reactive oxygen species; SCD1; stearoyl-CoA desaturase 1; SFA; saturated fatty acids; SREBP-1; sterol regulatory element binding protein-1; TBA; thiobarbituric acid; TBARS; thiobarbituric acid reactive substances; TAG; triacylglycerols; UCR; uncoupled control ratioHepatic steatosis; Mitochondria; Acylcarnitine; Fatty acid; Stearoyl-CoA desaturase 1; Oxidative stress

Interaction of enterocyte FABPs with phospholipid membranes: Clues for specific physiological roles by Lisandro J. Falomir-Lockhart; Gisela R. Franchini; María Ximena Guerbi; Judith Storch; Corsico Betina Córsico (pp. 452-459).

Intestinal and liver fatty acid binding proteins (IFABP and LFABP, respectively) are cytosolic soluble proteins with the capacity to bind and transport hydrophobic ligands between different sub-cellular compartments. Their functions are still not clear but they are supposed to be involved in lipid trafficking and metabolism, cell growth, and regulation of several other processes, like cell differentiation. Here we investigated the interaction of these proteins with different models of phospholipid membrane vesicles in order to achieve further insight into their specificity within the enterocyte. A combination of biophysical and biochemical techniques allowed us to determine affinities of these proteins to membranes, the way phospholipid composition and vesicle size and curvature modulate such interaction, as well as the effect of protein binding on the integrity of the membrane structure. We demonstrate here that, besides their apparently opposite ligand transfer mechanisms, both LFABP and IFABP are able to interact with phospholipid membranes, but the factors that modulate such interactions are different for each protein, further implying different roles for IFABP and LFABP in the intracellular context. These results contribute to the proposed central role of intestinal FABPs in the lipid traffic within enterocytes as well as in the regulation of more complex cellular processes.► We examine the capacity of intestinal and liver FABP to interact with model membranes. ► Both proteins interact with phospholipid membranes. ► Such interactions are modulated by different factors.

Keywords: Abbreviations; FAs; long chain fatty acids; FABPs; fatty acid-binding proteins; IFABP; intestinal fatty acid-binding protein; LFABP; liver fatty acid-binding protein; IFABP-HL; helixless IFABP; DPA; dipicolinic acid; SUVs; small unilamellar vesicles; LUVs; large unilamellar vesiclesFatty acid binding proteins; Membrane interaction; Intracellular fatty acid traffic; Model membranes

Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: Dynamic synergy and therapeutic utility by A.M. El-Mowafy; M.A. Abdel-Dayem; A. Abdel-Aziz; M.F. El-Azab; S.A. Said (pp. 460-467).

The omega-3 fatty acid eicosapentaenoic acid (EPA) is a superb nature's medicine, with still unfolding health benefits. Because hepatotoxicity is a prominent adverse drug reaction, we currently attempted a new approach in which EPA was challenged to both alleviate hepatotoxicity and provide synergy with anticonvulsant effects of valproate (VPA). Besides, we verified whether EPA may kinetically modulate the clearance rate of VPA. VPA (500mg/kg p.o., for 2weeks) caused rat hepatotoxicity that was manifested as notable (2- to 4-fold) rise in serum liver enzymes (GGT, ALT, and ALP), increased hepatic levels of lipid peroxides and TNF-α (3- and 7-fold) and activity of myeloperoxidase (MPO, 4-fold), lowering of serum albumin (42%), and depletion of liver reduced glutathione (GSH, 36%). Furthermore, histopathologic examination revealed hepatocellular degeneration, focal pericentral necrosis, infiltration of inflammatory cells, and steatosis. Joint treatment with EPA (300mg/kg) blunted the oxidative stress, TNF-α levels and MPO activity, while enhanced levels of serum albumin and hepatic GSH. EPA also ameliorated most of the hepatocellular anomalies evoked by VPA. Additionally, in a mouse PTZ convulsion model, EPA markedly augmented the anticonvulsant effects of VPA far beyond their single responses. On the other hand, pharmacokinetic analyses revealed that joint EPA administration had no effect on serum VPA concentrations. Collectively, results demonstrate for the first time that the ω-3 FA (EPA) markedly alleviated VPA-induced hepatotoxicity, oxidative stress, and inflammation, while enhanced its anticonvulsant effects without altering its clearance. Therapeutically, these protective and synergy profiles for EPA foster a more safe and efficacious drug combination regimen than VPA.► Valproate (VPA) caused liver cell injury and a rise in its oxidative stress level. ► Also, liver cell inflammation, necrosis and steatosis were evident with VPA. ► EPA notably alleviated liver toxicity caused by VPA by reversing the above effects. ► EPA synergized with anticonvulsant effects of VPA to permit lower/safer VPA doses. ► EPA did not alter VPA's plasma levels, thereby availing a promising joint therapy.

Keywords: Valproate; Hepatic injury; EPA; Oxidative stress; Inflammation

Insulin-stimulated glucose uptake and pathways regulating energy metabolism in skeletal muscle cells: The effects of subcutaneous and visceral fat, and long-chain saturated, n-3 and n-6 polyunsaturated fatty acids by Y.Y. Lam; G. Hatzinikolas; J.M. Weir; Janovska A. Janovská; A.J. McAinch; P. Game; P.J. Meikle; G.A. Wittert (pp. 468-475).

Aims. The study aims to determine the effect of long-chain saturated and polyunsaturated (PUFA) fatty acids, specifically palmitic acid (PA; 16:0), docosahexaenoic acid (DHA; 22:6n-3) and linoleic acid (LA; 18:2n-6), and their interactions with factors from adipose tissue, on insulin sensitivity and lipid metabolism in skeletal muscle. Methods. L6 myotubes were cultured with PA, DHA or LA (0.4mmol/l), with or without conditioned media from human subcutaneous (SC) and visceral (IAB) fat. Insulin-stimulated glucose uptake, lipid content, mRNA expression of key genes involved in nutrient utilization and protein expression of inhibitor protein inhibitor kappa B (IκB)-α and mammalian target of rapamycin (mTOR) were measured. Results. PA and IAB fat reduced insulin-stimulated glucose uptake and their combined effect was similar to that of PA alone. PA-induced insulin resistance was ameliorated by inhibiting the de novo synthesis of ceramide, IκBα degradation or mTOR activation. The PA effect was also partially reversed by DHA and completely by LA in the presence of SC fat. PA increased diacylglycerol content, which was reduced by LA and to a greater extent when either IAB or SC fat was also present. PA increased SCD1 whereas DHA and LA increased AMPKα2 mRNA. In the presence of SC or IAB fat, the combination of PA with either DHA or LA decreased SCD1 and increased AMPKα2 mRNA. Conclusions. PA-induced insulin resistance in skeletal muscle involves inflammatory (nuclear factor kappa B/mTOR) and nutrient (ceramide) pathways. PUFAs promote pathways, at a transcriptional level, that increase fat oxidation and synergize with factors from SC fat to abrogate PA-induced insulin resistance.► Interactions between adipokines and fatty acids regulate muscle insulin response. ► Diacylglycerol accumulation is associated with insulin resistance in muscle. ► Polyunsaturated fatty acids promote fat oxidation at a transcriptional level.

Keywords: Insulin resistance; Lipid metabolism; Adipokine

Genetic and functional studies of phosphatidyl-inositol 4-kinase type IIIα by Zsofia Szentpetery; Gergely Szakacs; Naveen Bojjireddy; Andrew W. Tai; Tamas Balla (pp. 476-483).

Phosphatidylinositol 4-kinase type IIIa (PI4KIIIα) is one of four mammalian PI 4-kinases that catalyzes the first committed step in polyphosphoinositide synthesis. PI4KIIIα has been linked to regulation of ER exit sites and to the synthesis of plasma membrane phosphoinositides and recent studies have also revealed its importance in replication of the Hepatitis C virus in liver. Two isoforms of the mammalian PI4KIIIα have been described and annotated in GenBank: a larger, ~230kDa (isoform 2) and a shorter splice variant containing only the ~97kDa C-terminus that includes the catalytic domain (isoform 1). However, Northern analysis of human tissues and cancer cells showed only a single transcript of ~7.5kb with the exception of the proerythroleukemia line K562, which contained significantly higher level of the 7.5kb transcript along with smaller ones of 2.4, 3.5 and 4.2kb size. Bioinformatic analysis also confirmed the high copy number of PI4KIIIα transcript in K562 cells along with several genes located in the same region in Chr22, including two pseudogenes that cover most exons coding for isoform 1, consistent with chromosome amplification. A panel of polyclonal antibodies raised against peptides within the C-terminal half of PI4KIIIα failed to detect the shorter isoform 1 either in COS-7 cells or K562 cells. Moreover, expression of a cDNA encoding isoform 1 yielded a protein of ~97kDa that showed no catalytic activity and failed to rescue hepatitis C virus replication. These data draw attention to PI4KIIIα as one of the genes found in Chr22q11, a region affected by chromosomal instability, but do not substantiate the existence of a functionally relevant short form of PI4KIIIα.► PI4KA, the gene encoding phosphatidylinositol 4-kinase IIIα is surrounded by two partial pseudogenes ► on Chr22q11. ► Most human tissues and cancer cells do not express transcripts corresponding to isoform 1 of PI4KIIIα. ► K562 proleukemia cells show high levels of full and partial PI4KIIIα transcripts as well as several other ► genes in the vicinity of PI4KA suggesting chromosome amplification. ► The shorter, isoform 1 of PI4KIIIα cannot be detected at the protein level. ► Expressed isoform 1 of PI4KIIIα shows no catalytic activity and cannot rescue hepatitic C viral replication in cells depleted in endogenous PI4KIIIα.

Keywords: Abbreviations; PtdIns; Phosphatidylinositol; PtdIns4; P; phosphatidylinositol 4-phosphate; PtdIns(4,5); P; ₂; phosphatidylinositol 4,5-bisphosphate; PI4KIIIα; phosphatidylinositol 4 kinase type IIIαPhosphoinositide; PI 4-kinase; Chromosome 22; K562 leukemia cells; Golgi; Endoplasmic reticulum

Liver conversion of docosahexaenoic and arachidonic acids from their 18-carbon precursors in rats on a DHA-free but α-LNA-containing n−3 PUFA adequate diet by Fei Gao; Hyung-Wook Kim; Miki Igarashi; Dale Kiesewetter; Lisa Chang; Kaizong Ma; Stanley I. Rapoport (pp. 484-489).

The long-chain polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA, 20:5n−3), docosahexaenoic acid (DHA, 22:6n−3), and arachidonic acid (AA, 20:4n−6), are critical for health. These PUFAs can be synthesized in liver from their plant-derived precursors, α-linolenic acid (α-LNA, 18:3n−3) and linoleic acid (LA, 18:2n−6). Vegetarians and vegans may have suboptimal long-chain n−3 PUFA status, and the extent of the conversion of α-LNA to EPA and DHA by the liver is debatable. We quantified liver conversion of DHA and other n−3 PUFAs from α-LNA in rats fed a DHA-free but α-LNA (n−3 PUFA) adequate diet, and compared results to conversion of LA to AA. [U-¹³C]LA or [U-¹³C]α-LNA was infused intravenously for 2h at a constant rate into unanesthetized rats fed a DHA-free α-LNA adequate diet, and published equations were used to calculate kinetic parameters. The conversion coefficient k^⁎ of DHA from α-LNA was much higher than for AA from LA (97.2×10−³ vs. 10.6×10−³min−¹), suggesting that liver elongation–desaturation is more selective for n−3 PUFA biosynthesis on a per molecule basis. The net daily secretion rate of DHA, 20.3μmol/day, exceeded the reported brain DHA consumption rate by 50-fold, suggesting that the liver can maintain brain DHA metabolism with an adequate dietary supply solely of α-LNA. This infusion method could be used in vegetarians or vegans to determine minimal daily requirements of EPA and DHA in humans.► DHA and AA conversion were determined in rats fed a DHA-free but α-LNA adequate diet. ► Conversion efficiency is much higher for DHA than AA ► DHA daily secretion rate exceeded the rat brain DHA consumption rate by 50-fold. ► The method could be used to determine the minimal daily DHA requirement in humans.

Keywords: Abbreviations; AA; arachidonic acid; DHA; docosahexaenoic acid; DPA; docosapentaenoic acid; ETA; eicosatrienoic acid; GC; gas chromatography; LA; linoleic acid; α-LNA; α-linolenic acid; γ-LNA; γ-linolenic acid; MS; Mass spectrometry; NCI; negative chemical ionization; PFB; pentafluorobenzyl; PUFA; polyunsaturated fatty acid; SIM; selected ion modeConversion; Arachidonic; Docosahexaenoic; Diet; Liver; Turnover

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BBA - Molecular and Cell Biology of Lipids (v.1811, #7-8)