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BBA - Molecular and Cell Biology of Lipids (v.1821, #10)

Editorial Board (pp. i).

Arachidonic acid stimulates DNA synthesis in brown preadipocytes through the activation of protein kinase C and MAPK by Bibian Garcia; Raquel Martinez-de-Mena; Maria-Jesus Obregon (pp. 1309-1315).

Arachidonic acid (AA) is a polyunsaturated fatty acid that stimulates the proliferation of many cellular types. We studied the mitogenic potential of AA in rat brown preadipocytes in culture and the signaling pathways involved. AA is a potent mitogen which induces 4-fold DNA synthesis in brown preadipocytes. The AA mitogenic effect increases by NE addition. AA also increases the mitogenic action of different growth factor combinations. Other unsaturated and saturated fatty acids do not stimulate DNA synthesis to the same extent as AA. We analyzed the role of PKC and MEK/MAPK signaling pathways. PKC inhibition by bisindolilmaleimide I (BIS) abolishes AA and phorbol ester stimulation of DNA synthesis and reduces the mitogenic activity of different growth factors in brown preadipocytes. Brown preadipocytes in culture express PKC α, δ, ε and ζ isoforms. Pretreatment with high doses of the phorbol ester PDBu, induces downregulation of PKCs ε and δ and reproduces the effect of BIS indicating that AA-dependent induction of DNA synthesis requires PKC activity. AA also activates MEK/MAPK pathway and the inhibition of MEK activity inhibits AA stimulation of DNA synthesis and brown adipocyte proliferation. Inhibition of PKC δ by rottlerin abolishes AA-dependent stimulation of DNA synthesis and MAPK activation, whereas PKC ε inhibition does not produce any effect. In conclusion, our results identify AA as a potent mitogen for brown adipocytes and demonstrate the involvement of the PDBu-sensitive PKC δ isoform and MEK/MAPK pathway in AA-induced proliferation of brown adipocytes. Increased proliferative activity might increase the thermogenic capacity of brown fat.► Araquidonic acid (AA) is a mitogen for brown adipocytes inducing DNA synthesis. ► NE increases the mitogenic action of AA, growth factors and NE. ► AA increases the action of other mitogens of brown adipocytes. ► The mitogenic actions of AA and other mitogens are mediated through PKC and MAPK. ► PKC delta seems involved in AA-induced proliferation.

Keywords: Araquidonic acid; Proliferation; Brown adipose tissue; PKC; MAPK

Vaccenic acid-mediated reduction in cytokine production is independent of c9, t11-CLA in human peripheral blood mononuclear cells by Anke Jaudszus; Gerhard Jahreis; Schlormann Wiebke Schlörmann; Janine Fischer; Ronny Kramer; Christian Degen; Carsten Rohrer; Alexander Roth; Holger Gabriel; Dagmar Barz; Michael Gruen (pp. 1316-1322).

The ruminant trans fatty acid vaccenic acid ( tVA) favorably alters markers of inflammation. However, it is not yet clear whether these effects are attributed to its endogenous partial conversion to c9, t11-CLA, which is known to possess anti-inflammatory properties. We compared the cytokine reducing potential of tVA to c9, t11-CLA in human T-helper (Th) cells as a main source of cytokine production during inflammation. Secondly, we assessed whether a bioconversion of tVA to c9, t11-CLA via stearoyl-CoA desaturase (SCD) encoded activity takes place in peripheral blood mononuclear cells (PBMC) in order to relate the outcomes of intracellular cytokine measurement to the degree of conversion. TVA reduced the percentage of both IL-2 and TNF-α expressing Th cells significantly, but to a lesser extent compared to c9, t11-CLA, as determined by flow cytometry after alloreactive stimulation of PBMC. Pre-treatment with the selective PPARγ antagonist T0070907 largely re-established the IL-2 and TNF-α positive Th cell population in both tVA and c9, t11-CLA treated cultures. Interestingly, while the portion of tVA dose-dependently increased within the cellular lipid fraction, the initially marginal amount of c9, t11-CLA remained unaltered. However, SCD mRNA although abundantly expressed in PBMC was not regulated by tVA. Conclusively, these results suggest that the cytokine reducing effect of tVA in human T cells is independent of c9, t11-CLA, since no bioconversion occurred. Moreover, the data provide evidence that tVA mechanistically acts in a manner similar to c9, t11-CLA.► Vaccenic acid ( tVA) represses cytokine production during T-helper (Th) cell activation. ► PPARγ is involved in a manner similar to c9, t11-CLA. ► TVA is not converted to c9, t11-CLA in human PBMC. ► Δ9-desaturase (SCD) mRNA is abundantly expressed in PBMC. ► SCD mRNA is not regulated by tVA in PBMC.

Keywords: Abbreviations; CD; cluster of differentiation; c; 9,; t; 11-CLA; cis; -9,; trans; -11-conjugated linoleic acid; Cys; ³¹³; cysteine residue 313; DMSO; dimethylsulfoxide; IL; interleukin; FA; fatty acid; FAME; fatty acid methyl esters; FBS; fetal bovine serum; mAb; monoclonal antibody; PBMC; peripheral blood mononuclear cells, PBS, phosphate-buffered saline; PMA; phorbol 12-myristate 13-acetate; PPAR; peroxisome proliferator-activated receptors; SCD; stearoyl-CoA desaturase (Δ9-desaturase); T0070907; 2-Chloro-5-nitro-N-4-pyridinylbenzamide; TNF-α; tumor necrosis factor alphaCLA; Cytokine; Conversion; Vaccenic acid; PBMC; Th cell

Palmitic acid follows a different metabolic pathway than oleic acid in human skeletal muscle cells; lower lipolysis rate despite an increased level of adipose triglyceride lipase by Siril S. Bakke; Cedric Moro; Nikolic Nataša Nikolić; Nina P. Hessvik; Pierre-Marie Badin; Line Lauvhaug; Katarina Fredriksson; Matthijs K.C. Hesselink; Mark V. Boekschoten; Sander Kersten; Michael Gaster; G. Hege Thoresen; Arild C. Rustan (pp. 1323-1333).

Development of insulin resistance is positively associated with dietary saturated fatty acids and negatively associated with monounsaturated fatty acids. To clarify aspects of this difference we have compared the metabolism of oleic (OA, monounsaturated) and palmitic acids (PA, saturated) in human myotubes. Human myotubes were treated with 100μM OA or PA and the metabolism of [¹⁴C]-labeled fatty acid was studied. We observed that PA had a lower lipolysis rate than OA, despite a more than two-fold higher protein level of adipose triglyceride lipase after 24h incubation with PA. PA was less incorporated into triacylglycerol and more incorporated into phospholipids after 24h. Supporting this, incubation with compounds modifying lipolysis and reesterification pathways suggested a less influenced PA than OA metabolism. In addition, PA showed a lower accumulation than OA, though PA was oxidized to a relatively higher extent than OA. Gene set enrichment analysis revealed that 24h of PA treatment upregulated lipogenesis and fatty acid β-oxidation and downregulated oxidative phosphorylation compared to OA. The differences in lipid accumulation and lipolysis between OA and PA were eliminated in combination with eicosapentaenoic acid (polyunsaturated fatty acid). In conclusion, this study reveals that the two most abundant fatty acids in our diet are partitioned toward different metabolic pathways in muscle cells, and this may be relevant to understand the link between dietary fat and skeletal muscle insulin resistance.► Palmitic acid had a lower lipolysis rate than oleic acid in human myotubes. ► Compared to oleic acid, palmitic acid upregulated adipose triglyceride lipase. ► Palmitic acid was less accumulated than oleic acid. ► Related to oleic acid, palmitic acid upregulated β-oxidation and was oxidized more. ► The two abundant fatty acids have different metabolic fates in myotubes.

Keywords: Abbreviations; ASMs; acid soluble metabolites; ACSL; long-chain fatty acyl-CoA synthetase; ATGL; adipose triglyceride lipase; BSA; bovine serum albumin; CA; cell-associated; CD36/FAT; fatty acid translocase; FDR; false discovery rate; CE; cholesteryl ester; CRAT; carnitine O-acetyltransferase; CPT1; carnitine palmitoyltransferase 1; DAG; diacylglycerol; DGAT; diacylglycerol acyltransferase; ECM; extracellular matrix; EPA; eicosapentaenoic acid; FADS2; fatty acid desaturase 2; FFA; free fatty acid; GSEA; gene set enrichment analysis; HADHA; mitochondrial trifunctional protein, alpha subunit; HSL; hormone-sensitive lipase; LD; lipid droplet; LMM; linear mixed models; MUFA; monounsaturated fatty acid; OA; oleic acid; PA; palmitic acid; PDK4; pyruvate dehydrogenase kinase isozyme 4; PL; phospholipid; PLIN; perilipin; PUFA; polyunsaturated fatty acid; SCD1; stearoyl-CoA desaturase 1; SFA; saturated fatty acid; SLC25A20; solute carrier family 25 (carnitine/acylcarnitine translocase), member 20; SPA; scintillation proximity assay; TAG; triacylglycerolHuman myotube; Lipid oxidation; Lipolysis; Adipose triglyceride lipase; Lipid droplet; Fatty acid

Mechanism and stereoselectivity of HDAC I inhibition by ( R)-9-hydroxystearic acid in colon cancer by Carola Parolin; Natalia Calonghi; Enrica Presta; Carla Boga; Paolo Caruana; Marina Naldi; Vincenza Andrisano; Lanfranco Masotti; Giorgio Sartor (pp. 1334-1340).

9-Hydroxystearic acid (9-HSA) belongs to the endogenous lipid peroxidation by-products that decrease in tumors, causing as a consequence the loss of one of the control mechanisms on cell division. It acts as a histone deacetylase (HDAC, E.C 3.5.1.98) inhibitor, and the interaction of the two enantiomers of 9-HSA with the catalytic site of the enzyme, investigated by using a molecular modelling approach, has been reported to be different. In this work we tested out this prediction by synthesizing the two enantiomers ( R)-9-HSA (R-9) and ( S)-9-HSA (S-9) starting from the natural source methyl dimorphecolate obtained from Dimorphotheca sinuata seeds and investigating their biological activity in HT29 cells. Both enantiomers inhibit the enzymatic activity of HDAC1, HDAC2 and HDAC3, R-9 being more active; R-9 and S-9 inhibitory effect induces an increase in histone H4 acetylation. We also demonstrate that the antiproliferative effect brought about by R-9 is more pronounced as well as we observe increase of p21 transcription and protein content, while the expression of cyclin D1 is decreased. Starting from these observations it can be hypothesized that the interaction of R-9 with HDAC1 induce conformational changes in the enzyme causing loss of its interaction with other proteins, like cyclin D1 itself.► 9-hydroxystearic acid (9-HSA) inhibition of class I HDACs is strictly stereospecific. ► ( R)-9-HSA (R-9), but not ( S)-9-HSA (S-9), upregulates p21WAF1 and reduces cyclin D1. ► HDAC1 and cyclin D1 form a complex that binds chromatin. ► R-9, but not S-9, causes HDAC1-cyclin D1 complex dissociation.

Keywords: Abbreviations; 9-HSA; 9-hydroxystearic acid; R-9; (; R; )-9-hydroxystearic acid; S-9; (; S; )-9-hydroxystearic acid; RT-PCR; Real time PCR; HDAC; histone deacetylase; HAT; histone acetyltransferase; PI; propidium iodide; CBP; chromatin bound proteins9-hydroxystearic acid; Colon cancer; Histone deacetylase; Cyclin D1; Protein interaction; Stereoselectivity

Dietary fat types differently modulate the activity and expression of mitochondrial carnitine/acylcarnitine translocase in rat liver by Paola Priore; Eleonora Stanca; Gabriele Vincenzo Gnoni; Luisa Siculella (pp. 1341-1349).

The carnitine/acylcarnitine translocase (CACT), an integral protein of the mitochondrial inner membrane, belongs to the carnitine-dependent system of fatty acid transport into mitochondria, where beta-oxidation occurs. CACT exchanges cytosolic acylcarnitine or free carnitine for carnitine in the mitochondrial matrix. The object of this study was to investigate in rat liver the effect, if any, of diets enriched with saturated fatty acids (beef tallow, BT, the control), n−3 polyunsaturated fatty acids (PUFA) (fish oil, FO), n−6 PUFA (safflower oil, SO), and mono-unsaturated fatty acids (MUFA) (olive oil, OO) on the activity and expression of CACT. Translocase exchange rates increased, in parallel with CACT mRNA abundance, upon FO-feeding, whereas OO-dietary treatment induced a decrease in both CACT activity and expression. No changes were observed upon SO-feeding. Nuclear run-on assay revealed that FO-treatment increased the transcriptional rate of CACT mRNA. On the other hand, only in the nuclei of hepatocytes from OO-fed rats splicing of the last intron of CACT pre-mRNA and the rate of formation of the 3′-end were affected. Overall, these findings suggest that compared to the BT‐enriched diet, the SO-enriched diet did not influence CACT activity and expression, whereas FO- and OO-feeding alters CACT activity in an opposite fashion, i.e. modulating its expression at transcriptional and post-transcriptional levels, respectively.► Wistar rats were fed on different dietary fat types using beef tallow as control. ► Fish- and olive oil-feeding oppositely alter hepatic CACT activity and expression. ► CACT activity and expression are unaffected by safflower oil-feeding. ► Fish oil-feeding stimulates transcriptional rate of CACT gene. ► Olive oil-feeding affects splicing and 3'-end formation of CACT pre-mRNA.

Keywords: Abbreviations; BT; beef tallow; CACT; carnitine/acylcarnitine translocase; CPT1; carnitine palmitoyl transferase 1; CPT2; carnitine palmitoyl transferase 2; FAME; fatty acid methyl ester; FO; fish oil; LCFA; long chain fatty acids; MUFA; monounsaturated fatty acids; OO; olive oil; PUFA; polyunsaturated fatty acids; SO; safflower oilBeta-oxidation; CACT; Gene regulation; Fish oil; Olive oil; Safflower oil

Sterols regulate 3β-hydroxysterol Δ24-reductase (DHCR24) via dual sterol regulatory elements: Cooperative induction of key enzymes in lipid synthesis by Sterol Regulatory Element Binding Proteins by Eser J. Zerenturk; Laura J. Sharpe; Andrew J. Brown (pp. 1350-1360).

3β-Hydroxysterol Δ24-reductase (DHCR24) catalyzes a final step in cholesterol synthesis, and has been ascribed diverse functions, such as being anti-apoptotic and anti-inflammatory. How this enzyme is regulated transcriptionally by sterols is currently unclear. Some studies have suggested that its expression is regulated by Sterol Regulatory Element Binding Proteins (SREBPs) while another suggests it is through the Liver X Receptor (LXR). However, these transcription factors have opposing effects on cellular sterol levels, so it is likely that one predominates. Here we establish that sterol regulation of DHCR24 occurs predominantly through SREBP-2, and identify the particular region of the DHCR24 promoter to which SREBP-2 binds. We demonstrate that sterol regulation is mediated by two sterol regulatory elements (SREs) in the promoter of the gene, assisted by two nearby NF-Y binding sites. Moreover, we present evidence that the dual SREs work cooperatively to regulate DHCR24 expression by comparison to two known SREBP target genes, the LDL receptor with one SRE, and farnesyl-diphosphate farnesyltransferase 1, with two SREs.► The DHCR24 promoter contains two sterol regulatory elements (SREs). ► Dual SREs display cooperativity to induce transcriptional regulation by SREBP-2. ► Cholesterol synthesis is an energetically expensive process. ► We introduce a novel mechanism of the transcriptional regulation of this process.

Keywords: Abbreviations; 24,25EC; 24(; S; ),25-epoxycholesterol; 25HC; 25-hydroxycholesterol; ABCA1; ATP-binding cassette transporter A1; ABCG1; ATP-binding cassette transporter G1; ACC; acetyl-CoA carboxylase; ACS1; acyl-CoA synthase; DHCR24; 3β-Hydroxysterol Δ24-reductase; DHCR7; 7-deydrocholesterol reductase; FASN; fatty acid synthase; FDFT1; farnesyl-diphosphate farnesyltransferase 1; FDPS; farnesyl diphosphate synthase; HMGCR; HMG-CoA reductase; HMGCS; HMG-CoA synthase; HSD17B7; hydroxysteroid (17-beta) dehydrogenase 7; LDLR; LDL receptor; LXR; liver X receptor; NF-Y; nuclear factor Y; PBGD; porphobilinogen deaminase; SQLE; squalene epoxidase; SRE; sterol regulatory element; SREBP; sterol regulatory element binding protein; TM7SF2; transmembrane 7 superfamily member 2DHCR24; SREBP; Regulation; SRE; Transcription; Seladin-1

OxLDL stimulates Id1 nucleocytoplasmic shuttling in endothelial cell angiogenesis via PI3K Pathway by Juhui Qiu; Qin Peng; Yiming Zheng; Jianjun Hu; Xiangdong Luo; Yanqun Teng; Tao Jiang; Tieying Yin; Chaojun Tang; Guixue Wang (pp. 1361-1369).

Angiogenesis plays remarkable roles in the development of atherosclerotic rupture plaques. However, its essential mechanism remains unclear. The purpose of the study was to investigate whether inhibitor of DNA binding-1 or inhibitor of differentiation 1 (Id1) promoted angiogenesis when exposed to oxidised low-density lipoprotein (oxLDL), and to determine the molecular mechanism involved. Using aortic ring assay and tube formation assay as a model system, a low concentration of oxLDL was found to induce angiogenic sprouting and capillary lumen formation of endothelial cell. But the Id1 expression was significantly upregulated by oxLDL at low and high concentrations. The Id1 was localised in the nuclei of the human umbilical vein endothelial cells in the control group and in the high-concentration oxLDL group. Id1 was translocated to the cytoplasm at low oxLDL concentrations. The nucleocytoplasmic shuttling at low oxLDL concentration was inhibited by treatment with the nuclear export inhibitor leptomycin B. Protein kinase A (PKA) inhibitor H89 promoted nuclear export of Id1, and phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 reduced the nuclear export of Id1. PI3K inhibition blocked oxLDL-induced angiogenesis. Low concentrations of oxLDL promoted angiogenic sprouting and capillary formation. And this process depends on nuclear export of Id1, which in turn is controlled by the PI3K pathway. This report presents a new link between oxLDL and Id1 localisation, and may provide a new insight into the interactions of ox-LDL and Id1 in the context of atherosclerosis.► Id1 is cytoplasm localisation in cells exposed to low oxLDL concentrations. ► Nuclear export of Id1 is controlled by CRM1/exportin. ► PI3K is critical for oxLDL-induced angiogenesis.

Keywords: Abbreviations; Id1; inhibitor of DNA binding-1 or inhibitor of differentiation 1; oxLDL; oxidised low-density lipoprotein; bHLH; basic helix–loop–helix; EC; endothelial cell; HUVECs; human umbilical vein endothelial cells; LMB; leptomycin B; PI3K; phosphatidylinositol-3-kinase; PKA; protein kinase A; IOD; integral optical density; LOX-1; lectin-like oxidised low density lipoprotein receptor-1Inhibitor of DNA binding-1 (Id1); Oxidised low-density lipoprotein (oxLDL); Angiogenesis; Nucleocytoplasmic shuttling; Phosphatidylinositol 3-kinase (PI3K)

Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4 by Stefan K. Nilsson; Fredrick Anderson; Madelene Ericsson; Mikael Larsson; Elena Makoveichuk; Aivar Lookene; Joerg Heeren; Gunilla Olivecrona (pp. 1370-1378).

Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.► We show that TG-rich lipoproteins protect LPL from inactivation by ANGPTLs. ► In serum, lipoproteins present are likely protecting LPL from inactivation by ANGPTLs. ► We provide evidence explaining why ANGPTLs do not correlate with TG levels in serum.

Keywords: Abbreviations; apo; apolipoprotein; BSA; bovine serum albumin; ccd; coiled-coil domain; DMEM; Dulbecco's modified eagle medium; GPIHBP1; glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1; HDL; high density lipoprotein; HSPG; heparin sulfate proteoglycan; LDL; low density lipoprotein; LDL-R; LDL-receptor; LPDS; lipoprotein deficient serum; LPL; lipoprotein lipase; LRP1; LDL receptor-related protein 1; PBS; phosphate buffered saline; SPR; surface plasmon resonance; TG; triacylglycerol; TRLs; triacylglycerol rich lipoproteins; VLDL; very low density lipoproteinANGPTL3; ANGPTL4; Lipoprotein lipase; Triacylglycerol metabolism; VLDL; Chylomicron

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BBA - Molecular and Cell Biology of Lipids (v.1821, #10)