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BBA - Molecular and Cell Biology of Lipids (v.1811, #1)
Regulation of mammalian desaturases by myristic acid: N-terminal myristoylation and other modulations by Vincent Rioux; Pedrono Frédérique Pédrono; Philippe Legrand (pp. 1-8).
Myristic acid, the 14-carbon saturated fatty acid (C14:0), usually accounts for small amounts (0.5%–1% weight of total fatty acids) in animal tissues. Since it is a relatively rare molecule in the cells, the specific properties and functional roles of myristic acid have not been fully studied and described. Like other dietary saturated fatty acids (palmitic acid, lauric acid), this fatty acid is usually associated with negative consequences for human health. Indeed, in industrialized countries, its excessive consumption correlates with an increase in plasma cholesterol and mortality due to cardiovascular diseases. Nevertheless, one feature of myristoyl-CoA is its ability to be covalently linked to the N-terminal glycine residue of eukaryotic and viral proteins. This reaction is called N-terminal myristoylation. Through the myristoylation of hundreds of substrate proteins, myristic acid can activate many physiological pathways. This review deals with these potentially activated pathways. It focuses on the following emerging findings on the biological ability of myristic acid to regulate the activity of mammalian desaturases: (i) recent findings have described it as a regulator of the Δ4-desaturation of dihydroceramide to ceramide; (ii) studies have demonstrated that it is an activator of the Δ6-desaturation of polyunsaturated fatty acids; and (iii) myristic acid itself is a substrate of some fatty acid desaturases. This article discusses several topics, such as the myristoylation of the dihydroceramide Δ4-desaturase, the myristoylation of the NADH-cytochrome b5 reductase which is part of the whole desaturase complex, and other putative mechanisms.► Myristic acid is specifically involved in protein N-myristoylation. ► Myristic acid activates dihydroceramide Δ4-desaturase 1 through its N-myristoylation. ► Myristic acid increases fatty acid Δ6-desaturase activity but FADS2 is not myristoylated. ► The myristoylation of the NADH-cytochrome b5 reductase can participate in the myristic acid associated-regulation of desaturases.
Keywords: Abbreviations; DES; dihydroceramide Δ4-desaturase; FADS; fatty acid desaturase; NCb5R; NADH-cytochrome b5 reductase; NMT; myristoyl-CoA: protein N-myristoyltransferase; PUFA; polyunsaturated fatty acids; SCD; stearoyl-CoA desaturase; SFA; saturated fatty acidsMyristic acid; Protein acylation; N-myristoylation; Fatty acid desaturase; Dihydroceramide desaturase
Regulation of mammalian desaturases by myristic acid: N-terminal myristoylation and other modulations by Vincent Rioux; Pedrono Frédérique Pédrono; Philippe Legrand (pp. 1-8).
Myristic acid, the 14-carbon saturated fatty acid (C14:0), usually accounts for small amounts (0.5%–1% weight of total fatty acids) in animal tissues. Since it is a relatively rare molecule in the cells, the specific properties and functional roles of myristic acid have not been fully studied and described. Like other dietary saturated fatty acids (palmitic acid, lauric acid), this fatty acid is usually associated with negative consequences for human health. Indeed, in industrialized countries, its excessive consumption correlates with an increase in plasma cholesterol and mortality due to cardiovascular diseases. Nevertheless, one feature of myristoyl-CoA is its ability to be covalently linked to the N-terminal glycine residue of eukaryotic and viral proteins. This reaction is called N-terminal myristoylation. Through the myristoylation of hundreds of substrate proteins, myristic acid can activate many physiological pathways. This review deals with these potentially activated pathways. It focuses on the following emerging findings on the biological ability of myristic acid to regulate the activity of mammalian desaturases: (i) recent findings have described it as a regulator of the Δ4-desaturation of dihydroceramide to ceramide; (ii) studies have demonstrated that it is an activator of the Δ6-desaturation of polyunsaturated fatty acids; and (iii) myristic acid itself is a substrate of some fatty acid desaturases. This article discusses several topics, such as the myristoylation of the dihydroceramide Δ4-desaturase, the myristoylation of the NADH-cytochrome b5 reductase which is part of the whole desaturase complex, and other putative mechanisms.► Myristic acid is specifically involved in protein N-myristoylation. ► Myristic acid activates dihydroceramide Δ4-desaturase 1 through its N-myristoylation. ► Myristic acid increases fatty acid Δ6-desaturase activity but FADS2 is not myristoylated. ► The myristoylation of the NADH-cytochrome b5 reductase can participate in the myristic acid associated-regulation of desaturases.
Keywords: Abbreviations; DES; dihydroceramide Δ4-desaturase; FADS; fatty acid desaturase; NCb5R; NADH-cytochrome b5 reductase; NMT; myristoyl-CoA: protein N-myristoyltransferase; PUFA; polyunsaturated fatty acids; SCD; stearoyl-CoA desaturase; SFA; saturated fatty acidsMyristic acid; Protein acylation; N-myristoylation; Fatty acid desaturase; Dihydroceramide desaturase
Hormone-sensitive lipase modulates adipose metabolism through PPARγ by Wen-Jun Shen; Zaixin Yu; Shailja Patel; Dyron Jue; Li-Fen Liu; Fredric B. Kraemer (pp. 9-16).
Hormone-sensitive lipase (HSL) is rate limiting for diacylglycerol and cholesteryl ester hydrolysis in adipose tissue and essential for complete hormone-stimulated lipolysis. Gene expression profiling in HSL−/− mice suggests that HSL is important for modulating adipogenesis and adipose metabolism. To test whether HSL is required for the supply of intrinsic ligands for PPARγ for normal adipose differentiation, HSL−/− and wild-type (WT) littermates were fed normal chow (NC) and high-fat (HF) diets supplemented with or without rosiglitazone (200mg/kg) for 16weeks. Results show that supplementing rosiglitazone to an NC diet completely normalized the decreased body weight and adipose depots in HSL−/− mice. Additionally, rosiglitazone resulted in similar serum glucose, total cholesterol, FFA, and adiponectin values in WT and HSL−/− mice. Furthermore, rosiglitazone normalized the expression of genes involved in adipocyte differentiation, markers of adipocyte differentiation, and enzymes involved in triacylglycerol synthesis and metabolism, and cholesteryl ester homeostasis, in HSL−/− mice. Supplementing rosiglitazone to an HF diet resulted in improved glucose tolerance in both WT and HSL−/− animals and also partial normalization in HSL−/− mice of abnormal WAT gene expression, serum chemistries, organ and body weight changes. In vitro studies showed that adipocytes from WT animals can provide ligands for activation of PPARγ and that activation is further boosted following lipolytic stimulation, whereas adipocytes from HSL−/− mice displayed attenuated activation of PPARγ, with no change following lipolytic stimulation. These results suggest that one of the mechanisms by which HSL modulates adipose metabolism is by providing intrinsic ligands or pro-ligands for PPARγ.►HSL is required for complete lipolysis. ►Disruption of HSL alters adipogenesis and adipose metabolism. ►Rosiglitazone reverses abnormalities in HSL−/− mice on chow, but not high-fat, diet. ►HSL−/− adipocytes release less ligands/pro-ligands that activate PPARγ. ►HSL modulates adipose metabolism by providing ligands/pro-ligands for PPARγ.
Keywords: Abbreviations; ACSL1; acyl coenzyme A synthetase family member 1; ATGL; adipose triglyceride lipase; BAT; brown adipose tissue; DAG; diacylglycerol; FABP4; fatty acid binding protein 4; HF; high fat; HSL; hormone-sensitive lipase; NC; normal chow; PEPCK; phosphoenolpyruvate carboxykinase; TAG; triacylglycerol; WAT; white adipose tissue; WT; wild typeKnockout; Rosiglitazone; Ligand
Hormone-sensitive lipase modulates adipose metabolism through PPARγ by Wen-Jun Shen; Zaixin Yu; Shailja Patel; Dyron Jue; Li-Fen Liu; Fredric B. Kraemer (pp. 9-16).
Hormone-sensitive lipase (HSL) is rate limiting for diacylglycerol and cholesteryl ester hydrolysis in adipose tissue and essential for complete hormone-stimulated lipolysis. Gene expression profiling in HSL−/− mice suggests that HSL is important for modulating adipogenesis and adipose metabolism. To test whether HSL is required for the supply of intrinsic ligands for PPARγ for normal adipose differentiation, HSL−/− and wild-type (WT) littermates were fed normal chow (NC) and high-fat (HF) diets supplemented with or without rosiglitazone (200mg/kg) for 16weeks. Results show that supplementing rosiglitazone to an NC diet completely normalized the decreased body weight and adipose depots in HSL−/− mice. Additionally, rosiglitazone resulted in similar serum glucose, total cholesterol, FFA, and adiponectin values in WT and HSL−/− mice. Furthermore, rosiglitazone normalized the expression of genes involved in adipocyte differentiation, markers of adipocyte differentiation, and enzymes involved in triacylglycerol synthesis and metabolism, and cholesteryl ester homeostasis, in HSL−/− mice. Supplementing rosiglitazone to an HF diet resulted in improved glucose tolerance in both WT and HSL−/− animals and also partial normalization in HSL−/− mice of abnormal WAT gene expression, serum chemistries, organ and body weight changes. In vitro studies showed that adipocytes from WT animals can provide ligands for activation of PPARγ and that activation is further boosted following lipolytic stimulation, whereas adipocytes from HSL−/− mice displayed attenuated activation of PPARγ, with no change following lipolytic stimulation. These results suggest that one of the mechanisms by which HSL modulates adipose metabolism is by providing intrinsic ligands or pro-ligands for PPARγ.►HSL is required for complete lipolysis. ►Disruption of HSL alters adipogenesis and adipose metabolism. ►Rosiglitazone reverses abnormalities in HSL−/− mice on chow, but not high-fat, diet. ►HSL−/− adipocytes release less ligands/pro-ligands that activate PPARγ. ►HSL modulates adipose metabolism by providing ligands/pro-ligands for PPARγ.
Keywords: Abbreviations; ACSL1; acyl coenzyme A synthetase family member 1; ATGL; adipose triglyceride lipase; BAT; brown adipose tissue; DAG; diacylglycerol; FABP4; fatty acid binding protein 4; HF; high fat; HSL; hormone-sensitive lipase; NC; normal chow; PEPCK; phosphoenolpyruvate carboxykinase; TAG; triacylglycerol; WAT; white adipose tissue; WT; wild typeKnockout; Rosiglitazone; Ligand
Incorporation profiles of conjugated linoleic acid isomers in cell membranes and their positional distribution in phospholipids by Papasani V. Subbaiah; Ian G. Gould; Samanta Lal; Buzulagu Aizezi (pp. 17-24).
Although the conjugated linoleic acids (CLA) have several isomer-specific biological effects including anti-carcinogenic and anti-adipogenic effects, their mechanisms of action remain unclear. To determine their potential effects on membrane structure and function, we studied the incorporation profiles of four CLA isomers ( trans-10 cis-12 (A), trans-9 trans-11 (B), cis-9 trans-11 (C), and cis-9 cis-11 (D)) in CHO and HepG2 cells. All four isomers were incorporated into cellular lipids as efficiently as linoleic acid (LA), with the majority of the incorporated CLA present in membrane rafts. Of the four isomers, only CLA-A increased the cholesterol content of the raft fraction. Over 50% of the incorporated CLAs were recovered in phosphatidylcholine of CHO cells, but in HepG2 the neutral lipids contained the majority of CLA. The desaturation index (18:1/18:0 and 16:1/16:0) was reduced by CLA-A, but increased by CLA-B, the effects being apparent mostly in raft lipids. The Δ9 desaturase activity was inhibited by CLAs A and C. Unlike LA, which was mostly found in the sn-2 position of phospholipids, most CLAs were also incorporated significantly into the sn-1 position in both cell types. These studies show that the incorporation profiles of CLA isomers differ significantly from that of LA, and this could lead to alterations in membrane function, especially in the raft-associated proteins.►Conjugated linoleic acids (CLA) incorporated into membrane rafts. ►Significant amounts of CLA incorporated into the sn-1 position of phospholipids. ►CLA isomers differ in their inhibition of Δ9 desaturase. ► Trans-10 cis-12 CLA increases cholesterol content of membrane rafts.
Keywords: Abbreviations; CLA; conjugated linoleic acid; DHA; docosahexaenoic acid; EPA; eicosapentaenoic acid; FFA; free fatty acid; LA; linoleic acid; PPAR; peroxisome proliferator-activated receptor; PBS; phosphate-buffered saline; PC; phosphatidylcholine; PE; phosphatidylethanolamine; SCD; stearoyl CoA desaturaseConjugated linoleic acid; Membrane raft; Desaturation index; Positional distribution; Stearoyl CoA desaturase; Raft cholesterol
Incorporation profiles of conjugated linoleic acid isomers in cell membranes and their positional distribution in phospholipids by Papasani V. Subbaiah; Ian G. Gould; Samanta Lal; Buzulagu Aizezi (pp. 17-24).
Although the conjugated linoleic acids (CLA) have several isomer-specific biological effects including anti-carcinogenic and anti-adipogenic effects, their mechanisms of action remain unclear. To determine their potential effects on membrane structure and function, we studied the incorporation profiles of four CLA isomers ( trans-10 cis-12 (A), trans-9 trans-11 (B), cis-9 trans-11 (C), and cis-9 cis-11 (D)) in CHO and HepG2 cells. All four isomers were incorporated into cellular lipids as efficiently as linoleic acid (LA), with the majority of the incorporated CLA present in membrane rafts. Of the four isomers, only CLA-A increased the cholesterol content of the raft fraction. Over 50% of the incorporated CLAs were recovered in phosphatidylcholine of CHO cells, but in HepG2 the neutral lipids contained the majority of CLA. The desaturation index (18:1/18:0 and 16:1/16:0) was reduced by CLA-A, but increased by CLA-B, the effects being apparent mostly in raft lipids. The Δ9 desaturase activity was inhibited by CLAs A and C. Unlike LA, which was mostly found in the sn-2 position of phospholipids, most CLAs were also incorporated significantly into the sn-1 position in both cell types. These studies show that the incorporation profiles of CLA isomers differ significantly from that of LA, and this could lead to alterations in membrane function, especially in the raft-associated proteins.►Conjugated linoleic acids (CLA) incorporated into membrane rafts. ►Significant amounts of CLA incorporated into the sn-1 position of phospholipids. ►CLA isomers differ in their inhibition of Δ9 desaturase. ► Trans-10 cis-12 CLA increases cholesterol content of membrane rafts.
Keywords: Abbreviations; CLA; conjugated linoleic acid; DHA; docosahexaenoic acid; EPA; eicosapentaenoic acid; FFA; free fatty acid; LA; linoleic acid; PPAR; peroxisome proliferator-activated receptor; PBS; phosphate-buffered saline; PC; phosphatidylcholine; PE; phosphatidylethanolamine; SCD; stearoyl CoA desaturaseConjugated linoleic acid; Membrane raft; Desaturation index; Positional distribution; Stearoyl CoA desaturase; Raft cholesterol
Influence of N-terminal helix bundle stability on the lipid-binding properties of human apolipoprotein A-I by Masafumi Tanaka; Padmaja Dhanasekaran; David Nguyen; Margaret Nickel; Yuki Takechi; Sissel Lund-Katz; Michael C. Phillips; Hiroyuki Saito (pp. 25-30).
As the principal component of high-density lipoprotein (HDL), apolipoprotein (apo) A-I plays essential roles in lipid transport and metabolism. Because of its intrinsic conformational plasticity and flexibility, the molecular details of the tertiary structure of lipid-free apoA-I have not been fully elucidated. Previously, we demonstrated that the stability of the N-terminal helix bundle structure is modulated by proline substitution at the most hydrophobic region (residues around Y18) in the N-terminal domain. Here we examine the effect of proline substitution at S55 located in another relatively hydrophobic region compared to most of the helix bundle domain to elucidate the influences on the helix bundle structure and lipid interaction. Fluorescence measurements revealed that the S55P mutation had a modest effect on the stability of the bundle structure, indicating that residues around S55 are not pivotally involved in the helix bundle formation, in contrast to the insertion of proline at position 18. Although truncation of the C-terminal domain (Δ190–243) diminishes the lipid binding of apoA-I molecule, the mutation S55P in addition to the C-terminal truncation (S55P/Δ190–243) restored the lipid binding, suggesting that the S55P mutation causes a partial unfolding of the helix bundle to facilitate lipid binding. Furthermore, additional proline substitution at Y18 (Y18P/S55P/Δ190–243), which leads to a drastic unfolding of the helix bundle structure, yielded a greater lipid binding ability. Thus, proline substitutions in the N-terminal domain of apoA-I that destabilized the helix bundle promoted lipid solubilization. These results suggest that not only the hydrophobic C-terminal helical domain but also the stability of the N-terminal helix bundle in apoA-I are important modulators of the spontaneous solubilization of membrane lipids by apoA-I, a process that leads to the generation of nascent HDL particles.►S55P mutation had a modest effect on the stability of the bundle structure of apoA-I. ►S55P/Δ190–243 apoA-I restored the lipid binding despite the C-terminal truncation. ►Destabilized N-terminal helix bundle promoted lipid solubilization. ►Alterations in the stability of apoA-I appear to influence the production of HDL.
Keywords: Abbreviations; ABCA1; ATP-binding cassette transporter A1; ANS; 8-anilino-1-naphthalenesulfonic acid; apo; apolipoprotein; CD; circular dichroism; DMPC; dimyristoylphosphatidylcholine; GdnHCl; guanidine hydrochloride; HDL; high-density lipoprotein; HX; hydrogen–deuterium exchange; ITC; isothermal titration calorimetry; PC; phosphatidylcholine; SUV; small unilamellar vesicle; Trp; tryptophan; WT; wild-typeAmphipathic α-helix; Apolipoprotein A-I; Helix bundle structure; Lipid binding; Proline substitution
Influence of N-terminal helix bundle stability on the lipid-binding properties of human apolipoprotein A-I by Masafumi Tanaka; Padmaja Dhanasekaran; David Nguyen; Margaret Nickel; Yuki Takechi; Sissel Lund-Katz; Michael C. Phillips; Hiroyuki Saito (pp. 25-30).
As the principal component of high-density lipoprotein (HDL), apolipoprotein (apo) A-I plays essential roles in lipid transport and metabolism. Because of its intrinsic conformational plasticity and flexibility, the molecular details of the tertiary structure of lipid-free apoA-I have not been fully elucidated. Previously, we demonstrated that the stability of the N-terminal helix bundle structure is modulated by proline substitution at the most hydrophobic region (residues around Y18) in the N-terminal domain. Here we examine the effect of proline substitution at S55 located in another relatively hydrophobic region compared to most of the helix bundle domain to elucidate the influences on the helix bundle structure and lipid interaction. Fluorescence measurements revealed that the S55P mutation had a modest effect on the stability of the bundle structure, indicating that residues around S55 are not pivotally involved in the helix bundle formation, in contrast to the insertion of proline at position 18. Although truncation of the C-terminal domain (Δ190–243) diminishes the lipid binding of apoA-I molecule, the mutation S55P in addition to the C-terminal truncation (S55P/Δ190–243) restored the lipid binding, suggesting that the S55P mutation causes a partial unfolding of the helix bundle to facilitate lipid binding. Furthermore, additional proline substitution at Y18 (Y18P/S55P/Δ190–243), which leads to a drastic unfolding of the helix bundle structure, yielded a greater lipid binding ability. Thus, proline substitutions in the N-terminal domain of apoA-I that destabilized the helix bundle promoted lipid solubilization. These results suggest that not only the hydrophobic C-terminal helical domain but also the stability of the N-terminal helix bundle in apoA-I are important modulators of the spontaneous solubilization of membrane lipids by apoA-I, a process that leads to the generation of nascent HDL particles.►S55P mutation had a modest effect on the stability of the bundle structure of apoA-I. ►S55P/Δ190–243 apoA-I restored the lipid binding despite the C-terminal truncation. ►Destabilized N-terminal helix bundle promoted lipid solubilization. ►Alterations in the stability of apoA-I appear to influence the production of HDL.
Keywords: Abbreviations; ABCA1; ATP-binding cassette transporter A1; ANS; 8-anilino-1-naphthalenesulfonic acid; apo; apolipoprotein; CD; circular dichroism; DMPC; dimyristoylphosphatidylcholine; GdnHCl; guanidine hydrochloride; HDL; high-density lipoprotein; HX; hydrogen–deuterium exchange; ITC; isothermal titration calorimetry; PC; phosphatidylcholine; SUV; small unilamellar vesicle; Trp; tryptophan; WT; wild-typeAmphipathic α-helix; Apolipoprotein A-I; Helix bundle structure; Lipid binding; Proline substitution
Involvement of low-density lipoprotein receptor-related protein and ABCG1 in stimulation of axonal extension by apoE-containing lipoproteins by Michinori Matsuo; Robert B. Campenot; Dennis E. Vance; Kazumitsu Ueda; Jean E. Vance (pp. 31-38).
Apolipoprotein E (apoE)-containing lipoproteins (LpE) are produced by glial cells in the central nervous system (CNS). When LpE are supplied to distal axons, but not cell bodies, of CNS neurons (retinal ganglion cells) the rate of axonal extension is increased. In this study we have investigated the molecular requirements underlying the stimulatory effect of LpE on axonal extension. We show that enhancement of axonal growth by LpE requires the presence of the low-density lipoprotein receptor-related protein-1 (LRP1) in neurons since RNA silencing of LRP1 in neurons, or antibodies directed against LRP, suppressed the LpE-induced axonal extension. In contrast, an alternative LRP1 ligand, α2-macroglobulin, failed to stimulate axonal extension, suggesting that LpE do not exert their growth-stimulatory effect solely by activation of a LRP1-mediated signaling pathway. In addition, although apoE3-containing LpE enhanced axonal extension, apoE4-containing LpE did not. Over-expression of ABCG1 in rat cortical glial cells resulted in production of LpE that increased the rate of axonal extension to a greater extent than did expression of an inactive, mutant form of ABGC1. Furthermore, reconstituted lipoprotein particles containing apoE3, phosphatidylcholine and sphingomyelin, but not cholesterol, stimulated axonal extension, suggesting that sphingomyelin, but not cholesterol, is involved in the stimulatory effect of LpE. These observations demonstrate that LpE and LRP1 promote axonal extension, and suggest that lipids exported to LpE by ABCG1 are important for the enhancement of axonal extension mediated by LpE.► Glia-derived apoE-containing lipoproteins (LpE) stimulate axonal extension. ► The enhancement of axonal growth by LpE requires LRP1. ► ApoE3-containing LpE stimulate axonal growth, whereas apoE4-containing lipoproteins do not. ► LpE generated by glia over-expressing active ABGG1 enhance axon growth.
Keywords: Abbreviations; ABC; ATP-binding cassette; apo; apolipoprotein; CNS; central nervous system; LpE; apoE-containing lipoproteins; LRP; low-density lipoprotein receptor-related protein; PC; phosphatidylcholine; RGC; retinal ganglion cells; rHDL; reconstituted high-density lipoproteins; SM; sphingomyelinApolipoprotein E; Glia; Neurons; Axonal extension; ABCG1; LDL receptor-related protein; Cholesterol
Involvement of low-density lipoprotein receptor-related protein and ABCG1 in stimulation of axonal extension by apoE-containing lipoproteins by Michinori Matsuo; Robert B. Campenot; Dennis E. Vance; Kazumitsu Ueda; Jean E. Vance (pp. 31-38).
Apolipoprotein E (apoE)-containing lipoproteins (LpE) are produced by glial cells in the central nervous system (CNS). When LpE are supplied to distal axons, but not cell bodies, of CNS neurons (retinal ganglion cells) the rate of axonal extension is increased. In this study we have investigated the molecular requirements underlying the stimulatory effect of LpE on axonal extension. We show that enhancement of axonal growth by LpE requires the presence of the low-density lipoprotein receptor-related protein-1 (LRP1) in neurons since RNA silencing of LRP1 in neurons, or antibodies directed against LRP, suppressed the LpE-induced axonal extension. In contrast, an alternative LRP1 ligand, α2-macroglobulin, failed to stimulate axonal extension, suggesting that LpE do not exert their growth-stimulatory effect solely by activation of a LRP1-mediated signaling pathway. In addition, although apoE3-containing LpE enhanced axonal extension, apoE4-containing LpE did not. Over-expression of ABCG1 in rat cortical glial cells resulted in production of LpE that increased the rate of axonal extension to a greater extent than did expression of an inactive, mutant form of ABGC1. Furthermore, reconstituted lipoprotein particles containing apoE3, phosphatidylcholine and sphingomyelin, but not cholesterol, stimulated axonal extension, suggesting that sphingomyelin, but not cholesterol, is involved in the stimulatory effect of LpE. These observations demonstrate that LpE and LRP1 promote axonal extension, and suggest that lipids exported to LpE by ABCG1 are important for the enhancement of axonal extension mediated by LpE.► Glia-derived apoE-containing lipoproteins (LpE) stimulate axonal extension. ► The enhancement of axonal growth by LpE requires LRP1. ► ApoE3-containing LpE stimulate axonal growth, whereas apoE4-containing lipoproteins do not. ► LpE generated by glia over-expressing active ABGG1 enhance axon growth.
Keywords: Abbreviations; ABC; ATP-binding cassette; apo; apolipoprotein; CNS; central nervous system; LpE; apoE-containing lipoproteins; LRP; low-density lipoprotein receptor-related protein; PC; phosphatidylcholine; RGC; retinal ganglion cells; rHDL; reconstituted high-density lipoproteins; SM; sphingomyelinApolipoprotein E; Glia; Neurons; Axonal extension; ABCG1; LDL receptor-related protein; Cholesterol
Mouse serum paraoxonase-1 lactonase activity is specific for medium-chain length fatty acid lactones by Philip W. Connelly; Clive M. Picardo; Philip M. Potter; John F. Teiber; Graham F. Maguire; Dominic S. Ng (pp. 39-45).
Recent studies suggest that paraoxonase-1 (PON1), complexed with high-density lipoproteins, is the major lactonase in the circulation. Using 5-hydroxy eicosatetraenoate δ-lactone (5-HETEL) as the substrate, we observed lactonase activity in serum from Pon1−/− mice. However, 6–12 carbon fatty acid γ- and δ-lactones were not hydrolyzed in serum from Pon1−/− mice. Serum from both wild-type and Pon1−/− mice contained a lactonase activity towards 5-HETEL and 3-oxo-dodecanoyl-homoserine lactone that was resistant to inactivation by EDTA. This lactonase activity was sensitive to the serine esterase inhibitor phenyl methyl sulfonyl fluoride and co-eluted with carboxylesterase activity by size-exclusion chromatography. Analysis of serum from the Es1e mouse strain, which has a deficiency in the carboxylesterase, ES-1, proved that this activity was due to ES-1. PON1 activity predominated at early time points (30s), whereas both PON1 and ES-1 contributed equally at later time points (15min). When both PON1 and ES-1 were inhibited, 5-HETEL was stable in mouse serum. Thus, while long-chain fatty acid lactones are substrates for PON1, they can be hydrolyzed by ES-1 at neutral pH. In contrast, medium-chain length fatty acid lactones are stable in mouse serum in the absence of PON1, suggesting that PON1 plays a specific role in the metabolism of these compounds.► Mouse serum contains two lactonase activities, paraoxonase-1 and carboxylesterase, that can hydrolyze 5-hydroxyeicosatetraenoate lactone and 3-oxo-C12-homoserine lactone. ► Only the EDTA-sensitive paraoxonase-1 lactonase is detectable in human serum. ► In the absence of lactonase activities, fatty acid lactones are stable in a serum milieu. ► Hydrolysis of medium-chain fatty acid lactones in serum is specific for paraoxonase-1.
Keywords: Abbreviations; DTPA; diethylenetriamine pentaacetic acid; EDTA; ethylenediaminetetraacetic acid; FPLC; Fast Protein Liquid Chromatography; HETE; hydroxyeicosatetraenoate; HETEL; hydroxyeicosatetraenoate delta lactone; HDL; high-density lipoprotein; MOPS; 3-(; N; -morpholino)propanesulfonic acid; PMSF; phenylmethylsulfonyl fluoride; PON1; paraoxonase-1Paraoxonase-1; Carboxylesterase; Lactone; Lactonase; High-density lipoprotein; ES-1; Mouse serum; δ-Lactones; γ-Lactones
Mouse serum paraoxonase-1 lactonase activity is specific for medium-chain length fatty acid lactones by Philip W. Connelly; Clive M. Picardo; Philip M. Potter; John F. Teiber; Graham F. Maguire; Dominic S. Ng (pp. 39-45).
Recent studies suggest that paraoxonase-1 (PON1), complexed with high-density lipoproteins, is the major lactonase in the circulation. Using 5-hydroxy eicosatetraenoate δ-lactone (5-HETEL) as the substrate, we observed lactonase activity in serum from Pon1−/− mice. However, 6–12 carbon fatty acid γ- and δ-lactones were not hydrolyzed in serum from Pon1−/− mice. Serum from both wild-type and Pon1−/− mice contained a lactonase activity towards 5-HETEL and 3-oxo-dodecanoyl-homoserine lactone that was resistant to inactivation by EDTA. This lactonase activity was sensitive to the serine esterase inhibitor phenyl methyl sulfonyl fluoride and co-eluted with carboxylesterase activity by size-exclusion chromatography. Analysis of serum from the Es1e mouse strain, which has a deficiency in the carboxylesterase, ES-1, proved that this activity was due to ES-1. PON1 activity predominated at early time points (30s), whereas both PON1 and ES-1 contributed equally at later time points (15min). When both PON1 and ES-1 were inhibited, 5-HETEL was stable in mouse serum. Thus, while long-chain fatty acid lactones are substrates for PON1, they can be hydrolyzed by ES-1 at neutral pH. In contrast, medium-chain length fatty acid lactones are stable in mouse serum in the absence of PON1, suggesting that PON1 plays a specific role in the metabolism of these compounds.► Mouse serum contains two lactonase activities, paraoxonase-1 and carboxylesterase, that can hydrolyze 5-hydroxyeicosatetraenoate lactone and 3-oxo-C12-homoserine lactone. ► Only the EDTA-sensitive paraoxonase-1 lactonase is detectable in human serum. ► In the absence of lactonase activities, fatty acid lactones are stable in a serum milieu. ► Hydrolysis of medium-chain fatty acid lactones in serum is specific for paraoxonase-1.
Keywords: Abbreviations; DTPA; diethylenetriamine pentaacetic acid; EDTA; ethylenediaminetetraacetic acid; FPLC; Fast Protein Liquid Chromatography; HETE; hydroxyeicosatetraenoate; HETEL; hydroxyeicosatetraenoate delta lactone; HDL; high-density lipoprotein; MOPS; 3-(; N; -morpholino)propanesulfonic acid; PMSF; phenylmethylsulfonyl fluoride; PON1; paraoxonase-1Paraoxonase-1; Carboxylesterase; Lactone; Lactonase; High-density lipoprotein; ES-1; Mouse serum; δ-Lactones; γ-Lactones
Membrane lipid composition differentially modulates the function of human plasma platelet activating factor-acetylhydrolase by Abhay H. Pande; Vikas A. Tillu (pp. 46-56).
Human plasma platelet activating factor-acetylhydrolase (HpPAF-AH) is a calcium-independent phospholipase that catalyzes the hydrolysis of ester bond at the sn-2 position of phospholipid substrates. The enzyme belongs to group VIIA of the phospholipase A2 superfamily and is associated with the lipids. Circulating form of HpPAF-AH resides on the lipoprotein particles and acts on a wide variety of substrates, including oxidized phospholipids. In this study we have characterized the effect of lipid composition of the membrane vesicles on the function of purified HpPAF-AH. Lipid composition of the vesicles was varied by incorporating varying amounts of cholesterol in the matrix phospholipids, POPC and DPPC, and its effect on the membrane binding, membrane penetration and the activity of the enzyme was determined. Physicochemical properties of the phospholipid vesicles were characterized by using different fluorescent probes. For the first time our results show that (a) membrane binding of HpPAF-AH increases the activity of enzyme (interfacial activation) and (b) lipid composition of membrane vesicles, by changing the physicochemical properties, differentially modulates the binding, partial membrane penetration and the activity of the enzyme.► Human plasma platelet activating factor-acetylhydrolase (HpPAF-AH) enzyme is associated with the lipids. ► Membrane binding of HpPAF-AH significantly increases the activity of the enzyme. ► The enzyme shows exquisite sensitivity to the lipid composition and the physical properties of the membrane.
Keywords: Abbreviations; Br; 2; PC; 1-palmitoyl-2-stearoyl-dibromo-; sn; -glycero-3-phosphocholine; Chol; cholesterol; DPPC; 1,2-dipalmitoyl-; sn; -glycero-3-phosphocholine; F-DHPE; N-(Fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-; sn; -glycero-3-phosphoethanolamine; GP; generalized polarizations; HDL; high density lipoprotein; HpPAF-AH; human plasma platelet activating factor-acetylhydrolase; Laurdan; 2-dimethylamino-(6-lauroyl)-naphthalene; LDL; low-density lipoprotein; Ox-PL; oxidized phospholipids; POPC; 1-palmitoyl-2-oleoyl-; sn; -glycero-3-phosphocholine; Py-PE; 1,2-dioleoyl-; sn; -glycero-3-phosphoethanolamine-N-(1-pyrenesulfonyl); PLA; 2; phospholipase A; 2; SUV; small unilamellar vesicle; Trp; tryptophanEnzyme activity; Fluorescence spectroscopy; Acrylamide quenching; Depth-dependent fluorescence quenching; Laurdan generalized parameter; Lp-PLA; 2
Membrane lipid composition differentially modulates the function of human plasma platelet activating factor-acetylhydrolase by Abhay H. Pande; Vikas A. Tillu (pp. 46-56).
Human plasma platelet activating factor-acetylhydrolase (HpPAF-AH) is a calcium-independent phospholipase that catalyzes the hydrolysis of ester bond at the sn-2 position of phospholipid substrates. The enzyme belongs to group VIIA of the phospholipase A2 superfamily and is associated with the lipids. Circulating form of HpPAF-AH resides on the lipoprotein particles and acts on a wide variety of substrates, including oxidized phospholipids. In this study we have characterized the effect of lipid composition of the membrane vesicles on the function of purified HpPAF-AH. Lipid composition of the vesicles was varied by incorporating varying amounts of cholesterol in the matrix phospholipids, POPC and DPPC, and its effect on the membrane binding, membrane penetration and the activity of the enzyme was determined. Physicochemical properties of the phospholipid vesicles were characterized by using different fluorescent probes. For the first time our results show that (a) membrane binding of HpPAF-AH increases the activity of enzyme (interfacial activation) and (b) lipid composition of membrane vesicles, by changing the physicochemical properties, differentially modulates the binding, partial membrane penetration and the activity of the enzyme.► Human plasma platelet activating factor-acetylhydrolase (HpPAF-AH) enzyme is associated with the lipids. ► Membrane binding of HpPAF-AH significantly increases the activity of the enzyme. ► The enzyme shows exquisite sensitivity to the lipid composition and the physical properties of the membrane.
Keywords: Abbreviations; Br; 2; PC; 1-palmitoyl-2-stearoyl-dibromo-; sn; -glycero-3-phosphocholine; Chol; cholesterol; DPPC; 1,2-dipalmitoyl-; sn; -glycero-3-phosphocholine; F-DHPE; N-(Fluorescein-5-thiocarbamoyl)-1,2-dihexadecanoyl-; sn; -glycero-3-phosphoethanolamine; GP; generalized polarizations; HDL; high density lipoprotein; HpPAF-AH; human plasma platelet activating factor-acetylhydrolase; Laurdan; 2-dimethylamino-(6-lauroyl)-naphthalene; LDL; low-density lipoprotein; Ox-PL; oxidized phospholipids; POPC; 1-palmitoyl-2-oleoyl-; sn; -glycero-3-phosphocholine; Py-PE; 1,2-dioleoyl-; sn; -glycero-3-phosphoethanolamine-N-(1-pyrenesulfonyl); PLA; 2; phospholipase A; 2; SUV; small unilamellar vesicle; Trp; tryptophanEnzyme activity; Fluorescence spectroscopy; Acrylamide quenching; Depth-dependent fluorescence quenching; Laurdan generalized parameter; Lp-PLA; 2
Erratum to “Facilitation of fatty acid uptake by CD36 in insulin-producing cells reduces fatty-acid-induced insulin secretion and glucose regulation of fatty acid oxidation” [Biochim. Biophys. Acta 1801 (2010) 191–197]
by Tina Wallin; Zuheng Ma; Hirotaka Ogata; Jorgensen Ingrid Hals Jørgensen; Mariella Iezzi; Haiyan Wang; Claes B. Wollheim; Bjorklund Anneli Björklund (pp. 57-57).
Erratum to “Facilitation of fatty acid uptake by CD36 in insulin-producing cells reduces fatty-acid-induced insulin secretion and glucose regulation of fatty acid oxidation” [Biochim. Biophys. Acta 1801 (2010) 191–197]
by Tina Wallin; Zuheng Ma; Hirotaka Ogata; Jorgensen Ingrid Hals Jørgensen; Mariella Iezzi; Haiyan Wang; Claes B. Wollheim; Bjorklund Anneli Björklund (pp. 57-57).