Total Lipid Synthesis Research Articles

Bidirectional Regulation of Sodium Acetate on Macrophage Activity and Its Role in Lipid Metabolism of Hepatocytes

Short-chain fatty acids (SCFAs) are important metabolites of the intestinal flora that are closely related to the development of non-alcoholic fatty liver disease (NAFLD). Moreover, studies have shown that macrophages have an important role in the progression of NAFLD and that a dose effect of sodium acetate (NaA) on the regulation of macrophage activity alleviates NAFLD; however, the exact mechanism of action remains unclear. This study aimed to assess the effect and mechanism of NaA on regulating the activity of macrophages. RAW264.7 and Kupffer cells cell lines were treated with LPS and different concentrations of NaA (0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, and 5 mM). Low doses of NaA (0.1 mM, NaA-L) significantly increased the expression of inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin 1 beta (IL-1β); it also increased the phosphorylation of inflammatory proteins nuclear factor-κB p65 (NF-κB p65) and c-Jun (p < 0.05), and the M1 polarization ratio of RAW264.7 or Kupffer cells. Contrary, a high concentration of NaA (2 mM, NaA-H) reduced the inflammatory responses of macrophages. Mechanistically, high doses of NaA increased intracellular acetate concentration in macrophages, while a low dose had the opposite effect, consisting of the trend of changes in regulated macrophage activity. Besides, GPR43 and/or HDACs were not involved in the regulation of macrophage activity by NaA. NaA significantly increased total intracellular cholesterol (TC), triglycerides (TG), and lipid synthesis gene expression levels in macrophages and hepatocytes at either high or low concentrations. Furthermore, NaA regulated the intracellular AMP/ATP ratio and AMPK activity, achieving a bidirectional regulation of macrophage activity, in which the PPARγ/UCP2/AMPK/iNOS/IκBα/NF-κB signaling pathway has an important role. In addition, NaA can regulate lipid accumulation in hepatocytes by NaA-driven macrophage factors through the above-mentioned mechanism. The results revealed that the mode of NaA bi-directionally regulating the macrophages further affects hepatocyte lipid accumulation.

LPGAT1 controls the stearate/palmitate ratio of phosphatidylethanolamine and phosphatidylcholine in sn-1 specific remodeling

Most mammalian phospholipids contain a saturated fatty acid at the sn-1 carbon atom and an unsaturated fatty acid at the sn-2 carbon atom of the glycerol backbone group. While the sn-2 linked chains undergo extensive remodeling by deacylation and reacylation (Lands cycle), it is not known how the composition of saturated fatty acids is controlled at the sn-1 position. Here, we demonstrate that lysophosphatidylglycerol acyltransferase 1 (LPGAT1) is an sn-1 specific acyltransferase that controls the stearate/palmitate ratio of phosphatidylethanolamine (PE) and phosphatidylcholine. Bacterially expressed murine LPGAT1 transferred saturated acyl-CoAs specifically into the sn-1 position of lysophosphatidylethanolamine (LPE) rather than lysophosphatidylglycerol and preferred stearoyl-CoA over palmitoyl-CoA as the substrate. In addition, genetic ablation of LPGAT1 in mice abolished 1-LPE:stearoyl-CoA acyltransferase activity and caused a shift from stearate to palmitate species in PE, dimethyl-PE, and phosphatidylcholine. Lysophosphatidylglycerol acyltransferase 1 KO mice were leaner and had a shorter life span than their littermate controls. Finally, we show that total lipid synthesis was reduced in isolated hepatocytes of LPGAT1 knockout mice. Thus, we conclude that LPGAT1 is an sn-1 specific LPE acyltransferase that controls the stearate/palmitate homeostasis of PE and the metabolites of the PE methylation pathway and that LPGAT1 plays a central role in the regulation of lipid biosynthesis with implications for body fat content and longevity.

Changes in Lipid Composition of Streptomyces massasporeus CNMN-AC-06 Biomass after Long-Term Storage

Aim. The aim of the research was to determine changes in content and composition of Streptomyces massasporeus CNMN-Ac-06 strain biomass lipid complex during cultivation in various nutrient media after long-term storage. Methods. To obtain the inoculum, S. massasporeus CNMN-Ac-06 strain was cultivated in Dulaney medium. For biomass accumulation, inoculum was cultivated in M-I, SP-I and SP-III. The amount of biomass was determined on the 5th day of culture growth. Intracellular lipids were extracted from streptomycete biomass by Folch method modified in our laboratory. The qualitative and quantitative characteristic of lipid complex composition was determined by thin-layer chromatography. 10% solution of phosphomolybdic acid in ethanol was used as developer. The quantity of individual lipid fractions was determined by densitometry. Results. The studied strain was cultivated in three nutrient liquid media. Cultivation of the strain in M-I medium increases the biomass yield up to 11.53 g/l. In case of SP-III, on the contrary, at the beginning of research, the biomass yield was higher than after storage. The best result of the synthesis of total lipids was noted after SP-I medium use. Analysis of the quantity of main lipid fractions in the biomass showed that the maximum percentage of phospholipids was 12.15% after cultivation in SP-I medium. The amount of sterols in biomass was: in M-I medium – 8.96%, in SP-I medium – 12.15% and in SP-III medium – 14.17%. The smallest amount of mono- and diglycerides in the total lipids of the biomass of this strain was observed after cultivation in SP-III medium, sterol esters in SP-I medium, and waxes in M-I medium. The studies shown that the highest amount of biomass of the strain S. massasporeus CNMN-Ac-06 was noted after cultivation in nutrient medium M-I (11.53 g/l), and the maximum percentage of total lipids after cultivation in medium SP-I (15.85%). Conclusions. The experiments shown that in order to increase the biomass of S. massasporeus CNMN-Ac-06 strain, it is the best to cultivate this microorganism in complex SP-I medium. But, a significant amount of such physiologically important lipid fractions like phospholipids was obtained in SP-I medium and sterols in SP-I and SP-III media.

Efficient Total Synthesis of Lipid I and Lipid II Analogues

Efficient Total Synthesis of Lipid I and Lipid II Analogues

Lipid composition of biomass of streptomyces under the effect of electromagnetic radiation of the millimeter range of low intensity

The influence of electromagnetic radiation of the mm range of low intensity on lipid fractions in the biomass of strains Streptomyces canosus CNMN-Ac-02 and Streptomyces massasporeus CNMN-AC-06 was studied. The investigations showed different reactions to the impact of the physical factor, which can be explained by individual features of the studied strains. A decrease in total amount of lipids, and a sharp increase of the amount of phospholipids and sterols in biomass of S. canosus CNMN-Ac-02 occurred, whereas in the biomass of Streptomyces massasporeus CNMN-Ac-06, the synthesis of total lipids significantly increased, and the amount of phospholipids and sterols increased slightly.

Oleaginous yeast Cryptococcus curvatus exhibits interplay between biosynthesis of intracellular sugars and lipids

AbstractPatterns of the biosynthesis of major metabolites of the oleaginous yeast Cryptococcus curvatus NRRL Y‐1511 were investigated during cultivation on sugar‐based media. When lactose or sucrose was employed as substrate under nitrogen‐limited conditions, the yeast strain accumulated high quantities of intra‐cellular total sugars (ITS) at the beginning of fermentation (up to 68% w/w), with ITS values progressively decreasing to 20%, w/w, at the end of the fermentation. Decrease in ITS content and consumption of extra‐cellular lactose led to a subsequent rise in lipid accumulation, reaching 29.8% in dry cell weight at 80 g/L of initial lactose concentration. Lactose was a more favorable substrate for lipid production than sucrose. In nitrogen‐excess conditions, ITS were produced in significant quantities despite the continuous presence of nitrogen in the medium. Growth on lactose was not followed by secretion of extra‐cellular β‐galactosidase. High quantities of extra‐cellular invertase were observed during growth on sucrose. The composition of ITS was highly influenced by the sugar used as substrate. Cellular lipids contained mainly palmitic and to lesser extent linoleic and stearic acids. This is the first report in the literature that demonstrates the interplay between the biosynthesis of intra‐cellular total sugars and lipid synthesis for oleaginous yeast strains.Practical applications: Cryptococcus curvatus represents a promising candidate for the successful production of microbial lipids and polysaccharides during growth on several types of low‐cost sugars utilized as substrates. Thus, C. curvatus could be used to produce a variety of metabolites useful for industrial biotechnology.Interplay between the biosynthesis of intra‐cellular total sugars produced per unit of dry weight (YITS/X %, w/w) and intra‐cellular lipids produced per unit of dry weight (YL/X %, w/w) of Cryptococcus curvatus, during growth on lactose, under nitrogen‐limited conditions.

Abstract 1905: Influence of serum and oxygen on lipid biosynthesis and energy metabolism in murine glioblastoma.

Abstract Glucose and glutamine are essential energy metabolites for brain tumor growth and survival under both normoxic and hypoxic conditions. Carbons derived from either metabolite can be used for lipid synthesis. Here, we used uniformly labeled C14-glucose and C14-glutamine to examine de novo lipid synthesis in the VM-M3 murine glioblastoma cells. The major lipids synthesized included phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), phosphatidic acid (PA), cholesterol (Chol), and cardiolipin (CL). De novo lipid synthesis was greater with glucose than with glutamine as the metabolic substrate under normoxia. Conversely, glutamine was the preferred substrate for lipid synthesis under anoxia. Lactate was produced largely from glucose carbons with minimal lactate derived from glutamine. Total lipid synthesis, using either glucose or glutamine, was greater in media without serum than in media containing 10% FBS under normoxia. Significant triglyceride accumulation was observed only under anoxia. Our findings show that lipid biosynthesis using glucose or glutamine is dependent on the type of growth environment, and that the VM-M3 glioblastoma cells can grow under anoxia only through acquisition of lipids, especially cholesterol, from serum. Supported in part from Boston College Res. Expense Fund. Citation Format: Nathan Ta, Thomas Seyfried. Influence of serum and oxygen on lipid biosynthesis and energy metabolism in murine glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2013-1905

Zilpaterol hydrochloride alters abundance of β-adrenergic receptors in bovine muscle cells but has little effect on de novo fatty acid biosynthesis in bovine subcutaneous adipose tissue explants

We predicted that zilpaterol hydrochloride (ZH), a β-adrenergic receptor (AR) agonist, would depress mRNA and protein abundance of β-AR in bovine satellite cells. We also predicted that ZH would decrease total lipid synthesis in bovine adipose tissue. Bovine satellite cells isolated from the semimembranosus muscle were plated on tissue culture plates coated with reduced growth factor matrigel or collagen. Real-time quantitative PCR was used to measure specific gene expression after 48 h of ZH exposure in proliferating satellite cells and fused myoblasts. There was no effect of ZH dose on [(3)H]thymidine incorporation into DNA in proliferating myoblasts. Zilpaterol hydrochloride at 1 µM decreased (P < 0.05) β1-AR mRNA, and 0.01 and 1 µM ZH decreased (P < 0.05) β2-AR and β3-AR mRNA in myoblasts. The expression of IGF-I mRNA tended to increase (P = 0.07) with 1 µM ZH. There was no effect (P > 0.10) of ZH on the β-AR or IGF-I gene expression in fused myotube cultures at 192 h or on fusion percentage. The β2-AR antagonist ICI-118, 551 at 0.1 µM attenuated (P < 0.05) the effect of 0.1 µM ZH to reduce expression of β1- and β2-AR mRNA. The combination of 0.01 µM ZH and 0.1 µM ICI-118, 551 caused an increase (P < 0.05) in β1-AR gene expression. There was no effect (P > 0.10) of ICI-118, 551 or ZH on β3-AR or IGF-I. Western blot analysis revealed that the protein content of β2-AR in ZH-treated myotube cultures decreased (P < 0.05) relative to control. Total lipid synthesis from acetate was increased by ZH in bovine subcutaneous adipose tissue explants in the absence of theophylline but was decreased by ZH when theophylline was included in the incubation medium. These data indicate that ZH alters mRNA and protein concentrations of β-AR in satellite cell cultures, which in turn could affect responsiveness of cells to prolonged ZH exposure in vivo. Similar to other β-adrenergic agonists, ZH had only modest effects on lipid metabolism in adipose tissue explants.

Overexpression of long chain acyl‐CoA synthetase 1 increases fatty acid oxidation in primary human skeletal myotubes

In liver, long chain acyl-CoA synthetase (ACSL) activates fatty acids and plays a key role in their partitioning toward oxidation or storage, but little data exist from human skeletal muscle. The purpose of this study was to determine the effects of ACSL-1 overexpression (ACSL-1OEX) on fatty acid oxidation (FAO; CO2 production and O2 consumption) and total lipid synthesis in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (N=5) were transfected with ACSL-1 plasmid DNA, differentiated into myotubes and harvested (7 d) to measure FAO ([1-14C] palmitate), or permeabilized for determination of mitochondrial respiration. The protein levels of ACSL-1 were 38% higher in ACSL-1OEX HSKMC. Both complete (CO2) and incomplete (ASM) FAO increased by approximately 2-fold (P < 0.05). In permeabilized HSKMC supported by fatty acids, both maximal ADP-stimulated (state 3) and maximal uncoupled (FCCP-linked) oxygen consumption were significantly increased in ACSL-1OEX (P<0.05), implying greater fatty acid catabolic flux capacity. However, ACSL-1 overexpression did not affect total lipid synthesis. These data demonstrate that ACSL-1 overexpression in HSKMC increases FAO as well as maximal stimulated (ADP & FCCP) respiration without affecting total lipid storage, suggesting that activation of fatty acids is at least partially rate limiting for fatty acid oxidation. Supported by NIH DK075880 (RNC) and DK073488 (PDN).

Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment

Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD+ salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease.

Adipocytes with increased hexosamine flux exhibit insulin resistance, increased glucose uptake, and increased synthesis and storage of lipid

The hexosamine signaling pathway has been shown to serve a nutrient-sensing function. We have previously shown that overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine-fructose-6-phosphate amidotransferase) in adipose tissue of transgenic mice results in skeletal muscle insulin resistance and altered regulation of leptin and adiponectin. To dissect the pathways by which the hexosamine pathway affects fuel storage and energy homeostasis, we have examined the characteristics of adipocytes from these animals. After 3 mo of age, epididymal fat pads from adult transgenic animals are 42% heavier (P = 0.003) and individual adipocytes are 23% larger in diameter (P < 0.05) than those from littermate wild-type controls. Isolated adipocytes from transgenic mice are insulin resistant, with a 2.5-fold increase in the ED50 for stimulation of 2-deoxy-D-glucose uptake. However, maximal insulin-stimulated glucose uptake is increased in transgenic adipocytes by 39% (P < 0.05). This upregulation of glucose uptake was associated with a 41% increase in the expression of GLUT4 mRNA and a 28% increase in GLUT4 protein in transgenics compared with controls (P < 0.05). GLUT1 mRNA and protein did not significantly differ between fasted control and transgenics. Total lipid synthesis was also increased in epididymal adipocytes from transgenic animals by 206% compared with controls (P < 0.05). Fatty acid oxidation was increased 1.6-fold in the transgenic adipocytes (P < 0.05). We conclude that the hexosamine signaling pathway upregulates fat storage in adipocytes in states of carbohydrate excess, in part by increasing GLUT4 and glucose uptake and by augmenting fatty acid synthesis.

Porcine leptin inhibits lipogenesis in porcine adipocytes.

The present study examined whether recombinant porcine leptin alters lipid synthesis in porcine adipocytes. The stromal-vascular cell fraction of neonatal pig subcutaneous adipose tissue was isolated by collagenase digestion, filtration, and subsequent centrifugation. These cells were seeded on 25-cm2 tissue culture flasks and proliferated to confluency in 10% (vol/vol) fetal bovine serum in Dulbecco's modified Eagle medium/F12 (DMEM/F12, 50:50). Cultures were differentiated using 2.5% pig serum (vol/vol), 10 nM insulin, 100 nM hydrocortisone. After 7 d of lipid filling, cultures were washed free of this medium, incubated overnight in DMEM/F12 containing 2% pig serum (vol/vol), and then used for experiments. Acute experiments assessed U-(14)C-glucose or 1-(14)C-palmitate metabolism in cultures exposed to porcine leptin (0 to 1,000 ng/mL medium) for 4 h. Chronic experiments used cultures incubated with 0 to 1,000 ng porcine leptin/mL medium for 44 h before measurements of U-(14)C-glucose and 1-(14)C-palmitate oxidation and incorporation into lipid. Another experiment examined whether chronic leptin treatment alters insulin responsiveness by including insulin (10 nM) with incubations containing leptin. Leptin had no acute effects on glucose oxidation or conversion to lipid (P > 0.05). Acute leptin treatment decreased palmitate incorporation into lipids up to 45% (P < 0.05). Chronic leptin exposure decreased glucose oxidation (21%), total lipid synthesis (18%), and fatty acid synthesis (23%) at 100 ng/mL medium (P < 0.05). Insulin increased rates of glucose oxidation, total lipid, and fatty acid synthesis (P < 0.05); however, chronic exposure to 10 ng leptin/mL medium decreased the effectiveness of 10 nM insulin to affect these measures of glucose metabolism by approximately 18 to 46% (P < 0.05). Higher concentrations of leptin inhibited all effects of insulin on glucose metabolism (P < 0.05). Chronic exposure to leptin increased palmitate oxidation by 36% (P < 0.05). Chronic leptin exposure decreased palmitate incorporation into total lipids by 40% at 100 ng/mL medium (P < 0.05). Lipoprotein lipase activity was not affected (P > 0.05) by leptin. These data indicate that leptin functions to promote partitioning of energy away from lipid accretion within porcine adipose tissue by inhibiting glucose oxidation and lipogenesis indirectly, by decreasing insulin-mediated stimulation of lipogenesis, and by stimulating fatty acid oxidation while inhibiting fatty acid esterification.

Porcine leptin alters isolated adipocyte glucose and fatty acid metabolism

This study examined if leptin can acutely affect glucose or fatty acid metabolism in pig adipocytes and whether leptin’s actions on lipogenesis are manifested through interaction with insulin or growth hormone. Subcutaneous adipose tissue was obtained from ∼55 kg crossbred barrows at the USDA abattoir. Isolated adipocytes were prepared using a collagenase procedure. Experiments assessed U- 14 C -glucose or 1- 14 C -palmitate metabolism in isolated adipocytes exposed to: basal medium (control), 100 nM insulin, 100 ng/ml porcine growth hormone, 100 ng/ml recombinant porcine leptin, and combinations of these hormones. Treatments were performed in triplicate and the experiment was repeated with adipocytes isolated from five different animals. Cell aliquots (250 μl) were added to 1 ml of incubation medium, then incubated for 2 h at 37 °C for measurement of glucose and palmitate oxidation or incorporation into lipid. Incubation of isolated adipocytes with insulin increased glucose oxidation rate by 18% ( P<0.05), while neither growth hormone nor leptin affected glucose oxidation ( P>0.5). Total lipid synthesis from glucose was increased by approximately 25% by 100 nM insulin or insulin+growth hormone ( P<0.05). Insulin+leptin reduced the insulin response by 37% ( P<0.05). The combination of all three hormones increased total lipid synthesis by 35%, relative to controls ( P<0.05), a rate similar to insulin alone. Fatty acid synthesis was elevated by insulin (32%, P<0.05) or growth hormone (13%, P<0.05). Leptin had no effect on fatty acid synthesis ( P>0.05). Leptin reduced the esterification rate by 10% ( P<0.05). Growth hormone and insulin could overcome leptin’s inhibition of palmitate esterification ( P>0.05).

Leukotrienantagonisten bei atopischen Erkrankungen und Akne

Leukotriene, Produkte des Arachidonsäurestoffwechsels, spielen eine zentrale Rolle bei der Entwicklung entzündlicher Prozesse. Durch die katalytische Wirkung der 5-Lipoxygenase entstehen Leukotrien-B4, eine stark chemoattraktive Substanz, und die Entzündungsmediatoren Cysteinyl-Leukotriene C4, D4 und E4. Leukotriene binden sich an spezifische G-Protein-gebundene Rezeptoren, nämlich den hochaffinen, Leukotrien-B4-spezifischen B-LT1-Rezeptor der Leukozyten, den Leukotrien-B4-spezifischen B-LT2-Rezeptor mit breiter Gewebeverteilung und niedriger Affinität, den LTC4- und LTD4-spezifischen Cysteinyl-LT1-Rezeptor bei glatten Muskelzellen und Endothelzellen postkapillärer Venolen und den Cysteinyl-LT2-Rezeptor bei Gehirn, Milz, Purkinje-Herzfibern und Nebennierenrinde. Darüber hinaus sind bestimmte Leukotriene Liganden der Peroxisomproliferation-aktivierenden Rezeptoren (PPAR). Die Entdeckung des Wirkmechanismus der Leukotriene führte zur Entwicklung von Wirkstoffen, die Schlüsselschritte des 5-Lipoxygenase-Synthesewegs beeinflussen, nämlich 5-Lipoxygenase-Inhibitoren, B-LT2-Rezeptor-Antagonisten, FLAP-Inhibitoren und Cysteinyl-LT1-Rezeptorblocker. Ihre Wirkung wurde auf verschiedene entzündliche und/oder hyperproliferative Hautkrankheiten untersucht. Der Einsatz der Leukotrienantagonisten bei atopischen Erkrankungen und bei der Akne ist der Gegenstand dieser Übersicht. Niedrig dosierte inhalative Glukokortikoide (äquivalent zu 400 µg/d Beclometason) scheinen in der Behandlung von mildem bis mäßigem Asthma bei Erwachsenen effektiver als Leukotrienantagonisten zu sein. Für die Behandlung des kindlichen Asthmas liegen keine ausreichenden Daten vor. Die Zugabe von Leukotrienantagonisten zu inhalativen Glukokortikoiden kann ein Asthma bronchiale in bescheidenem Ausmaß bessern, jedoch ist sie nicht geeignet, um Glukokortikoide einzusparen. Bei der allergischen Rhinitis/Rhinokonjunktivitis sind Leukotrienantagonisten vergleichbar wirksam wie die nichtsedierenden Antihistaminika und weniger wirksam als intranasale Glukokortikoide. Die Kombination eines Leukotrienantagonisten und eines Antihistaminikums ist nicht wirksamer als eine der beiden Substanzen allein. Die Datenlage der Therapie der atopischen Dermatitis mit Leukotrienantagonisten ist noch schwach, allerdings zeigt sich wie bei den anderen Erkrankungen des Atopiekreises eine mäßige aber signifikante Besserung der Erkrankung im Vergleich zu Plazebo. Die systemische Therapie der Akne mit Leukotrienantagonisten ist diesen Substanzen vorbehalten, die gleichzeitig PPAR-Liganden sind. Besonders geeignet sind 5-Lipoxygenase-Inhibitoren/PPARα-Liganden, z. B. Zileuton, die zur Abnahme der gesamten Talglipide und der pro-inflammatorischen Lipidfraktionen sowie zur signifikanten Reduktion der entzündlichen Akneläsionen führen.

ChemInform Abstract: The First Total Synthesis of Lipid II: The Final Monomeric Intermediate in Bacterial Cell Wall Biosynthesis.

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Synthesis of hybrid lipid probes: derivatives of phosphatidylethanolamine-extended phosphatidylinositol 4,5-bisphosphate (Pea-PIP(2)).

The total asymmetric synthesis of a novel hybrid lipid possessing a 2,3-diacylthreitol backbone, rather than a 1,2-diacylglycerol backbone, is described. The title compound, Pea-PIP(2), possesses a phosphatidylethanolamine (PE) headgroup at the 1-position and a phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) headgroup at the 4-position. Reporters (biotin, fluorophores, spin label) were covalently attached to the free amino group of the PE, such that these reporters were targeted to the lipid-water interface. The diacyl moieties allow incorporation of Pea-PIP(2) into a lipid bilayer, while the PtdIns(4,5)P(2) moiety in the aqueous layer was specifically recognized by PtdIns(4,5)P(2)-specific binding proteins.

The first total synthesis of lipid II: the final monomeric intermediate in bacterial cell wall biosynthesis.

Bacterial peptidoglycan is composed of a network of beta-[1,4]-linked glyan strands that are cross-linked through pendant peptide chains. The final product, the murein sacculus, is a single, covalently closed macromolecule that precisely defines the size and shape of the bacterial cell. The recent increase in bacterial resistance to cell wall active agents has led to a resurgence of activity directed toward improving our understanding of the resistance mechanisms at the molecular level. The biosynthetic enzymes and their natural substrates can be invaluable tools in this endeavor. While modern experimental techniques have led to isolation and purification of the biosynthetic enzymes utilized in peptidoglycan biosynthesis, securing useful quantities of their requisite substrates from natural substrates has remained problematic. In an effort to address this issue, we report the first total synthesis of lipid II (4), the final monomeric intermediate utilized by Gram positive bacteria for peptidoglycan biosynthesis.

Lipid II: total synthesis of the bacterial cell wall precursor and utilization as a substrate for glycosyltransfer and transpeptidation by penicillin binding protein (PBP) 1b of Escherichia coli.

An essential feature in the life cycle of both gram positive and gram negative bacteria is the production of new cell wall. Also known as murein, the cell wall is a two-dimensional polymer, consisting of a linear, repeating N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (GlcNAc) motif, cross-linked via peptides appended to MurNAc. The final steps in the maturation of murein are catalyzed by a single, bifunctional enzyme, known as a high MW, class A penicillin binding protein (PBP). PBPs catalyze polymerization of the sugar units (glycosyltransfer), as well as peptide cross-linking (transpeptidation) utilizing Lipid II as substrate. Detailed enzymology on this enzyme has been limited, due to difficulties in obtaining sufficient amounts of Lipid II, as well as the availability of a convenient and informative assay. We report the total chemical synthesis of Lipid II, as well as the development of an appropriate assay system and the observation of both catalytic transformations.

The Total Synthesis of Lipid I

A total synthesis of lipid I (4), a membrane-associated intermediate in the bacterial cell wall (peptidoglycan) biosynthesis pathway, is reported. This highly convergent synthesis will enable further studies on bacterial resistance mechanisms and may provide insight toward the development of new chemotherapeutic agents with novel modes of action.

Larval growth and biosynthesis of reserves in mosquitoes

Developmental instars of four species of mosquitoes have been analyzed for growth and synthesis of biomass with respect to their caloric content of protein, lipids, and carbohydrates for each instar of Aedes aegypti and Culex pipiens of the subfamily Culicinae, and Anopheles albimanus, and An. gambiae of the subfamily Anophelinae. The diameter of the thorax grows during the intermolt, reflecting continuous increase in biomass because it correlates significantly with the larval synthesis of total protein, lipids, and carbohydrates. For Ae. aegypti the fourth instar was sexed to disclose the sex-specific synthetic potential. In Ae. aegypti the protein increased in linear proportion with larval body size, whereas lipid synthesis followed a significant, exponential regression, which was clearly steeper in male larvae and most pronounced in the last instar. When normalized for size, the size-specific protein and lipid contents showed minimal levels of 0.25 and 0.1, respectively, regardless of standard or crowded rearing conditions. The rate of lipid synthesis in Ae. aegypti was determined by incubating fourth instar larvae with 14C-acetate and estimating the lipids. The rate was highest in the early larvae and decreased towards the end shortly before pupation; in male larvae incorporation was twice the rate of female larvae. Cx. pipiens reached the largest body sizes of all species tested, with protein and lipids increasing linearly with size. Their minimal levels of size-specific caloric contents were around 0.35 for protein and 0.25 for lipids. Anopheles also showed a linear relationship between larval size and caloric protein and lipid contents. Their minimal threshold levels in size-specific contents were 0.35 for protein and 0.2 for total lipids, similar to Culex, but slightly higher than in Aedes. Starvation of Ae. aegypti larvae and subsequent feeding partially improved their lipid contents, but never to the levels of non-starving, optimal controls. Conversely, well-fed final instars exposed to complete starvation showed a tremendous reduction of the protein and lipids contents in the surviving imagines, accompanied by 73% mortality. These results demonstrate the biosynthetic plasticity and the significance of the phagoperiod in Ae. aegypti during the final fourth instar for growth. The characteristic differences between these two subfamilies in their larval physiology are discussed in relation to ecological factors as encountered in the field under natural conditions, and in relation to our earlier findings on the reproductive physiology.