Inhibitors Of Lipid Droplet Formation Research Articles

Transcriptomic analysis of cyanobacterial alkane overproduction reveals stress-related genes and inhibitors of lipid droplet formation.

The cyanobacterium Nostoc punctiforme can form lipid droplets (LDs), internal inclusions containing triacylglycerols, carotenoids and alkanes. LDs are enriched for a 17 carbon-long alkane in N. punctiforme , and it has been shown that the overexpression of the aar and ado genes results in increased LD and alkane production. To identify transcriptional adaptations associated with increased alkane production, we performed comparative transcriptomic analysis of an alkane overproduction strain. RNA-seq data identified a large number of highly upregulated genes in the overproduction strain, including genes potentially involved in rRNA processing, mycosporine-glycine production and synthesis of non-ribosomal peptides, including nostopeptolide A. Other genes encoding helical carotenoid proteins, stress-induced proteins and those for microviridin synthesis were also upregulated. Construction of N. punctiforme strains with several upregulated genes or operons on multi-copy plasmids resulted in reduced alkane accumulation, indicating possible negative regulators of alkane production. A strain containing four genes for microviridin biosynthesis completely lost the ability to synthesize LDs. This strain exhibited wild-type growth and lag phase recovery under standard conditions, and slightly faster growth under high light. The transcriptional changes associated with increased alkane production identified in this work will provide the basis for future experiments designed to use cyanobacteria as a production platform for biofuel or high-value hydrophobic products.

ChemInform Abstract: Absolute Stereochemistry of Pentacecilides, New Inhibitors of Lipid Droplet Formation in Mouse Macrophages, Produced by Penicillium cecidicola FKI‐3765‐1.

AbstractThe structure of the new pentacecilide D (Id), produced by Penicillium cecidicola FKI‐3765‐1 is determined.

ChemInform Abstract: Phenochalasins, Inhibitors of Lipid Droplet Formation in Mouse Macrophages, Produced by Phomopsis sp. FT-0211.

Phomopsis sp. FT-0211, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. Structurally related new compounds designated phenochalasins A and B were isolated from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography and preparative HPLC. Phenochalasin A caused a dose-dependent reduction in the number and size of lipid droplets in macrophages without any cytotoxic effect at least up to 20 microm. On the other hand, phenochalasin B showed inhibition of lipid droplet formation with a severe cytotoxic effect on macrophages.

Absolute stereochemistry of pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1

The structure of a new pentacecilide congener, pentacecilide D, produced by Penicillium cecidicola FKI-3765-1 was elucidated by various NMR experiments. The absolute stereochemistry of pentacecilides was elucidated by using the modified Mosher method for pentacecilide C. The inhibitory activity of all pentacecilides against lipid droplet formation and acyl-CoA:cholesterol acyltransferase isozymes was compared.

Heterofibrins: inhibitors of lipid droplet formation from a deep-water southern Australian marine sponge, Spongia (Heterofibria) sp.

A bioassay-guided search for inhibitors of lipid droplet formation in a deep-water southern Australian marine sponge, Spongia (Heterofibria) sp., yielded six new compounds, fatty acids heterofibrins A1 (1) and B1 (4), along with related monolactyl and dilactyl esters, heterofibrins A2 (2), B2 (5), A3 (3) and B3 (6). Heterofibrin structures were assigned on the basis of detailed spectroscopic analysis, with comparison to chiral synthetic model compounds. All heterofibrins possess a diyne-ene moiety, while the monolactyl and dilactyl moiety featured in selected heterofibrins is unprecedented in the natural products literature. SAR by co-metabolite studies on the heterofibrins confirmed them to be non-cytotoxic, with the carboxylic acids 1 and 4 inhibiting lipid droplet formation in A431 fibroblast cell lines. Such inhibitors have potential application in the management of obesity, diabetes and atherosclerosis

Erratum: Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1: II. Structure elucidation

Correction to: The Journal of Antibiotics (2009) 62, 207–211; doi:10.1038/ja.2009.19 The authors of the above article noted an error in publication of this paper in Figures 1 and 4 and in the legend of Figure 3. The correct figures and Figure 3 legend are shown below. Figure 3 1H–1H COSY and 13C–1H HMBC experiments of pentacecilides C (a), B (b) and A (c).

Erratum: Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1: I. Taxonomy, fermentation, isolation and biological properties

Erratum: Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1: I. Taxonomy, fermentation, isolation and biological properties

ChemInform Abstract: Pentacecilides, New Inhibitors of Lipid Droplet Formation in Mouse Macrophages Produced by Penicillium cecidicola FKI‐3765‐1. Part 2. Structure Elucidation.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Pentacecilides, New Inhibitors of Lipid Droplet Formation in Mouse Macrophages, Produced by Penicillium cecidicola FKI‐3765‐1. Part 1. Taxonomy, Fermentation, Isolation and Biological Properties.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages produced by Penicillium cecidicola FKI-3765-1: II. Structure elucidation

The structures of pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages produced by Penicillium cecidicola FKI-3765-1, were elucidated by spectroscopic studies, including various NMR experiments. Pentacecilides have a common pentacyclic meroterpene core, which contains an aromatic ring and a delta-lactone ring.

Pentacecilides, new inhibitors of lipid droplet formation in mouse macrophages, produced by Penicillium cecidicola FKI-3765-1: I. Taxonomy, fermentation, isolation and biological properties

New compounds designated pentacecilides A to C were isolated from the fermentation broth of Penicillium cecidicola FKI-3765-1 by solvent extraction, silica gel column chromatography and preparative HPLC. Pentacecilides A and B dose-dependently inhibited lipid droplet formation in mouse macrophages. Furthermore, pentacecilides A and B were found to inhibit the synthesis of cholesteryl ester in mouse macrophages with respective IC(50) values of 3.65 and 4.76 microM without any cytotoxic effect, but pentacecilide C showed almost no activity. The study of the mechanism of action strongly suggested that pentacecilides A and B inhibit acyl-CoA: cholesterol acyltransferase activity in macrophages.

K97-0239A and B, new inhibitors of macrophage foam cell formation, produced by <i>Streptomyces</i> sp. K97-0239

Streptomyces sp. K97-0239, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. Two compounds, K97-0239A and B, were isolated from the culture broth of the producing strain, and their structures were elucidated by spectroscopic analyses including various NMR experiments. They were cyclic lipopeptides comprising 2, 3-diaminopropionic acid, 4-(aminomethyl)-2, 2-dimethyl-5-oxo-1-imidazolidineacetic acid and phenylalanine/leucine as ring units, and 3-(13-hydroxytetradeca-2, 4-dienoylamino)-acrylic acid as lipophilic side chains. They caused a dose-dependent reduction in the number and size of cytosolic lipid droplets in macrophages at least up to 15μM without any cytotoxic effect on macrophages. [14C] Cholesteryl ester synthesis from [14C] oleic acid by macrophages was inhibited by K97-0239s with IC50 values of 1.5-1.7μM.

ChemInform Abstract: Beauveriolides, Specific Inhibitors of Lipid Droplet Formation in Mouse Macrophages, Produced by Beauveria sp. FO‐6979.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Phenochalasins, Inhibitors of Lipid Droplet Formation in Mouse Macrophages, Produced by Phomopsis sp. FT-0211.

Phomopsis sp. FT-0211, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. Structurally related new compounds designated phenochalasins A and B were isolated from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography and preparative HPLC. Phenochalasin A caused a dose-dependent reduction in the number and size of lipid droplets in macrophages without any cytotoxic effect at least up to 20 microm. On the other hand, phenochalasin B showed inhibition of lipid droplet formation with a severe cytotoxic effect on macrophages.

Beauveriolides, specific inhibitors of lipid droplet formation in mouse macrophages, produced by Beauveria sp. FO-6979.

Beauveria sp. FO-6979, a soil isolate, was found to produce inhibitors of lipid droplet formation in mouse peritoneal macrophages. A new compound beauveriolide III was isolated along with a known compound beauveriolide I from the fermentation broth of the producing strain by solvent extraction, ODS column chromatography, silica gel column chromatography and preparative HPLC. Beauveriolides I and III caused a reduction in the number and size of cytosolic lipid droplets in macrophages at 10 microM without any cytotoxic effect on macrophages.

Structure elucidation of fungal phenochalasins, novel inhibitors of lipid droplet formation in mouse macrophages.

The structures of phenochalasins A and B were elucidated by spectroscopic studies including various NMR measurements. Phenochalasins A and B have the cytochalasan skeleton of the 21,23-dioxa, 17,22-dione moiety containing unique phenyl and O-methyl phenyl residues at the C-10 position, respectively.