Functional and structural properties of mammalian acyl-coenzyme A thioesterases.
ABSTRACT Acyl-coenzyme A thioesterases (Acots) play important cellular roles in mammalian fatty acid metabolism through modulation of cellular concentrations of activated fatty acyl-CoAs. Acots catalyse the hydrolysis of the thioester bond present within acyl-CoA ester molecules to yield coenzyme A (CoASH) and the corresponding non-esterified fatty acid. Acyl-CoA thioesterases are expressed ubiquitously in both prokaryotes and eukaryotes and, in higher order organisms, the enzymes are expressed and localised in a tissue-dependent manner within the cytosol, mitochondria, peroxisomes and endoplasmic reticulum. Recent studies have led to advances in the functional and structural characterization of many mammalian Acot family members. These include the structure determination of both type-I and type-II Acot family members, structural elucidation of the START domain of ACOT11, identification of roles in arachidonic acid and inflammatory prostaglandin production by Acot7, and inclusion of a 13th Acot family member. Here, we review and analyse the current literature on mammalian Acots with respect to their characterization and summarize the current knowledge on the structure, function and regulation of this enzyme family.
Article: Metabolism, Compartmentation, Transport and Production of Acetate in the Cortical Brain Tissue Slice.[show abstract] [hide abstract]
ABSTRACT: Acetate is a two carbon intermediate in metabolism. It is an accepted marker of astrocytic metabolism, and a substrate for production of metabolites such as glutamine, glutamate and GABA. However, anomalies exist in the current explanations of compartmentation and metabolism of acetate. Here, we investigated these anomalies by examining transport, production and metabolism of acetate. Acetate is a good substrate for the neuronal monocarboxylate transporter MCT2 (K(M) = 2.58 ± 0.8) and the glial MCT1 but a poor substrate for the glial MCT4. Acetate is accumulated by brain cortical tissue slices to concentrations in excess of those in the media, suggesting active transport, possibly via the sodium dependent SMCT. [2-(13)C]Acetate is produced from [3-(13)C]pyruvate, [3-(13)C]lactate and [1-(13)C]glucose with the rate of production related to acetyl-CoA levels, which is likely generated in a ubiquitous cytosolic compartment via acetyl-CoA hydrolase. Citrate breakdown occurs in response to demand for acetyl-CoA units; this citrate is not derived from acetate carbon but its fate is influenced by acetate levels. Finally, use of acetate is altered by levels of nicotinamide or NAD(+). This suggests that metabolism of acetate is controlled rigorously at the enzyme level, via changes in the acetylation status of acetyl-CoA synthetase and is not regulated by restriction of uptake.Neurochemical Research 08/2012; · 2.24 Impact Factor
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ABSTRACT: Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on lipid metabolism, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and (1)H nuclear magnetic resonance were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify possible mechanisms underlying altered circulating lipid levels. Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group. In serum of quercetin-fed mice, triglycerides (TG) were decreased with 14% (p<0.001) and total poly unsaturated fatty acids (PUFA) were increased with 13% (p<0.01). Palmitic acid, oleic acid, and linoleic acid were all decreased by 9-15% (p<0.05) in quercetin-fed mice. Both palmitic acid and oleic acid can be oxidized by omega (ω)-oxidation. Gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially ω-oxidation. At the gene level, this was reflected by the up-regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor constitutive androstane receptor (Car; official symbol Nr1i3) were also up-regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid ω-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects on CVD.PLoS ONE 01/2013; 8(1):e51588. · 4.09 Impact Factor
Article: Protective efficacy of orally administered, heat-killed Lactobacillus pentosus b240 against influenza A virus.[show abstract] [hide abstract]
ABSTRACT: Influenza A(H1N1)pdm virus caused the first human pandemic of the 21st century. Although various probiotic Lactobacillus species have been shown to have anti-microbial effects against pneumonia-inducing pathogens, the prophylactic efficacy and mechanisms behind their protection remain largely unknown. Here, we evaluated the prophylactic efficacy of heat-killed Lactobacillus pentosus b240 against lethal influenza A(H1N1)pdm virus infection in a mouse model. To further define the protective responses induced by b240, we performed virologic, histopathologic, and transcriptomic analyses on the mouse lungs. Although we did not observe an appreciable effect of b240 on virus growth, cytokine production, or histopathology, gene expressional analysis revealed that oral administration of b240 differentially regulates antiviral gene expression in mouse lungs. Our results unveil the possible mechanisms behind the protection mediated by b240 against influenza virus infection and provide new insights into probiotic therapy.Scientific Reports 03/2013; 3:1563.