Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.2.1.3 (acyl-CoA synthetase)
1,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is an important hormone for the regulation of food intake, energy expenditure and reproduction in mammals, but information regarding its role in teleosts remains scant. In the present study, the gene structures of grass carp (Ctenopharyngodon idellus) and silver carp (Hypophthalmichthys molitrix) leptins were characterized. Recombinant grass carp leptin (rgc-LEP) was expressed in Escherichia coli and purified, and identified by mass spectrometric analysis. A strong anorexic effect on food intake was observed in grass carp on the first day after intraperitoneal (IP) injection of rgc-LEP, but not during the following days. Body weight of the leptin group (LEP group) and the pair-fed group (PF group) showed no difference throughout the experimental period. The acute and chronic effects on the expression of key genes correlating to food intake, energy expenditure, lipid metabolism and digestion were further characterized by real-time PCR. Accordingly, the mRNA levels of neuropeptide Y (NPY), Stearoyl-CoA desaturase 1 (SCD1) and lipoprotein lipase (LPL) were significantly reduced whereas the mRNA levels of uncoupling protein 2 (UCP2), bile salt-activated lipase (BSAL) and fatty acid elongase (ELO) were significantly elevated on the first day after injection. No effect on the expression of these genes (except LPL) was observed on day 13. In contrast to the down-regulation by exogenous leptin in mammals, the mRNA level of grass carp leptin was elevated 5.76-fold on the first day after rgc-LEP treatment. Our results suggest that leptin has an acute effect on the regulation of food intake, energy expenditure and lipid metabolism in grass carp, but the effect can be rapidly counteracted through mechanisms that are currently unknown.
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PMID:Gene structure, recombinant expression and functional characterization of grass carp leptin. 1985 95

A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.
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PMID:Discovery of novel benzoxazinones as potent and orally active long chain fatty acid elongase 6 inhibitors. 1988 81

The "lipotoxic footprint" of cardiac maladaptation in diet-induced obesity is poorly defined. We investigated how manipulation of dietary lipid and carbohydrate influenced potential lipotoxic species in the failing heart. In Wistar rats, contractile dysfunction develops at 48 weeks on a high-fat/high-carbohydrate "Western" diet, but not on low-fat/high-carbohydrate or high-fat diets. Cardiac content of the lipotoxic candidates--diacylglycerol, ceramide, lipid peroxide, and long-chain acyl-CoA species--was measured at different time points by high-performance liquid chromatography and biochemical assays, as was lipogenic capacity in the heart and liver by qRT-PCR and radiometric assays. Changes in membranes fluidity were also monitored using fluorescence polarization. We report that Western feeding induced a 40% decrease in myocardial palmitoleoyl-CoA content and a similar decrease in the unsaturated-to-saturated fatty acid ratio. These changes were associated with impaired cardiac mitochondrial membrane fluidity. At the same time, hepatic lipogenic capacity was increased in animals fed Western diet (+270% fatty acid elongase activity compared with high-fat diet), while fatty acid desaturase activity decreased over time. Our findings suggest that dysregulation of lipogenesis is a significant component of heart failure in diet-induced obesity.
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PMID:Western diet changes cardiac acyl-CoA composition in obese rats: a potential role for hepatic lipogenesis. 2009 77

The fatty acid composition in the seed oil was significantly modified following the introduction of transgenes. To further enhance the desirable characteristics of rapeseed oil, it would be beneficial to develop a new approach for the simultaneous silencing of two or more target genes. Our goals in the current study were to (1) increase oleic acid to more than 75%, (2) reduce polyunsaturated fatty acids (PUFA) to about 10% and erucic acid to zero, and (3) accomplish these changes in a single-transformation event. In a single transformation, two fragments amplified from the fatty acid (Delta12)-desaturase 2 (BnaFAD2) and fatty acid elongase 1 (BnaFAE1) genes of Brassica napus were linked together to form a fusion fragment. The fusion fragment was then used to assemble unique intron-spliced hairpin interfering constructs. In the transgenic plant FFRP4-4, the expression of BnaFAD2 and BnaFAE1 genes was completely inhibited. The composition of oleic acid in FFRP4-4 rose to 85%, PUFA dropped to 10% and erucic acid was undetectable. All hybrid F(1) seeds obtained from the reciprocal crossing of FFRP4-4 and GX-parents (with different genetic backgrounds) contained more than 80% oleic acid, about 10% PUFA and very low, or undetectable, erucic acid. The results confirmed that the fusion fragment silencing construct can simultaneously and effectively silence the target genes on a consistent basis. The strategy provides a useful tool for detecting gene function and advancing genetic engineering techniques for the improvement of agricultural crops.
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PMID:Simultaneous silencing of FAD2 and FAE1 genes affects both oleic acid and erucic acid contents in Brassica napus seeds. 2013 Aug 82

Very-long-chain fatty acids (VLCFAs) are essential for many aspects of plant development and necessary for the synthesis of seed storage triacylglycerols, epicuticular waxes, and sphingolipids. Identification of the acetyl-CoA carboxylase PASTICCINO3 and the 3-hydroxy acyl-CoA dehydratase PASTICCINO2 revealed that VLCFAs are important for cell proliferation and tissue patterning. Here, we show that the immunophilin PASTICCINO1 (PAS1) is also required for VLCFA synthesis. Impairment of PAS1 function results in reduction of VLCFA levels that particularly affects the composition of sphingolipids, known to be important for cell polarity in animals. Moreover, PAS1 associates with several enzymes of the VLCFA elongase complex in the endoplasmic reticulum. The pas1 mutants are deficient in lateral root formation and are characterized by an abnormal patterning of the embryo apex, which leads to defective cotyledon organogenesis. Our data indicate that in both tissues, defective organogenesis is associated with the mistargeting of the auxin efflux carrier PIN FORMED1 in specific cells, resulting in local alteration of polar auxin distribution. Furthermore, we show that exogenous VLCFAs rescue lateral root organogenesis and polar auxin distribution, indicating their direct involvement in these processes. Based on these data, we propose that PAS1 acts as a molecular scaffold for the fatty acid elongase complex in the endoplasmic reticulum and that the resulting VLCFAs are required for polar auxin transport and tissue patterning during plant development.
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PMID:Very-long-chain fatty acids are involved in polar auxin transport and developmental patterning in Arabidopsis. 2014 57

De novo lipogenesis (DNL) is a complex yet highly regulated metabolic pathway, and transcription factors such as liver X receptor (LXR), sterol regulatory element-binding protein-1c (SREBP-1c), and carbohydrate response element binding protein (ChREBP) exert significant control over the de novo synthesis of fatty acids. An increase in de novo lipogenesis (DNL) is an important contributor to increased fat mass, while a reduction in lipogenesis may be protective against the development of obesity. In this review, we explore fatty acid synthesis in the context of new insights gleaned from global and tissue-specific gene knockout mouse models of enzymes involved in fatty acid synthesis, namely acetyl-CoA carboxylase, fatty acid synthase, fatty acid elongase 6, and stearoyl-CoA desaturase 1. A disruption in fatty acid synthesis, induced by the deficiency of any one of these enzymes, affects lipid metabolism and in some cases may protect against obesity in a tissue and gene-specific manner, as discussed in detail in this review.
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PMID:Genetic control of de novo lipogenesis: role in diet-induced obesity. 2021 65

The development of the dauer form of Caenorhabditis elegans daf-2(e1370) enhances the expression of genes such as fatty acid desaturase fat-6 and fat-7 and fatty acid elongase elo-2, and increases the level of triglyceride (TAG). RNA interference (RNAi) of the fat-6, fat-7, and elo-2 genes lowers fat accumulation in the nematode. We recently clarified the fact that RNAi of fat-related genes, especially fat-2, reduced fat accumulation and activated DAF-16. FAT-2 regulates the first step of polyunsaturated fatty acid (PUFA) synthesis. RNAi of fat-2 induced nuclear translocation of DAF-16 and increased the level of TAG that could be detected by Oil Red-O, but suppressed the accumulation of lipid dyed by Nile red. TAG levels are also increased in the adult daf-2(e1370), whereas Nile red staining showed fat reduction. Introduction of RNAi of fat-2, fat-6, fat-7, and elo-2 genes into the daf-16 deficient worm recovered Nile red-stained lipid storage. These results suggest that Nile red stained the lipids except TAG, and that the levels of these lipids are regulated by daf-16. In fat-2, fat-6, fat-7, and elo-2-RNAi worms, the Nile red-stained fat level was restored through addition of fatty acids, especially PUFA. This suggests that reduction of Nile red-dyed lipid reflects the disorder of fatty acid metabolism. Furthermore, treatment of the fat-2-RNAi worm with PUFA--using the fatty acids from linoleic acid through eicosapentaenoic acid--suppressed nuclear localization of DAF-16. These results suggest that PUFA acts as a mediator of daf-2/insulin signaling and that daf-16 might be involved in fatty acid homeostasis under the control of PUFA.
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PMID:Polyunsaturated fatty acids are involved in regulatory mechanism of fatty acid homeostasis via daf-2/insulin signaling in Caenorhabditis elegans. 2022 39

Exercise has been linked to a reduced cancer risk in animal models. However, the underlying mechanisms are unclear. This study assessed the effect of exercise with dietary consideration on the phospholipid profile in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tissues. CD-1 mice were randomly assigned to one of the three groups: ad libitum-fed sedentary control; ad libitum-fed treadmill exercise at 13.4 m/min for 60 min/d, 5 d/wk (Ex+AL); and treadmill-exercised but pair-fed with the same amount as the control (Ex+PF). After 14 weeks, Ex+PF but not Ex+AL mice showed approximately 25% decrease in both body weight and body fat when compared with the controls. Of the total 338 phospholipids determined by electrospray ionization-tandem mass spectrometry, 57 were significantly changed, and 25 species could distinguish effects of exercise and diet treatments in a stepwise discriminant analysis. A 36% to 75% decrease of phosphatidylinositol (PI) levels in Ex+PF mice occurred along with a significant reduction of PI 3-kinase in TPA-induced skin epidermis, as measured by both Western blotting and immunohistochemistry. In addition, approximately 2-fold increase of the long-chain polyunsaturated fatty acids, docosahexaenoic and docosapentaenoic acids, in phosphatidylcholines, phosphatidylethanolamines, and lysophosphatidylethanolamines was observed in the Ex+PF group. Microarray analysis indicated that the expression of fatty acid elongase-1 increased. Taken together, these data indicate that exercise with controlled dietary intake, but not exercise alone, significantly reduced body weight and body fat as well as modified the phospholipid profile, which may contribute to cancer prevention by reducing TPA-induced PI 3-kinase and by enhancing omega-3 fatty acid elongation.
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PMID:Weight Loss via exercise with controlled dietary intake may affect phospholipid profile for cancer prevention in murine skin tissues. 2023

Elevated hepatic fatty acid elongase-5 (Elovl5) activity lowers blood glucose in fasted chow-fed C57BL/6J mice. As high-fat diets induce hyperglycemia and suppress hepatic Elovl5 activity, we tested the hypothesis that elevated hepatic Elovl5 expression attenuates hyperglycemia in high-fat-diet-induced obese mice. Increasing hepatic Elovl5 activity by a recombinant adenoviral approach restored blood glucose and insulin, HOMA-IR, and glucose tolerance to normal values in obese mice. Elevated Elovl5 activity increased hepatic content of Elovl5 products (20:3,n-6, 22:4,n-6) and suppressed levels of enzymes (Pck1, G6Pc) and transcription factors (FoxO1 and PGC1alpha, but not CRTC2) involved in gluconeogenesis. Effects of Elovl5 on FoxO1 nuclear abundance correlated with increased phosphorylation of FoxO1, Akt, and the catalytic unit of PP2A, as well as a decline in cellular abundance of TRB3. Such changes are mechanistically linked to the regulation of FoxO1 nuclear abundance and gluconeogenesis. These results show that Elovl5 activity impacts the hepatic abundance and phosphorylation status of multiple proteins involved in gluconeogenesis. Our findings establish a link between fatty acid elongation and hepatic glucose metabolism and suggest a role for regulators of Elovl5 activity in the treatment of diet-induced hyperglycemia.
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PMID:Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese C57BL/6J mice. 2048 98

Although saturated and monounsaturated very-long-chain fatty acids (VLCFAs) have long been associated with undesirable effects on health, including obesity, heart failure, and atherosclerosis, the physiological role of endogenous synthesis is largely unknown. The fatty acid elongase ELOVL3 is involved in the synthesis of C20-C24 saturated and monounsaturated VLCFAs mainly in liver, brown and white adipose tissue, and triglyceride-rich glands such as the sebaceous and meibomian glands. Here we show that ablation of ELOVL3 leads to reduced adiponectin levels, constrained expansion of adipose tissue, and resistance against diet-induced obesity, a situation that is more exaggerated in female mice. Both female and male knockout mice show reduced hepatic lipogenic gene expression and triglyceride content, a situation that is associated with reduced de novo fatty acid synthesis and uptake. As a consequence, the VLDL-triglyceride level in serum is significantly reduced. Remarkably, despite increased energy expenditure, markedly reduced serum levels of leptin, and increased expression of orexigenic peptides in the hypothalamus, the Elovl3(-/-) mice do not compensate by increased food intake. Thus, these results reveal that C20-C22 saturated and monounsaturated VLCFAs produced by ELOVL3 are indispensable for appropriate synthesis of liver triglycerides, fatty acid uptake, and storage in adipose tissue.
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PMID:Ablation of the very-long-chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity. 2060 47


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