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《Cell metabolism》2022,34(11):1675-1699
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F. X. Meng M. Li M. Z. Song L. X. Yuan Y. F. Gong Y. X. Qian G. Shi R. X. Wang 《Journal of fish biology》2018,92(1):85-93
This study was conducted to determine the mechanism by which di‐2‐ethylhexyl phthalate (DEHP) exposure influences lipid metabolism of juvenile yellow catfish Tachysurus fulvidraco. Fish were exposed to three DEHP concentrations (0, 0·1 and 0·5 mg l?1 DEHP) for 8 weeks. Fatty acid synthase (FAS) activity significantly decreased with increasing DEHP concentrations, the highest value was in the Tween control group, whereas the lowest activities of carnitine palmitoyltransferase (CPT) and lipoprotein lipase (LPL) were in this group. The messenger (m)RNA levels of 6‐phospho‐gluconate dehydrogenase (6PGD), FAS and acetyl‐CoA carboxylase a (ACCa) significantly increased with increasing DEHP concentration, the highest values were in the 0·5 mg l?1 DEHP group. The mRNA level of peroxisome proliferator‐activated receptor γ (PPARγ) was lower in Tween control than in fish exposed to 0·1 and 0·5 mg l?1 DEHP. The highest mRNA level of ACCb was in the 0·1 mg l?1 DEHP group. These results indicate that DEHP exposure can disturb lipid metabolism at the enzymatic and mRNA levels in Pelteobagrus fulvidraco. 相似文献
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Emily M. Christensen Alexandra N. Bogner Anke Vandekeere Gabriela S. Tam Sagar M. Patel Donald F. Becker Sarah-Maria Fendt John J. Tanner 《The Journal of biological chemistry》2020,295(52):18316
Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the biosynthetic half-reaction of the proline cycle by reducing Δ1-pyrroline-5-carboxylate (P5C) to proline through the oxidation of NAD(P)H. Many cancers alter their proline metabolism by up-regulating the proline cycle and proline biosynthesis, and knockdowns of PYCR1 lead to decreased cell proliferation. Thus, evidence is growing for PYCR1 as a potential cancer therapy target. Inhibitors of cancer targets are useful as chemical probes for studying cancer mechanisms and starting compounds for drug discovery; however, there is a notable lack of validated inhibitors for PYCR1. To fill this gap, we performed a small-scale focused screen of proline analogs using X-ray crystallography. Five inhibitors of human PYCR1 were discovered: l-tetrahydro-2-furoic acid, cyclopentanecarboxylate, l-thiazolidine-4-carboxylate, l-thiazolidine-2-carboxylate, and N-formyl l-proline (NFLP). The most potent inhibitor was NFLP, which had a competitive (with P5C) inhibition constant of 100 μm. The structure of PYCR1 complexed with NFLP shows that inhibitor binding is accompanied by conformational changes in the active site, including the translation of an α-helix by 1 Å. These changes are unique to NFLP and enable additional hydrogen bonds with the enzyme. NFLP was also shown to phenocopy the PYCR1 knockdown in MCF10A H-RASV12 breast cancer cells by inhibiting de novo proline biosynthesis and impairing spheroidal growth. In summary, we generated the first validated chemical probe of PYCR1 and demonstrated proof-of-concept for screening proline analogs to discover inhibitors of the proline cycle. 相似文献
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载脂蛋白E (apoE)是脂质代谢中的重要分子,通过调节细胞增殖、能量代谢、氧化应激、机体固有免疫等方式,在多种恶性肿瘤的发生发展中发挥重要作用,并影响患者的治疗效果,已成为潜在的肿瘤标志物和有潜力的治疗靶点,对于深入理解多种恶性肿瘤的病因学,推动恶性肿瘤的预防及开发新的治疗策略具有重要意义。本文对apoE的生物化学与分子生物学属性进行介绍,并梳理apoE在各个癌种的发生发展中发挥的作用,总结apoE与肿瘤的各种生物学特性之间的关系,探讨其作为肿瘤标志物与治疗靶点的潜力和应用价值。 相似文献
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Paul R. S. Baker Aaron M. Armando J. Larry Campbell Oswald Quehenberger Edward A. Dennis 《Journal of lipid research》2014,55(11):2432-2442
Phospholipids serve as central structural components in cellular membranes and as potent mediators in numerous signaling pathways. There are six main classes of naturally occurring phospholipids distinguished by their distinct polar head groups that contain many unique molecular species with distinct fatty acid composition. Phospholipid molecular species are often expressed as isobaric species that are denoted by the phospholipid class and the total number of carbon atoms and double bonds contained in the esterified fatty acyl groups (e.g., phosphatidylcholine 34:2). Techniques to separate these molecules exist, and each has positive and negative attributes. Hydrophilic interaction liquid chromatography uses polar bonded silica to separate lipids by polar head group but not by specific molecular species. Reversed phase (RP) chromatography can separate by fatty acyl chain composition but not by polar head group. Herein we describe a new strategy called differential ion mobility spectrometry (DMS), which separates phospholipid classes by their polar head group. Combining DMS with current LC methods enhances phospholipid separation by increasing resolution, specificity, and signal-to-noise ratio. Additional application of specialized information-dependent acquisition methodologies along with RP chromatography allows full isobaric resolution, identification, and compositional characterization of specific phospholipids at the molecular level. 相似文献
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Kumari Aditi Akanksha Singh Mallikarjun N Shakarad Namita Agrawal 《Experimental biology and medicine (Maywood, N.J.)》2022,247(2):152
Huntington’s disease (HD) is a devastating polyglutamine disorder characterized by extensive neurodegeneration and metabolic abnormalities at systemic, cellular and intracellular levels. Metabolic alterations in HD manifest as abnormal body weight, dysregulated biomolecule levels, impaired adipocyte functions, and defective energy state which exacerbate disease progression and pose acute threat to the health of challenged individuals in form of insulin resistance, cardiovascular disease, and energy crisis. To colossally mitigate disease symptoms, we tested the efficacy of curcumin in Drosophila model of HD. Curcumin is the bioactive component of turmeric (Curcuma longa Linn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content, and carbohydrate level in HD flies. In addition, curcumin administration lowered elevated reactive-oxygen-species levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in HD flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in HD flies and can prove beneficial in alleviating the complexities associated with HD. 相似文献
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The possible implication of NADP-dependent malic enzyme (NADP-ME; L-malate:NADP oxidoreductase [oxaloacetate-decarboxylating], EC 1.1.1.40) in fatty acid synthesis was examined in Ricinus communis L. cotyledons, NADP-ME catalyses the conversion of L-malate to pyruvate and NADPH, potential substrates for fatty acid synthesis. NADP-ME activity and protein levels were monitored during germination, up to 20 days postimbibition. The developmental profile showed a peak in activity (6 times with respect to the basal value) and immunoreactive protein (a single 72-kDa band using anti-maize NADP-ME antibodies) around day 7. The enzyme was partially purified (41-fold) and its kinetics characterized. The optimum pH was around 7.1. Km values for L-malate and NADP+ were 0.68 m M and 8.2 μ M respectively. The enzyme used Mg2+ or Mn2+ as essential cofactors. Several metabolites were assayed as potential enzyme modulators. Succinate, CoA, acetyl-CoA and palmitoyl-CoA were activators of NADP-ME, at saturating or sub-saturating substrate concentrations, K2 values for CoA and derivative compounds were in the micromolar range (i.e., 0.8 μ M for acetyl-CoA). No significant effects were obtained with other Krebs cycle intermediates and amino acids (i.e. 2-oxoglutarate, glutamate, glutamine, fumarate). The activity was 29 times higher in the forward (decarboxylating) direction compared to the reverse direction. These results hint at cotyledon NADP-ME behaving as a regulatory enzyme in R. communis . Its activity is responsive to metabolites of the fatty acid synthesis pathway, and thus a role in this metabolism is suggested. 相似文献
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体内肉碱来源及其对脂类代谢的影响 总被引：7，自引：0，他引：7
肉碱是体内一种有多种生理功能的氨基酸类物质,其在脂类代谢过程中有重要的调节作用,近年来在甘油三脂血症、肾透析患者的脂代谢障碍的辅助治疗中取得了较好疗效。本文就肉碱的来源和对脂类代谢的影响进行了讨论。 相似文献
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Nirmala Chandrasekar Anand Selvaraj Puvanakrishnan Rengarajulu 《Molecular and cellular biochemistry》1999,197(1-2):31-37
This study was carried out to evaluate whether curcumin, a potent antioxidant, had any specific role in the synthesis and degradation of collagen in rat heart with mocardial necrosis, induced by isoproterenol.HCI (ISO). Myocardial necrosis was induced by administration of ISO (30 mg/100 g body weight subcutaneously twice at an interval of 24 h) and studies on collagen metabolism were carried out with curcumin (200 mg/kg) pre-and co-treatment with ISO. The incorporation of 14C-proline into collagen was studied as an index of collagen synthesis. The heart weight /body weight ratio,heart RNA/DNA ratio and protein were found to increase significantly in ISO administered animals. Curcumin pre- and co-treatment with ISO reversed these changes and attenuated the development of cardiac hypertrophy two weeks after the second dose of ISO. Increased fractional synthesis rate and enhanced degradation of newly synthesized collagen were observed in ISO administered animals. Curcumin pre- and co-treatment with ISO was noticed to decrease the degree of degradation of the existing collagen matrix and collagen synthesis, two weeks after the second dose of ISO. The observed effects could be due to free radical scavenging capacity and inhibition of lysosomal enzyme release by curcumin. 相似文献
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Beysen C Murphy EJ Nagaraja H Decaris M Riiff T Fong A Hellerstein MK Boyle PJ 《Journal of lipid research》2008,49(12):2657-2663
Treatment of type 2 diabetes mellitus (T2DM) patients with pioglitazone results in a more favorable lipid profile, and perhaps more favorable cardiac outcomes, than treatment with rosiglitazone. Pioglitazone treatment increases VLDL-triacylglycerol clearance, but the role of de novo lipogenesis (DNL) has not been explored, and no direct comparison has been made between the thiazolidinediones (TZDs). Twelve subjects with T2DM and hypertriacylglyceridemia were randomized to either rosiglitazone or pioglitazone treatment. Stable isotope infusion studies were performed at baseline and after 20 weeks of treatment. Both treatments reduced glucose and HbA(1c) concentrations equally. Pioglitazone treatment resulted in a 40% reduction in hepatic DNL (P < 0.01) and in a 25% reduction in hepatic glucose production (P < 0.05), while rosiglitazone did not significantly change either parameter, although comparisons of changes between treatments were not significantly different. These pilot results indicate that pioglitazone reduces hepatic DNL while rosiglitazone does not. Larger follow-up studies are required to confirm differential effects of these agents definitively. The reduction in DNL may underlie altered assembly or atherogenicity of lipoprotein particles and may reflect PPARalpha or other non-PPARgamma actions on the liver by pioglitazone. These differences might help explain previously reported differences in lipid profiles and cardiovascular disease outcomes for rosiglitazone and pioglitazone. 相似文献
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Lipid metabolism is a complex biochemical process that participates in the regulation of cell survival and death. Ferroptosis is a form of iron-dependent regulated cell death driven by abnormal lipid metabolism, leading to lipid peroxidation and subsequent plasma membrane rupture. A variety of antioxidant systems and membrane repair pathways can diminish oxidative damage, enabling survival and growth in response to ferroptotic signals. Such impairment of ferroptosis machinery is implicated in various pathological conditions and diseases, especially cancer and tissue damage. It is discussed here how lipid metabolism pathways, including lipid synthesis, degradation, storage, transformation, and utilization, modulate ferroptosis sensitivity or tolerance in different models, especially cancer. 相似文献
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Daniel E. Cooper Trisha J. Grevengoed Eric L. Klett Rosalind A. Coleman 《The Journal of biological chemistry》2015,290(24):15112-15120
Glycerol-3-phosphate acyltransferase-4 (GPAT4) null pups grew poorly during the suckling period and, as adults, were protected from high fat diet-induced obesity. To determine why Gpat4−/− mice failed to gain weight during these two periods of high fat feeding, we examined energy metabolism. Compared with controls, the metabolic rate of Gpat4−/− mice fed a 45% fat diet was 12% higher. Core body temperature was 1 ºC higher after high fat feeding. Food intake, fat absorption, and activity were similar in both genotypes. Impaired weight gain in Gpat4−/− mice did not result from increased heat loss, because both cold tolerance and response to a β3-adrenergic agonist were similar in both genotypes. Because GPAT4 comprises 65% of the total GPAT activity in brown adipose tissue (BAT), we characterized BAT function. A 45% fat diet increased the Gpat4−/− BAT expression of peroxisome proliferator-activated receptor α (PPAR) target genes, Cpt1α, Pgc1α, and Ucp1, and BAT mitochondria oxidized oleate and pyruvate at higher rates than controls, suggesting that fatty acid signaling and flux through the TCA cycle were enhanced. To assess the role of GPAT4 directly, neonatal BAT preadipocytes were differentiated to adipocytes. Compared with controls, Gpat4−/− brown adipocytes incorporated 33% less fatty acid into triacylglycerol and 46% more into the pathway of β-oxidation. The increased oxidation rate was due solely to an increase in the oxidation of exogenous fatty acids. These data suggest that in the absence of cold exposure, GPAT4 limits excessive fatty acid oxidation and the detrimental induction of a hypermetabolic state. 相似文献
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Aas V Rokling-Andersen MH Kase ET Thoresen GH Rustan AC 《Journal of lipid research》2006,47(2):366-374
This study was conducted to evaluate the chronic effects of eicosapentaenoic acid (EPA) on fatty acid and glucose metabolism in human skeletal muscle cells. Uptake of [14C]oleate was increased >2-fold after preincubation of myotubes with 0.6 mM EPA for 24 h, and incorporation into various lipid classes showed that cellular triacylgycerol (TAG) and phospholipids were increased 2- to 3-fold compared with control cells. After exposure to oleic acid (OA), TAG was increased 2-fold. Insulin (100 nM) further increased the incorporation of [14C]oleate into all lipid classes for EPA-treated myotubes. Fatty acid beta-oxidation was unchanged, and complete oxidation (CO2) decreased in EPA-treated cells. Basal glucose transport and oxidation (CO2) were increased 2-fold after EPA, and insulin (100 nM) stimulated glucose transport and oxidation similarly in control and EPA-treated myotubes, whereas these responses to insulin were abolished after OA treatment. Lower concentrations of EPA (0.1 mM) also increased fatty acid and glucose uptake. CD36/FAT (fatty acid transporter) mRNA expression was increased after EPA and OA treatment compared with control cells. Moreover, GLUT1 expression was increased 2.5-fold by EPA, whereas GLUT4 expression was unchanged, and activities of the mitogen-activated protein kinase p38 and extracellular signal-regulated kinase were decreased after treatment with OA compared with EPA. Together, our data show that chronic exposure of myotubes to EPA promotes increased uptake and oxidation of glucose despite a markedly increased fatty acid uptake and synthesis of complex lipids. 相似文献
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Lipids play critical roles in several major chronic diseases of our times, including those that involve inflammatory sequelae such as metabolic syndrome including obesity, insulin sensitivity, and cardiovascular diseases. However, defining the substrate specificity of enzymes of lipid metabolism is a challenging task. For example, phospholipase A2 (PLA2) enzymes constitute a superfamily of degradative, biosynthetic, and signaling enzymes that all act stereospecifically to hydrolyze and release the fatty acids of membrane phospholipids. This review focuses on how membranes interact allosterically with enzymes to regulate cell signaling and metabolic pathways leading to inflammation and other diseases. Our group has developed “substrate lipidomics” to quantify the substrate phospholipid specificity of each PLA2 and coupled this with molecular dynamics simulations to reveal that enzyme specificity is linked to specific hydrophobic binding subsites for membrane phospholipid substrates. We have also defined unexpected headgroup and acyl chain specificity for each of the major human PLA2 enzymes, which explains the observed specificity at a structural level. Finally, we discovered that a unique hydrophobic binding site—and not each enzyme’s catalytic residues or polar headgroup binding site—predominantly determines enzyme specificity. We also discuss how PLA2s release specific fatty acids after allosteric enzyme association with membranes and extraction of the phospholipid substrate, which can be blocked by stereospecific inhibitors. After decades of work, we can now correlate PLA2 specificity and inhibition potency with molecular structure and physiological function. 相似文献