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1.
J Transl Med ; 22(1): 290, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500157

RESUMO

Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in maintaining redox and metabolic balance, regulating endoplasmic reticulum stress, modulating chemoresistance, and providing essential biomolecules and ATP have been well established in tumor cells. The balance between lipid droplet formation and catabolism is critical to maintaining energy metabolism in tumor cells, while the process of energy metabolism affects various functions essential for tumor growth. The imbalance of synthesis and catabolism of fatty acids in tumor cells leads to the alteration of lipid droplet content in tumor cells. Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2, the enzymes that catalyze the final step of triglyceride synthesis, participate in the formation of lipid droplets in tumor cells and in the regulation of cell proliferation, migration and invasion, chemoresistance, and prognosis in tumor. Several diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 inhibitors have been developed over the past decade and have shown anti-tumor effects in preclinical tumor models and improvement of metabolism in clinical trials. In this review, we highlight key features of fatty acid metabolism and different paradigms of diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 activities on cell proliferation, migration, chemoresistance, and prognosis in tumor, with the hope that these scientific findings will have potential clinical implications.


Assuntos
Diacilglicerol O-Aciltransferase , Neoplasias , Animais , Humanos , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Triglicerídeos/metabolismo , Metabolismo dos Lipídeos , Lipogênese , Proliferação de Células , Mamíferos/metabolismo
2.
Clin Transl Sci ; 17(2): e13687, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38362827

RESUMO

Co-administration of clesacostat (acetyl-CoA carboxylase inhibitor, PF-05221304) and ervogastat (diacylglycerol O-acyltransferase inhibitor, PF-06865571) in laboratory models improved non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) end points and mitigated clesacostat-induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion-transporting polypeptide-mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time-dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer-term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non-randomized, open-label, fixed-sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1-7) and co-administered with ervogastat 300 mg b.i.d. (Days 8-14). Mean systemic clesacostat exposures, when co-administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration-time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1-7) and co-administered with clesacostat 15 mg b.i.d. (Days 8-14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co-administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co-administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Piridinas , Adulto , Humanos , Voluntários Saudáveis , Citocromo P-450 CYP3A , Inibidores Enzimáticos/efeitos adversos , Interações Medicamentosas , Diacilglicerol O-Aciltransferase
3.
Cell Metab ; 36(3): 617-629.e7, 2024 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-38340721

RESUMO

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.


Assuntos
Diacilglicerol O-Aciltransferase , Hepatopatia Gordurosa não Alcoólica , Animais , Camundongos , Diacilglicerol O-Aciltransferase/metabolismo , Retículo Endoplasmático/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fosfatidiletanolaminas/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
4.
J Agric Food Chem ; 72(7): 3584-3595, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38344823

RESUMO

Astaxanthin esters are a major form of astaxanthin found in nature. However, the exact mechanisms of the biosynthesis and storage of astaxanthin esters were previously unknown. We found that Schizochytrium sp. synthesized both astaxanthin and docosahexaenoic acid (DHA)-enriched lipids. The major type of astaxanthin produced was free astaxanthin along with astaxanthin-DHA monoester and other esterified forms. DHA accounted for 41.0% of the total fatty acids from astaxanthin monoesters. These compounds were deposited mainly in lipid droplets. The biosynthesis of the astaxanthin esters was mainly carried out by a novel diacylglycerol acyltransferase ScDGAT2-1, while ScDGAT2-2 was involved only in the production of triacylglycerol. We also identified astaxanthin ester synthases from the astaxanthin-producing algae Haematococcus pluvialis and Chromochloris zofingiensis, as well as a thraustochytrid Hondaea fermentalgiana with an unknown carotenoid profile. This investigation enlightens the application of thraustochytrids for the production of both DHA and astaxanthin and provides enzyme resources for the biosynthesis of astaxanthin esters in the engineered microbes.


Assuntos
Clorofíceas , Estramenópilas , Ésteres , Diacilglicerol O-Aciltransferase/genética , Xantofilas , Estramenópilas/genética , Ácidos Docosa-Hexaenoicos
5.
Nat Commun ; 15(1): 79, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167301

RESUMO

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)-dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug-resistant cancer cells, such as 5-fluorouracil-resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil-resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.


Assuntos
Ferroptose , Neoplasias , Humanos , Gotículas Lipídicas/metabolismo , Ácidos Graxos Insaturados/metabolismo , Peroxidação de Lipídeos , Triglicerídeos/metabolismo , Pontos de Checagem do Ciclo Celular , Neoplasias/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico
6.
Int J Biol Macromol ; 259(Pt 1): 129078, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38176490

RESUMO

Docosahexaenoic acid (DHA) is known to have numerous health benefits and immense dietary value. There is a pressing need to have a deeper understanding of DHA metabolism. Acyl CoA: Diacylglycerol Acyltransferase (DGAT) is an important enzyme of lipid anabolism and an essential piece of the puzzle. Aurantiochytrium limacinum, a primary producer of DHA, is a good model for studying DHA metabolism. Thus, we aimed to investigate important lipid metabolic genes from A. limacinum. We cloned four putative DGATs (DGAT2a, DGAT2b, DGAT2c, and DGAT2d) from A. limacinum and performed detailed in vivo and in vitro characterization. Functional characterization showed that not all the studied genes exhibited DGAT activity. DGAT2a and DGAT2d conferred DGAT activity whereas DGAT2b showed wax synthase (WS) activity and DGAT2c showed dual function of both WS and DGAT. Based on their identified function, DGAT2b and DGAT2c were renamed as AlWS and AlWS/DGAT respectively. DGAT2a was found to exhibit a preference for DHA as a substrate. DGAT2d was found to have robust activity and emerged as a promising candidate for genetic engineering aimed at increasing oil yield. The study enriches our knowledge of lipid biosynthetic enzymes in A. limacinum, which can be utilized to design suitable application strategies.


Assuntos
Diacilglicerol O-Aciltransferase , Engenharia Genética , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Lipídeos
7.
Artigo em Inglês | MEDLINE | ID: mdl-38266530

RESUMO

Triacylglycerol (TAG) is crucial in animal energy storage and membrane biogenesis. The conversion of diacylglycerol (DAG) to triacylglycerol (TAG) is catalyzed by diacylglycerol acyltransferase enzymes (DGATs), which are encoded by genes belonging to two distinct gene families. Although arthropods are known to possess DGATs activities and utilize the glycerol-3-phosphate pathway and MAG pathway for TAG biosynthesis, the sequence characterization and evolutionary history of DGATs in arthropods remains unclear. This study aimed to comparatively evaluate genomic analyses of DGATs in 13 arthropod species and 14 outgroup species. We found that arthropods lack SOAT2 genes within the DGAT1 family, while DGAT2, MOGAT3, AWAT1, and AWAT2 were absent from in DGAT2 family. Gene structure and phylogenetic analyses revealed that DGAT1 and DGAT2 genes come from different gene families. The expression patterns of these genes were further analyzed in crustaceans, demonstrating the importance of DGAT1 in TAG biosynthesis. Additionally, we identified the DGAT1 gene in Swimming crab (P. trituberculatus) undergoes a mutually exclusive alternative splicing event in the molt stages. Our newly determined DGAT inventory data provide a more complete scenario and insights into the evolutionary dynamics and functional diversification of DGATs in arthropods.


Assuntos
Artrópodes , Diacilglicerol O-Aciltransferase , Animais , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Filogenia , Artrópodes/genética , Artrópodes/metabolismo , Triglicerídeos
8.
Cardiovasc Diabetol ; 23(1): 21, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195542

RESUMO

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.


Assuntos
Aterosclerose , MicroRNAs , Humanos , Fatores de Ribosilação do ADP , Espessura Intima-Media Carotídea , Diacilglicerol O-Aciltransferase , MicroRNAs/genética , Pró-Proteína Convertase 9 , Proteína Smad7 , Aterosclerose/genética
9.
Plant Physiol ; 194(2): 1024-1040, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-37930282

RESUMO

In the acyl-CoA-independent pathway of triacylglycerol (TAG) synthesis unique to plants, fungi, and algae, TAG formation is catalyzed by the enzyme phospholipid:diacylglycerol acyltransferase (PDAT). The unique PDAT gene of the model diatom Phaeodactylum tricornutum strain CCMP2561 boasts 47 single nucleotide variants within protein coding regions of the alleles. To deepen our understanding of TAG synthesis, we observed the allele-specific expression of PDAT by the analysis of 87 published RNA-sequencing (RNA-seq) data and experimental validation. The transcription of one of the two PDAT alleles, Allele 2, could be specifically induced by decreasing nitrogen concentrations. Overexpression of Allele 2 in P. tricornutum substantially enhanced the accumulation of TAG by 44% to 74% under nutrient stress; however, overexpression of Allele 1 resulted in little increase of TAG accumulation. Interestingly, a more serious growth inhibition was observed in the PDAT Allele 1 overexpression strains compared with Allele 2 counterparts. Heterologous expression in yeast (Saccharomyces cerevisiae) showed that enzymes encoded by PDAT Allele 2 but not Allele 1 had TAG biosynthetic activity, and 7 N-terminal and 3 C-terminal amino acid variants between the 2 allele-encoded proteins substantially affected enzymatic activity. P. tricornutum PDAT, localized in the innermost chloroplast membrane, used monogalactosyldiacylglycerol and phosphatidylcholine as acyl donors as demonstrated by the increase of the 2 lipids in PDAT knockout lines, which indicated a common origin in evolution with green algal PDATs. Our study reveals unequal roles among allele-encoded PDATs in mediating carbon storage and growth in response to nitrogen stress and suggests an unsuspected strategy toward lipid and biomass improvement for biotechnological purposes.


Assuntos
Diacilglicerol O-Aciltransferase , Diatomáceas , Diacilglicerol O-Aciltransferase/metabolismo , Diatomáceas/genética , Diatomáceas/metabolismo , Alelos , Especificidade por Substrato , Plantas/metabolismo , Fosfolipídeos , Nitrogênio , Triglicerídeos/metabolismo
10.
Oncogene ; 43(2): 136-150, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37973951

RESUMO

Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor.


Assuntos
Fenofibrato , Neoplasias da Próstata , Humanos , Masculino , Autofagia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Fenofibrato/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Estresse Oxidativo , Próstata/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo
12.
Proc Natl Acad Sci U S A ; 120(51): e2302161120, 2023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38079544

RESUMO

Gastroenteritis is among the leading causes of mortality globally in infants and young children, with rotavirus (RV) causing ~258 million episodes of diarrhea and ~128,000 deaths annually in infants and children. RV-induced mechanisms that result in diarrhea are not completely understood, but malabsorption is a contributing factor. RV alters cellular lipid metabolism by inducing lipid droplet (LD) formation as a platform for replication factories named viroplasms. A link between LD formation and gastroenteritis has not been identified. We found that diacylglycerol O-acyltransferase 1 (DGAT1), the terminal step in triacylglycerol synthesis required for LD biogenesis, is degraded in RV-infected cells by a proteasome-mediated mechanism. RV-infected DGAT1-silenced cells show earlier and increased numbers of LD-associated viroplasms per cell that translate into a fourfold-to-fivefold increase in viral yield (P < 0.05). Interestingly, DGAT1 deficiency in children is associated with diarrhea due to altered trafficking of key ion transporters to the apical brush border of enterocytes. Confocal microscopy and immunoblot analyses of RV-infected cells and DGAT1-/- human intestinal enteroids (HIEs) show a decrease in expression of nutrient transporters, ion transporters, tight junctional proteins, and cytoskeletal proteins. Increased phospho-eIF2α (eukaryotic initiation factor 2 alpha) in DGAT1-/- HIEs, and RV-infected cells, indicates a mechanism for malabsorptive diarrhea, namely inhibition of translation of cellular proteins critical for nutrient digestion and intestinal absorption. Our study elucidates a pathophysiological mechanism of RV-induced DGAT1 deficiency by protein degradation that mediates malabsorptive diarrhea, as well as a role for lipid metabolism, in the pathogenesis of gastroenteritis.


Assuntos
Gastroenterite , Infecções por Rotavirus , Rotavirus , Criança , Lactente , Humanos , Pré-Escolar , Rotavirus/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Replicação Viral , Diarreia , Infecções por Rotavirus/genética
13.
Appl Environ Microbiol ; 89(11): e0100123, 2023 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-37874286

RESUMO

IMPORTANCE: Since the global market for sterols and vitamin D are grown with a high compound annual growth rate, a sustainable source of these compounds is required to keep up with the increasing demand. Thraustochytrid is a marine oleaginous microorganism that can synthesize several sterols, which are stored as SE in lipid droplets. DGAT2C is an unconventional SE synthase specific to thraustochytrids. Although the primary structure of DGAT2C shows high similarities with that of DGAT, DGAT2C utilizes sterol as an acceptor substrate instead of diacylglycerol. In this study, we examined more detailed enzymatic properties, intracellular localization, and structure-activity relationship of DGAT2C. Furthermore, we successfully developed a method to increase sterol and provitamin D3 productivity of thraustochytrid by more than threefold in the process of elucidating the function of the DGAT2C-specific N-terminal region. Our findings could lead to sustainable sterol and vitamin D production using thraustochytrid.


Assuntos
Esterol O-Aciltransferase , Esteróis , Gotículas Lipídicas , Vitamina D , Diacilglicerol O-Aciltransferase/genética
14.
FASEB J ; 37(11): e23209, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37779421

RESUMO

The roles of DGAT1 and DGAT2 in lipid metabolism and insulin responsiveness of human skeletal muscle were studied using cryosections and myotubes prepared from muscle biopsies from control, athlete, and impaired glucose regulation (IGR) cohorts of men. The previously observed increases in intramuscular triacylglycerol (IMTG) in athletes and IGR were shown to be related to an increase in lipid droplet (LD) area in type I fibers in athletes but, conversely, in type II fibers in IGR subjects. Specific inhibition of both diacylglycerol acyltransferase (DGAT) 1 and 2 decreased fatty acid (FA) uptake by myotubes, whereas only DGAT2 inhibition also decreased fatty acid oxidation. Fatty acid uptake in myotubes was negatively correlated with the lactate thresholds of the respective donors. DGAT2 inhibition lowered acetate uptake and oxidation in myotubes from all cohorts whereas DGAT1 inhibition had no effect. A positive correlation between acetate oxidation in myotubes and resting metabolic rate (RMR) from fatty acid oxidation in vivo was observed. Myotubes from athletes and IGR had higher rates of de novo lipogenesis from acetate that were normalized by DGAT2 inhibition. Moreover, DGAT2 inhibition in myotubes also resulted in increased insulin-induced Akt phosphorylation. The differential effects of DGAT1 and DGAT2 inhibition suggest that the specialized role of DGAT2 in esterifying nascent diacylglycerols and de novo synthesized FA is associated with synthesis of a pool of triacylglycerol, which upon hydrolysis results in effectors that promote mitochondrial fatty acid oxidation but decrease insulin signaling in skeletal muscle cells.


Assuntos
Diacilglicerol O-Aciltransferase , Fibras Musculares Esqueléticas , Masculino , Humanos , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Glucose/metabolismo , Insulina , Acetatos , Triglicerídeos/metabolismo , Ácidos Graxos/metabolismo
15.
Bioresour Technol ; 389: 129850, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37813314

RESUMO

Low (15 °C) and high (35 °C) temperatures significantly increased DHA as a percentage of total fatty acids (TFAs) to 43.6 % and 40.46 %, respectively (1.28- and 1.18-fold of that at 25 °C, respectively). The incompleteness of the FAS pathway indicates that DHA synthesis does not occur via this pathway. Meanwhile, Comparative transcriptome analysis showed that the PUFA synthase pathway might be responsible for DHA synthesis in C. sp. SUN. Additionally, the three diacylglycerol acyltransferases all had a substrate preference for saturated fatty acid (SFA)-CoA, which also contributed to the decreased SFA and increased DHA at both low and high temperatures. Additionally, WGCNA analysis identifies key regulatory genes that may be involved in temperature-regulated DHA proportion. The findings of this study indicate the mechanisms of temperature-regulated DHA accumulation in C. sp. SUN and shed light on the manipulation of DHA proportion by changes in temperature.


Assuntos
Ácidos Docosa-Hexaenoicos , Ácidos Graxos , Ácidos Graxos/metabolismo , Diacilglicerol O-Aciltransferase , Temperatura , Diglicerídeos , Ácidos Graxos Insaturados
16.
Sci Rep ; 13(1): 14805, 2023 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-37684349

RESUMO

Stimulation of glucose uptake in response to ischemic metabolic stress is important for cardiomyocyte function and survival. Chronic exposure of cardiomyocytes to fatty acids (FA) impairs the stimulation of glucose uptake, whereas induction of lipid droplets (LD) is associated with preserved glucose uptake. However, the mechanisms by which LD induction prevents glucose uptake impairment remain elusive. We induced LD with either tetradecanoyl phorbol acetate (TPA) or 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR). Triacylglycerol biosynthesis enzymes were inhibited in cardiomyocytes exposed to FA ± LD inducers, either upstream (glycerol-3-phosphate acyltransferases; GPAT) or downstream (diacylglycerol acyltransferases; DGAT) of the diacylglycerol step. Although both inhibitions reduced LD formation in cardiomyocytes treated with FA and LD inducers, only DGAT inhibition impaired metabolic stress-stimulated glucose uptake. DGAT inhibition in FA plus TPA-treated cardiomyocytes reduced triacylglycerol but not diacylglycerol content, thus increasing the diacylglycerol/triacylglycerol ratio. In cardiomyocytes exposed to FA alone, GPAT inhibition reduced diacylglycerol but not triacylglycerol, thus decreasing the diacylglycerol/triacylglycerol ratio, prevented PKCδ activation and improved metabolic stress-stimulated glucose uptake. Changes in AMP-activated Protein Kinase activity failed to explain variations in metabolic stress-stimulated glucose uptake. Thus, LD formation regulates metabolic stress-stimulated glucose uptake in a manner best reflected by the diacylglycerol/triacylglycerol ratio.


Assuntos
Diacilglicerol O-Aciltransferase , Miócitos Cardíacos , Transporte Biológico , Ácidos Graxos , Acetato de Tetradecanoilforbol , Glucose
17.
Nature ; 621(7977): 171-178, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37648867

RESUMO

Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.


Assuntos
Aciltransferases , Triglicerídeos , Animais , Humanos , Camundongos , Aciltransferases/metabolismo , Coenzima A/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Escherichia coli/metabolismo , Homeostase , Triglicerídeos/biossíntese , Metabolismo Energético , Nutrientes/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo
18.
Mol Metab ; 76: 101791, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37586657

RESUMO

OBJECTIVES: Polyunsaturated fatty acids (PUFAs) are structural components of membrane phospholipids and precursors of oxygenated lipid mediators with diverse functions, including the control of cell growth, inflammation and tumourigenesis. However, the molecular pathways that control the availability of PUFAs for lipid mediator production are not well understood. Here, we investigated the crosstalk of three pathways in the provision of PUFAs for lipid mediator production: (i) secreted group X phospholipase A2 (GX sPLA2) and (ii) cytosolic group IVA PLA2 (cPLA2α), both mobilizing PUFAs from membrane phospholipids, and (iii) adipose triglyceride lipase (ATGL), which mediates the degradation of triacylglycerols (TAGs) stored in cytosolic lipid droplets (LDs). METHODS: We combined lipidomic and functional analyses in cancer cell line models to dissect the trafficking of PUFAs between membrane phospholipids and LDs and determine the role of these pathways in lipid mediator production, cancer cell proliferation and tumour growth in vivo. RESULTS: We demonstrate that lipid mediator production strongly depends on TAG turnover. GX sPLA2 directs ω-3 and ω-6 PUFAs from membrane phospholipids into TAG stores, whereas ATGL is required for their entry into lipid mediator biosynthetic pathways. ATGL controls the release of PUFAs from LD stores and their conversion into cyclooxygenase- and lipoxygenase-derived lipid mediators under conditions of nutrient sufficiency and during serum starvation. In starving cells, ATGL also promotes the incorporation of LD-derived PUFAs into phospholipids, representing substrates for cPLA2α. Furthermore, we demonstrate that the built-up of TAG stores by acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is required for the production of mitogenic lipid signals that promote cancer cell proliferation and tumour growth. CONCLUSION: This study shifts the paradigm of PLA2-driven lipid mediator signalling and identifies LDs as central lipid mediator production hubs. Targeting DGAT1-mediated LD biogenesis is a promising strategy to restrict lipid mediator production and tumour growth.


Assuntos
Gotículas Lipídicas , Neoplasias , Humanos , Gotículas Lipídicas/metabolismo , Fosfolipases A2 do Grupo X/metabolismo , Lipase/metabolismo , Ácidos Graxos Insaturados/metabolismo , Fosfolipídeos/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Neoplasias/metabolismo , Proliferação de Células
19.
PeerJ ; 11: e15724, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37583911

RESUMO

Background: Olive (Olea europaea L.) oil accumulate more diacylglycerols (DAG) than mostly vegetable oils. Unsaturated fatty acids-enriched DAG consumption enhanced wellness in subjects. However, the mechanism of DAG accumulation is not yet fully understood. Methods: In this study, gene network of DAG accumulation and fatty acid composition in the two olive mesocarps ("Chenggu 32" (CG) and "Koroneiki" (QJ)) were investigated by integrating lipidome and transcriptome techniques. Results: A total of 1,408 lipid molecules were identified by lipidomic analysis in olive mesocarp, of which DAG (DAG36:3, DAG36:4 and DAG36:5) showed higher content, and triacylglycerols (TAG54:3, TAG54:4) exhibited opposite trend in CG. Specifically, DAG was rich in polyunsaturated fatty acids (especially C18:2) at the sn-2 position, which was inconsistent with TAG at the same positions (Primarily C18:1). Transcriptomic analysis revealed that phospholipase C (NPC, EC 3.1.4.3) were up-regulated relative to QJ, whereas diacylglycerol kinase (ATP) (DGK, EC 2.7.1.107), diacylglycerol acyltransferase (DGAT, EC 2.3.1.20), and phospholipid: diacylglycerol acyltransferase (PDAT, EC 2.3.1.158) were down-regulated. Conclusion: We speculated that the non-acyl coenzyme A pathway played a significant role in DAG biosynthesis. Additionally, fatty acyl-ACP thioesterase B (FATB, EC 3.1.2.14), stearoyl [acyl-carrier-protein] 9-desaturase (SAD, EC 1.14.19.2) and omega-6 fatty acid desaturase (FAD2, EC 1.14.19.6) were highly expressed in CG and may be involved in regulating fatty acid composition. Meanwhile, phospholipase A1 (LCAT, EC 3.1.1.32) involved in the acyl editing reaction facilitated PUFA linkage at the sn-2 position of DAG. Our findings provide novel insights to increase the DAG content, improve the fatty acid composition of olive oil, and identify candidate genes for the production of DAG-rich oils.


Assuntos
Olea , Humanos , Olea/genética , Lipidômica , Diacilglicerol O-Aciltransferase/genética , Diglicerídeos/metabolismo , Transcriptoma/genética , Ácidos Graxos , Ácidos Graxos Insaturados
20.
BMC Plant Biol ; 23(1): 370, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37491206

RESUMO

BACKGROUND: Extensive population growth and climate change accelerate the search for alternative ways of plant-based biomass, biofuel and feed production. Here, we focus on hitherto unknow, new promising cold-stimulated function of phospholipid:diacylglycerol acyltransferase1 (PDAT1) - an enzyme catalyzing the last step of triacylglycerol (TAG) biosynthesis. RESULT: Overexpression of AtPDAT1 boosted seed yield by 160% in Arabidopsis plants exposed to long-term cold compared to standard conditions. Such seeds increased both their weight and acyl-lipids content. This work also elucidates PDAT1's role in leaves, which was previously unclear. Aerial parts of AtPDAT1-overexpressing plants were characterized by accelerated growth at early and vegetative stages of development and by biomass weighing three times more than control. Overexpression of PDAT1 increased the expression of SUGAR-DEPENDENT1 (SDP1) TAG lipase and enhanced lipid remodeling, driving lipid turnover and influencing biomass increment. This effect was especially pronounced in cold conditions, where the elevated synergistic expression of PDAT1 and SDP1 resulted in double biomass increase compared to standard conditions. Elevated phospholipid remodeling also enhanced autophagy flux in AtPDAT1-overexpresing lines subjected to cold, despite the overall diminished autophagy intensity in cold conditions. CONCLUSIONS: Our data suggest that PDAT1 promotes greater vitality in cold-exposed plants, stimulates their longevity and boosts oilseed oil production at low temperature.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Fosfolipídeos/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Diglicerídeos/metabolismo , Triglicerídeos , Arabidopsis/metabolismo , Plantas/metabolismo , Sementes , Plantas Geneticamente Modificadas/metabolismo , Óleos de Plantas/metabolismo , Hidrolases de Éster Carboxílico/metabolismo
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