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1.
World J Gastroenterol ; 27(39): 6522-6526, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34754150

RESUMO

De novo lipogenesis (DNL) plays an important role in the pathogenesis of hepatic steatosis and also appears to be implicated in hepatic inflammation and fibrosis. Accordingly, the inhibition of acetyl-CoA carboxylase, which catalyzes the rate-limiting step of DNL, might represent a useful approach in the management of patients with nonalcoholic fatty liver disease (NAFLD). Animal studies and preliminary data in patients with NAFLD consistently showed an improvement in steatosis with the use of these agents. However, effects on fibrosis were variable and an increase in plasma triglyceride levels was observed. Therefore, more long-term studies are needed to clarify the role of these agents in NAFLD and to determine their risk/benefit profile.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Acetil-CoA Carboxilase/metabolismo , Animais , Humanos , Lipogênese , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo
2.
Elife ; 102021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467853

RESUMO

Stimulator of interferon genes (STING) plays an important role in innate immunity by controlling type I interferon response against invaded pathogens. In this work, we describe a previously unknown role of STING in lipid metabolism in Drosophila. Flies with STING deletion are sensitive to starvation and oxidative stress, have reduced lipid storage, and downregulated expression of lipid metabolism genes. We found that Drosophila STING interacts with lipid synthesizing enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). ACC and FASN also interact with each other, indicating that all three proteins may be components of a large multi-enzyme complex. The deletion of Drosophila STING leads to disturbed ACC localization and decreased FASN enzyme activity. Together, our results demonstrate a previously undescribed role of STING in lipid metabolism in Drosophila.


Assuntos
Proteínas de Drosophila , Drosophila melanogaster/genética , Metabolismo dos Lipídeos/genética , Proteínas de Membrana , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiologia , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Deleção de Genes , Técnicas de Inativação de Genes , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/fisiologia
3.
J Biol Chem ; 297(3): 101104, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34425110

RESUMO

Diabetic retinopathy (DR) is an increasingly frequent cause of blindness across populations; however, the events that initiate pathophysiology of DR remain elusive. Strong preclinical and clinical evidence suggests that abnormalities in retinal lipid metabolism caused by diabetes may account for the origin of this disease. A major arm of lipid metabolism, de novo biosynthesis, is driven by elevation in available glucose, a common thread binding all forms of vision loss in diabetes. Therefore, we hypothesized that aberrant retinal lipid biogenesis is an important promoter of early DR. In murine models, we observed elevations of diabetes-associated retinal de novo lipogenesis ∼70% over control levels. This shift was primarily because of activation of fatty acid synthase (FAS), a rate-limiting enzyme in the biogenic pathway. Activation of FAS was driven by canonical glucose-mediated disinhibition of acetyl-CoA carboxylase, a major upstream regulatory enzyme. Mutant mice expressing gain-of-function FAS demonstrated increased vulnerability to DR, whereas those with FAS deletion in rod photoreceptors maintained preserved visual responses upon induction of diabetes. Excess retinal de novo lipogenesis-either because of diabetes or because of FAS gain of function-was associated with modestly increased levels of palmitate-containing phosphatidylcholine species in synaptic membranes, a finding with as yet uncertain significance. These findings implicate glucose-dependent increases in photoreceptor de novo lipogenesis in the early pathogenesis of DR, although the mechanism of deleterious action of this pathway remains unclear.


Assuntos
Retinopatia Diabética/etiologia , Lipogênese/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Acetil-CoA Carboxilase/metabolismo , Animais , Diabetes Mellitus/metabolismo , Retinopatia Diabética/metabolismo , Ácido Graxo Sintases/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Retina/patologia
4.
Elife ; 102021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34382934

RESUMO

Alterations to the androgen receptor (AR) signalling axis and cellular metabolism are hallmarks of prostate cancer. This study provides insight into both hallmarks by uncovering a novel link between AR and the pentose phosphate pathway (PPP). Specifically, we identify 6-phosphogluoconate dehydrogenase (6PGD) as an androgen-regulated gene that is upregulated in prostate cancer. AR increased the expression of 6PGD indirectly via activation of sterol regulatory element binding protein 1 (SREBP1). Accordingly, loss of 6PGD, AR or SREBP1 resulted in suppression of PPP activity as revealed by 1,2-13C2 glucose metabolic flux analysis. Knockdown of 6PGD also impaired growth and elicited death of prostate cancer cells, at least in part due to increased oxidative stress. We investigated the therapeutic potential of targeting 6PGD using two specific inhibitors, physcion and S3, and observed substantial anti-cancer activity in multiple models of prostate cancer, including aggressive, therapy-resistant models of castration-resistant disease as well as prospectively collected patient-derived tumour explants. Targeting of 6PGD was associated with two important tumour-suppressive mechanisms: first, increased activity of the AMP-activated protein kinase (AMPK), which repressed anabolic growth-promoting pathways regulated by acetyl-CoA carboxylase 1 (ACC1) and mammalian target of rapamycin complex 1 (mTORC1); and second, enhanced AR ubiquitylation, associated with a reduction in AR protein levels and activity. Supporting the biological relevance of positive feedback between AR and 6PGD, pharmacological co-targeting of both factors was more effective in suppressing the growth of prostate cancer cells than single-agent therapies. Collectively, this work provides new insight into the dysregulated metabolism of prostate cancer and provides impetus for further investigation of co-targeting AR and the PPP as a novel therapeutic strategy.


Assuntos
Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Linhagem Celular , Emodina/análogos & derivados , Retroalimentação , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Via de Pentose Fosfato , Neoplasias da Próstata/genética , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
5.
Elife ; 102021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34254587

RESUMO

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood ß-hydroxybutarate (ß-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. ß-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of ß-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.


Assuntos
Anestésicos/metabolismo , Anestésicos/farmacologia , Ácido 3-Hidroxibutírico , Acetil-CoA Carboxilase/metabolismo , Animais , Citratos/metabolismo , Ácido Cítrico/metabolismo , Ácidos Graxos/metabolismo , Feminino , Glucose/metabolismo , Hipoglicemia , Isoflurano/metabolismo , Cetose , Masculino , Malonil Coenzima A/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias , Oxirredução
6.
J Clin Invest ; 131(16)2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34255743

RESUMO

In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden "foamy" macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiologia , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Proteínas Proto-Oncogênicas/metabolismo , Triglicerídeos/metabolismo , Proteínas Wnt/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Animais , Antituberculosos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Células Espumosas/metabolismo , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Isoniazida/administração & dosagem , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/efeitos dos fármacos , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Transdução de Sinais/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/microbiologia , Proteínas Wnt/deficiência , Proteínas Wnt/genética
7.
Anticancer Res ; 41(7): 3389-3400, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230134

RESUMO

BACKGROUND/AIM: Cholangiocarcinoma (CCA), a biliary cancer, is a health problem worldwide. The major problem in CCA treatment presents limited options. To date, targeting cancer metabolism is a promising anti-cancer strategy. To elucidate the functional importance of lipid metabolism in CCA, de novo lipogenesis was inhibited using 5-(tetradecyloxy)-2-furoic acid (TOFA), an acetyl CoA carboxylase inhibitor. MATERIALS AND METHODS: Anti-proliferative effects of TOFA were determined both in vitro and in vivo. Its inhibitory effect on cell-cycle and apoptosis was investigated by flow cytometry and western blot analysis of relevant markers. RESULTS: TOFA inhibited CCA cell growth, induced cell-cycle progression accompanied by apoptosis in a dose-dependent manner. Induction of p21, and caspase-3, -8, and -9 cleavages, while down-regulation of cyclin B1 and cyclin D1 were observed in TOFA-treated cells. The therapeutic potential was demonstrated in vivo. CONCLUSION: De novo lipogensis is essential for CCA cell growth and is an alternative target for CCA treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Furanos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos
8.
Biomed Res Int ; 2021: 9979768, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34258288

RESUMO

Materials and Methods: Rat L6 skeletal muscle cells were cultured in 25 cm2 flasks. These differentiated cells were treated, and then, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) (probe-based) was used to measure the relative mRNA expression level for metabolic, inflammatory, and nuclear receptor genes including peroxisome proliferator-activated receptor gamma (PGC-1α), carnitine palmitoyl transferase 1 beta (CPT1B), long-chain acyl-CoA de hydrogenase (LCAD), acetyl-CoA carboxylase beta (ACCß), pyruvate dehydrogenase kinase 4 (PDK4), hexokinase II (HKII), phosphofructokinase (PFK), interleukin-6 (IL-6), and nuclear receptor subfamily 4, group A (NR4A) at different treatment conditions. Results: Adenosine-5'-N-ethyluronamide (NECA), a stable adenosine analogue, significantly stimulate inflammatory mediator (IL-6) (p < 0.001) and nuclear receptors (NR4A) (p < 0.05) and significantly modulate metabolic (PFK, LCAD, PGC-1α, and CPT1B) gene expressions in skeletal muscle cells (p < 0.05, p < 0.05, p < 0.001, and p < 0.01, respectively). This present study shows that there is a noteworthy crosstalk between NECA and insulin at various metabolic levels including glycolysis (HKII), fatty acid oxidation (ACCß), and insulin sensitivity (PDK4). Conclusions: A novel crosstalk between adenosine analogue and insulin has been demonstrated for the first time; evidence has been gathered in vitro for the effects of NECA and insulin treatment on intracellular signaling pathways, in particular glycolysis and insulin sensitivity in skeletal muscle cells.


Assuntos
Adenosina-5'-(N-etilcarboxamida)/farmacologia , Adenosina/análogos & derivados , Insulina/metabolismo , Músculo Esquelético/citologia , Transdução de Sinais/efeitos dos fármacos , Acetil-CoA Carboxilase/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Adenosina/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Hexoquinase/metabolismo , Inflamação , Interleucina-6/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosfofrutoquinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética
9.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34073834

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid ß-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos/metabolismo , Lipogênese/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptores Purinérgicos P2Y2/metabolismo , Acetil-CoA Carboxilase/metabolismo , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Peso Corporal , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Ácido Graxo Sintases/metabolismo , Insulina/sangue , Resistência à Insulina/fisiologia , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/enzimologia , Obesidade/metabolismo , Receptores Purinérgicos P2Y2/deficiência , Receptores Purinérgicos P2Y2/genética , Estearoil-CoA Dessaturase/metabolismo
10.
Nutrients ; 13(6)2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34063748

RESUMO

A high-fat diet often leads to excessive fat deposition and adversely affects the organism. However, the mechanism of liver fat deposition induced by high fat is still unclear. Therefore, this study aimed at acetyl-CoA carboxylase (ACC) to explore the mechanism of excessive liver deposition induced by high fat. In the present study, the ORF of ACC1 and ACC2 were cloned and characterized. Meanwhile, the mRNA and protein of ACC1 and ACC2 were increased in liver fed with a high-fat diet (HFD) or in hepatocytes incubated with oleic acid (OA). The phosphorylation of ACC was also decreased in hepatocytes incubated with OA. Moreover, AICAR dramatically improved the phosphorylation of ACC, and OA significantly inhibited the phosphorylation of the AMPK/ACC pathway. Further experiments showed that OA increased global O-GlcNAcylation and agonist of O-GlcNAcylation significantly inhibited the phosphorylation of AMPK and ACC. Importantly, the disorder of lipid metabolism caused by HFD or OA could be rescued by treating CP-640186, the dual inhibitor of ACC1 and ACC2. These observations suggested that high fat may activate O-GlcNAcylation and affect the AMPK/ACC pathway to regulate lipid synthesis, and also emphasized the importance of the role of ACC in lipid homeostasis.


Assuntos
Acilação/efeitos dos fármacos , Gorduras na Dieta/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , N-Acetilglucosaminiltransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/metabolismo , Células Clonais , Dieta Hiperlipídica/efeitos adversos , Hepatócitos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Morfolinas/farmacologia , Ácido Oleico/farmacologia , Fosforilação/efeitos dos fármacos , Piperidinas/farmacologia , Ribonucleotídeos/metabolismo
11.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128473

RESUMO

Cancer cells reprogram lipid metabolism during their malignant progression, but limited information is currently available on the involvement of alterations in fatty acid synthesis in cancer development. We herein demonstrate that acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme for fatty acid synthesis, plays a critical role in regulating the growth and differentiation of leukemia-initiating cells. The Trib1-COP1 complex is an E3 ubiquitin ligase that targets C/EBPA, a transcription factor regulating myeloid differentiation, for degradation, and its overexpression specifically induces acute myeloid leukemia (AML). We identified ACC1 as a target of the Trib1-COP1 complex and found that an ACC1 mutant resistant to degradation because of the lack of a Trib1-binding site attenuated complex-driven leukemogenesis. Stable ACC1 protein expression suppressed the growth-promoting activity and increased ROS levels with the consumption of NADPH in a primary bone marrow culture, and delayed the onset of AML with increases in mature myeloid cells in mouse models. ACC1 promoted the terminal differentiation of Trib1-COP1-expressing cells and eradicated leukemia-initiating cells in the early phase of leukemic progression. These results indicate that ACC1 is a natural inhibitor of AML development. The upregulated expression of the ACC1 protein has potential as an effective strategy for cancer therapy.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Ácidos Graxos/biossíntese , Leucemia Mieloide Aguda/enzimologia , Proteínas de Neoplasias/metabolismo , Proteólise , Acetil-CoA Carboxilase/genética , Animais , Estabilidade Enzimática , Ácidos Graxos/genética , Células HEK293 , Células HL-60 , Humanos , Células K562 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Camundongos , Mutação , Proteínas de Neoplasias/genética , Células THP-1 , Células U937
12.
Biochem Biophys Res Commun ; 567: 138-142, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34153683

RESUMO

Liver X receptors (LXR) α and ß are a family of nuclear receptors that regulate lipogenesis by controlling the expression of the genes involved in the synthesis of fatty acids. MID1IP1, which encodes MIG12, is a target gene of LXR. MIG12 induces fatty acid synthesis by stimulating the polymerization-mediated activation of acetyl-CoA carboxylase (ACC). Here, we show that LXR's activation stimulates ACC polymerization in HepG2 cells by increasing the expression of MIG12. A knockdown of MID1IP1 abrogated the stimulation completely. The mutations of MIG12's leucine-zipper domain reduced the interaction between MIG12 and ACC, thus decreasing the MIG12's capacity to stimulate ACC polymerization. These results indicate that LXR's activation stimulates lipogenesis not only through the induction of the genes encoding lipogenic enzymes but also through MIG12's stimulation of ACC polymerization.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Receptores X do Fígado/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Lipogênese , Polimerização
13.
Microbiol Mol Biol Rev ; 85(3): e0003221, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34132100

RESUMO

Escherichia coli acetyl-CoA carboxylase (ACC), the enzyme responsible for synthesis of malonyl-CoA, the building block of fatty acid synthesis, is the paradigm bacterial ACC. Many reports on the structures and stoichiometry of the four subunits comprising the active enzyme as well as on regulation of ACC activity and expression have appeared in the almost 20 years since this subject was last reviewed. This review seeks to update and expand on these reports.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/metabolismo , Lipídeos/química
14.
J Biochem Mol Toxicol ; 35(7): e22797, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33957017

RESUMO

Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Increasing evidence shows that acetyl-CoA carboxylase 2 (ACC2) plays a crucial role in the metabolism of fatty acid, but its effect in podocyte injury of DN is still unclear. In this study, we investigated whether ACC2 could be a therapeutic target of lipid deposition induced by hyperglycemia in the human podocytes. Our results showed that high glucose (HG) triggered significant lipid deposition with a reduced ß-oxidation rate. It also contributed to the downregulation of phosphorylated ACC2 (p-ACC2), which is an inactive form of ACC2. Knockdown of ACC2 by sh-RNA reduced lipid deposition induced by HG. Additionally, ACC2-shRNA restored the expression of glucose transporter 4 (GLUT4) on the cell surface, which was downregulated in HG and normalized in the insulin signaling pathway. We verified that ACC2-shRNA alleviated cell injury, apoptosis, and restored the cytoskeleton disturbed by HG. Mechanistically, SIRT1/PGC-1α is close related to the insulin metabolism pathway. ACC2-shRNA could restore the expression of SIRT1/PGC-1α, which was downregulated in HG. Rescue experiment revealed that inhibition of SIRT1 by EX-527 counteracted the effect of ACC2-shRNA. Taken together, our data suggest that podocyte injury mediated by HG-induced insulin resistance and lipotoxicity could be alleviated by ACC2 inhibition via SIRT1/PGC-1α.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Glucose/farmacologia , Resistência à Insulina , Metabolismo dos Lipídeos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Podócitos/metabolismo , Sirtuína 1/metabolismo , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/genética , Humanos , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Sirtuína 1/genética
15.
Food Funct ; 12(12): 5274-5286, 2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34008635

RESUMO

Clarifying the health risks associated with the consumption of high-melting-temperature solid triacylglycerol (TAG) from milk fat has profound significance for the nutritional evaluation and development of new dairy products. Our previous work effectively separated butterfat into solid/liquid fractions (30S and 30L) at 30 °C and successfully reconstituted milk fat globules (MFGs) with these fractions. The current study examined the postprandial digestive and daily metabolic properties of a high-melting-temperature solid TAG fraction by performing animal experiments (rats) with 30S-reconstituted MFG emulsion gavage for 240 min and 30S-containing diet administration for 4 weeks. Compared to the consumption of whole butterfat, 30S consumption altered apolipoprotein levels and did not lead to dyslipidaemia in the rats. Conversely, 30S administration induced significant body weight loss by enhancing satiety signals (glucagon-like peptide 1, GLP-1; cholecystokinin, CCK; and peptide YY, PYY), increasing faecal losses, and upregulating the level of hepatic lipolysis-associated enzymes (hormone-sensitive lipase, HSL; adipose triglyceride lipase, ATGL; and protein kinase A, PKA). The 30S diet efficiently improved adipocyte hypertrophy and reduced fat accumulation by downregulating the level of acetyl-CoA carboxylase (ACC) in adipose tissue. This study is of relevance to nutrition science and the dairy industry.


Assuntos
Digestão , Glicolipídeos/metabolismo , Glicoproteínas/metabolismo , Gotículas Lipídicas/metabolismo , Leite/metabolismo , Temperatura , Triglicerídeos/metabolismo , Acetil-CoA Carboxilase/metabolismo , Tecido Adiposo/metabolismo , Animais , Disponibilidade Biológica , Bovinos , Lipólise/efeitos dos fármacos , Fígado/patologia , Masculino , Modelos Animais , Peptídeo YY , Período Pós-Prandial , Ratos , Esterol Esterase/metabolismo
16.
Plant Physiol ; 185(3): 892-901, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33793910

RESUMO

Hundreds of naturally occurring specialized fatty acids (FAs) have potential as desirable chemical feedstocks if they could be produced at large scale by crop plants; however, transgenic expression of their biosynthetic genes has generally been accompanied by dramatic reductions in oil yield. For example, expression of castor (Ricinus communis) FA hydroxylase (FAH) in the Arabidopsis thaliana FA elongation mutant fae1 resulted in a 50% reduction of FA synthesis rate that was attributed to inhibition of acetyl-CoA carboxylase (ACCase) by an undefined mechanism. Here, we tested the hypothesis that the ricinoleic acid-dependent decrease in ACCase activity is mediated by biotin attachment domain-containing (BADC) proteins. BADCs are inactive homologs of biotin carboxy carrier protein that lack a biotin cofactor and can inhibit ACCase. Arabidopsis contains three BADC genes. To reduce expression levels of BADC1 and BADC3 in fae1/FAH plants, a homozygous badc1,3/fae1/FAH line was created. The rate of FA synthesis in badc1,3/fae1/FAH seeds doubled relative to fae1/FAH, restoring it to fae1 levels, increasing both native FA and HFA accumulation. Total FA per seed, seed oil content, and seed yield per plant all increased in badc1,3/fae1/FAH, to 5.8 µg, 37%, and 162 mg, respectively, relative to 4.9 µg, 33%, and 126 mg, respectively, for fae1/FAH. Transcript levels of FA synthesis-related genes, including those encoding ACCase subunits, did not significantly differ between badc1,3/fae1/FAH and fae1/FAH. These results demonstrate that BADC1 and BADC3 mediate ricinoleic acid-dependent inhibition of FA synthesis. We propose that BADC-mediated FAS inhibition as a general mechanism that limits FA accumulation in specialized FA-accumulating seeds.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Biotina/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas
17.
Plant Physiol ; 185(3): 1091-1110, 2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33793919

RESUMO

De novo fatty acid biosynthesis in plants relies on a prokaryotic-type acetyl-CoA carboxylase (ACCase) that resides in the plastid compartment. The enzyme is composed of four subunits, one of which is encoded in the plastid genome, whereas the other three subunits are encoded by nuclear genes. The plastid gene (accD) encodes the ß-carboxyltransferase subunit of ACCase and is essential for cell viability. To facilitate the functional analysis of accD, we pursued a transplastomic knockdown strategy in tobacco (Nicotiana tabacum). By introducing point mutations into the translational start codon of accD, we obtained stable transplastomic lines with altered ACCase activity. Replacement of the standard initiator codon AUG with UUG strongly reduced AccD expression, whereas replacement with GUG had no detectable effects. AccD knockdown mutants displayed reduced ACCase activity, which resulted in changes in the levels of many but not all species of cellular lipids. Limiting fatty acid availability caused a wide range of macroscopic, microscopic, and biochemical phenotypes, including impaired chloroplast division, reduced seed set, and altered storage metabolism. Finally, while the mutants displayed reduced growth under photoautotrophic conditions, they showed exaggerated growth under heterotrophic conditions, thus uncovering an unexpected antagonistic role of AccD activity in autotrophic and heterotrophic growth.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Cloroplastos/metabolismo , Folhas de Planta/metabolismo , Plastídeos/metabolismo , Tabaco/metabolismo , Acetil-CoA Carboxilase/genética , Núcleo Celular/metabolismo , Plastídeos/genética , Sementes/metabolismo
18.
Life Sci ; 277: 119487, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33862107

RESUMO

AIMS: Nonalcoholic fatty liver disease (NAFLD) is a lipid metabolism disorder. Naringin (a main active ingredient in Ganshuang granules) is a flavanone that has been demonstrated to exert hepatoprotective and antifibrotic effects. The present study aimed to use a novel tissue-engineered fatty liver model to assess the effects and mechanisms of naringin on NAFLD. MAIN METHODS: Intracellular triglyceride (TG) was examined by oil red O staining and commercial kits. The proteins associated with lipid metabolism were measured by western blotting and/or qPCR. Very low-density lipoprotein (VLDL) was measured by ELISA. A CCK8 assay was used to assess the cytotoxicity of naringin. Molecular docking was used to predict the interactions and binding patterns between naringin and target proteins. KEY FINDINGS: Naringin significantly reduced intracellular TG accumulation by 52.7% in tissue-engineered fatty (TEF) livers, and also the level of pyruvate dehydrogenase kinase 4. Naringin downregulated CD36 and proliferator activated-receptor γ expression, reducing the uptake of FFAs; naringin also downregulated de novo liposynthetases by reducing acetyl CoA carboxylase, fatty acid synthetase etc. in TEF livers. Moreover, naringin increased the expression of proliferator activated-receptor α (PPAR-α) and carnitine palmitoyltransferase 1 to improve the oxidation of fatty acids. The levels of VLDL secreted from TEF livers were reduced by 24.7% after naringin treatment. Molecular docking analyses determined the bioactivity of naringin through its specific binding to CD36 and PPAR-α. SIGNIFICANCE: Naringin improved lipid metabolism disorders in TEF livers by reducing fatty acid uptake and de novo lipogenesis and increasing fatty acid oxidation. CD36 and PPAR-α might be specific targets of naringin.


Assuntos
Flavanonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Flavanonas/metabolismo , Células Hep G2 , Humanos , Lipogênese , Lipoproteínas VLDL/metabolismo , Fígado/metabolismo , Masculino , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Oxirredução , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
19.
J Chem Ecol ; 47(3): 248-264, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33779878

RESUMO

The European grapevine moth, Lobesia botrana, uses (E,Z)-7,9-dodecadienyl acetate as its major sex pheromone component. Through in vivo labeling experiments we demonstrated that the doubly unsaturated pheromone component is produced by ∆11 desaturation of tetradecanoic acid, followed by chain shortening of (Z)-11-tetradecenoic acid to (Z)-9-dodecenoic acid, and subsequently introduction of the second double bond by an unknown ∆7 desaturase, before final reduction and acetylation. By sequencing and analyzing the transcriptome of female pheromone glands of L. botrana, we obtained 41 candidate genes that may be involved in sex pheromone production, including the genes encoding 17 fatty acyl desaturases, 13 fatty acyl reductases, 1 fatty acid synthase, 3 acyl-CoA oxidases, 1 acetyl-CoA carboxylase, 4 fatty acid transport proteins and 2 acyl-CoA binding proteins. A functional assay of desaturase and acyl-CoA oxidase gene candidates in yeast and insect cell (Sf9) heterologous expression systems revealed that Lbo_PPTQ encodes a ∆11 desaturase producing (Z)-11-tetradecenoic acid from tetradecanoic acid. Further, Lbo_31670 and Lbo_49602 encode two acyl-CoA oxidases that may produce (Z)-9-dodecenoic acid by chain shortening (Z)-11-tetradecenoic acid. The gene encoding the enzyme introducing the E7 double bond into (Z)-9-dodecenoic acid remains elusive even though we assayed 17 candidate desaturases in the two heterologous systems.


Assuntos
Dodecanol/análogos & derivados , Atrativos Sexuais/biossíntese , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Sequência de Aminoácidos , Animais , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Mariposas , Ácido Mirístico/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Saccharomyces cerevisiae/metabolismo , Células Sf9/metabolismo , Transcriptoma
20.
Biosci Biotechnol Biochem ; 85(5): 1183-1193, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33704405

RESUMO

Obesity is one of the most critical risk factors for diabetes mellitus and plays a significant role in diabetic nephropathy (DN). The present investigation aimed to evaluate the possible mechanism of action of vitexin on obesity-induced DN in a high-fat diet (HFD)-fed experimental C57BL/6 mice model. Obesity was induced in male C57BL/6 mice by chronic administration of HFD, and mice were concomitantly treated with vitexin (15, 30, and 60 mg/kg, p.o.). HFD-induced increased renal oxido-nitrosative stress and proinflammatory cytokine levels were significantly inhibited by vitexin. The Western blot analysis suggested that alteration in renal NF-κB, IκBα, nephrin, AMPK, and ACC phosphorylation levels was effectively restored by vitexin treatment. Histological aberration induced in renal tissue after chronic administration of HFD was also reduced by vitexin. In conclusion, vitexin suppressed the progression of obesity-induced DN via modulation of NF-κB/IkBα and AMPK/ACC pathways in an experimental model of HFD-induced DN in C57BL/6J mice.


Assuntos
Fármacos Antiobesidade/farmacologia , Apigenina/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Fármacos Antiobesidade/isolamento & purificação , Apigenina/isolamento & purificação , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica , Hipoglicemiantes/isolamento & purificação , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Masculino , Malondialdeído/antagonistas & inibidores , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Extratos Vegetais/química , Transdução de Sinais , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Trigonella/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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