Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.517
Filtrar
1.
Int J Mol Sci ; 22(15)2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34361032

RESUMO

17,18-Epoxyeicosatetraenoic acid (17,18-EEQ) and 19,20-epoxydocosapentaenoic acid (19,20-EDP) are bioactive epoxides produced from n-3 polyunsaturated fatty acid eicosapentaenoic acid and docosahexaenoic acid, respectively. However, these epoxides are quickly metabolized into less active diols by soluble epoxide hydrolase (sEH). We have previously demonstrated that an sEH inhibitor, t-TUCB, decreased serum triglycerides (TG) and increased lipid metabolic protein expression in the brown adipose tissue (BAT) of diet-induced obese mice. This study investigates the preventive effects of t-TUCB (T) alone or combined with 19,20-EDP (T + EDP) or 17,18-EEQ (T + EEQ) on BAT activation in the development of diet-induced obesity and metabolic disorders via osmotic minipump delivery in mice. Both T + EDP and T + EEQ groups showed significant improvement in fasting glucose, serum triglycerides, and higher core body temperature, whereas heat production was only significantly increased in the T + EEQ group. Moreover, both the T + EDP and T + EEQ groups showed less lipid accumulation in the BAT. Although UCP1 expression was not changed, PGC1α expression was increased in all three treated groups. In contrast, the expression of CPT1A and CPT1B, which are responsible for the rate-limiting step for fatty acid oxidation, was only increased in the T + EDP and T + EEQ groups. Interestingly, as a fatty acid transporter, CD36 expression was only increased in the T + EEQ group. Furthermore, both the T + EDP and T + EEQ groups showed decreased inflammatory NFκB signaling in the BAT. Our results suggest that 17,18-EEQ or 19,20-EDP combined with t-TUCB may prevent high-fat diet-induced metabolic disorders, in part through increased thermogenesis, upregulating lipid metabolic protein expression, and decreasing inflammation in the BAT.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Ácidos Araquidônicos/uso terapêutico , Benzoatos/uso terapêutico , Obesidade/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Adipogenia , Tecido Adiposo Marrom/citologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Ácidos Araquidônicos/administração & dosagem , Ácidos Araquidônicos/farmacologia , Benzoatos/administração & dosagem , Benzoatos/farmacologia , Glicemia/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Dieta Hiperlipídica , Epóxido Hidrolases/antagonistas & inibidores , Ácidos Graxos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacologia
2.
Front Immunol ; 12: 649197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34234772

RESUMO

Persistent antigen exposure during chronic hepatitis B infection leads to exhausted immune responses, thus impeding viral control. In recent years, immunometabolism opens new therapeutic possibilities for the modulation of immune responses. Herein, we investigated the immunomodulatory effect of L-carnitine (L-Cn) on immune cells in chronic HBV infection. In this study, 141 treatment-naïve patients with chronic HBV infection, 38 patients who achieved HBsAg loss following antiviral treatment, and 47 patients who suffered from HBV-related HCC from real-life clinical practice were recruited. The plasma L-Cn levels were measured by ELISA. RNA sequencing was conducted to define the transcriptional profiles of peripheral blood mononuclear cells after L-Cn stimulation. In vitro assays were performed to assess the effect of L-Cn on immune cells; the frequencies and function of immune cells were analyzed by flow cytometry. We found that compared with patients with HBsAg loss, patients with HBsAg positivity and patients who suffered from HBV-related HCC had higher levels of L-Cn, and the plasma levels of L-Cn in the HBeAg-positive chronic hepatitis patients who had elevated ALT were significantly higher than that of HBeAg-negative chronic infection and HBsAg loss groups. Moreover, a positive correlation between plasma levels of L-Cn and HBsAg levels was found. Additionally, RNA sequencing analysis demonstrated that L-Cn altered the transcriptional profiles related to immune response. In vitro assays revealed that L-Cn suppressed the proliferation of and IFN-γ production by CD4+ and CD8+ T cells. It also down-regulated the proliferation and IgG production of B cells. Notably, L-Cn enhanced IL-10 secretion from regulatory T cells and up-regulated the expression of inhibitory receptors on T cells. Moreover, a variant in CPT2 (rs1799821) was confirmed to be associated with L-Cn levels as well as complete response in CHB patients following Peg-IFNα antiviral therapy. Taken together, the immunosuppressive properties of L-Cn may hinder the control of HBV in chronic HBV infection, implicating that L-Cn manipulation might influence the prognosis of patients with HBV infection.


Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/imunologia , Carnitina/sangue , Hepatite B Crônica/imunologia , Neoplasias Hepáticas/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proliferação de Células , Estudos Transversais , Feminino , Antígenos E da Hepatite B/sangue , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Hepatite B Crônica/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
3.
Nutr Metab Cardiovasc Dis ; 31(8): 2490-2506, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34172319

RESUMO

BACKGROUND AND AIMS: Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications. METHODS AND RESULTS: Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action. In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (-34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (-71% and -64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose-response efficacy. CONCLUSIONS: Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.


Assuntos
Colesterol/biossíntese , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/biossíntese , Hepatócitos/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipogênese/efeitos dos fármacos , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/sangue , Ácidos Graxos/farmacologia , Hepatócitos/enzimologia , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/enzimologia , Lipase Lipoproteica/metabolismo , Masculino , Mesocricetus , Perilipina-1/metabolismo , Proteínas Quinases/metabolismo , Coelhos , Ratos Wistar
4.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066911

RESUMO

Previous studies suggest that statins may disturb skeletal muscle lipid metabolism potentially causing lipotoxicity with insulin resistance. We investigated this possibility in wild-type mice (WT) and mice with skeletal muscle PGC-1α overexpression (PGC-1α OE mice). In WT mice, simvastatin had only minor effects on skeletal muscle lipid metabolism but reduced glucose uptake, indicating impaired insulin sensitivity. Muscle PGC-1α overexpression caused lipid droplet accumulation in skeletal muscle with increased expression of the fatty acid transporter CD36, fatty acid binding protein 4, perilipin 5 and CPT1b but without significant impairment of muscle glucose uptake. Simvastatin further increased the lipid droplet accumulation in PGC-1α OE mice and stimulated muscle glucose uptake. In conclusion, the impaired muscle glucose uptake in WT mice treated with simvastatin cannot be explained by lipotoxicity. PGC-1α OE mice are protected from lipotoxicity of fatty acids and triglycerides by increased the expression of FABP4, formation of lipid droplets and increased expression of CPT1b.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sinvastatina/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/sangue , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/sangue , Glucose/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/ultraestrutura , Tamanho do Órgão/efeitos dos fármacos , Perilipina-5/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
5.
Int J Mol Sci ; 22(9)2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-34063237

RESUMO

Muscle carnitine palmitoyltransferase II (CPT II) deficiency is associated with various mutations in CPT2 gene. In the present study, the impact of the two CPT II variants P50H and Y479F were characterized in terms of stability and activity in vitro in comparison to wildtype (WT) and the well investigated variant S113L. While the initial enzyme activity of all variants showed wild-type-like behavior, the activity half-lives of the variants at different temperatures were severely reduced. This finding was validated by the investigation of thermostability of the enzymes using nano differential scanning fluorimetry (nanoDSF). Further, it was studied whether the protein stabilizing diphosphatidylglycerol cardiolipin (CL) has an effect on the variants. CL indeed had a positive effect on the stability. This effect was strongest for WT and least pronounced for variant P50H. Additionally, CL improved the catalytic efficiency for CPT II WT and the investigated variants by twofold when carnitine was the varied substrate due to a decrease in KM. However, there was no influence detected for the variation of substrate palmitoyl-CoA. The functional consequences of the stabilization by CL in vivo remain open.


Assuntos
Cardiolipinas/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Músculos/metabolismo , Carnitina , Carnitina O-Palmitoiltransferase/deficiência , Humanos , Cinética , Erros Inatos do Metabolismo Lipídico , Erros Inatos do Metabolismo , Mutação
6.
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
7.
J Biol Chem ; 297(1): 100884, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34146544

RESUMO

The mechanistic target of rapamycin (mTOR) is often referred to as a master regulator of the cellular metabolism that can integrate the growth factor and nutrient signaling. Fasting suppresses hepatic mTORC1 activity via the activity of the tuberous sclerosis complex (TSC), a negative regulator of mTORC1, to suppress anabolic metabolism. The loss of TSC1 in the liver locks the liver in a constitutively anabolic state even during fasting, which was suggested to regulate peroxisome proliferator-activated receptor alpha (PPARα) signaling and ketogenesis, but the molecular determinants of this regulation are unknown. Here, we examined if the activation of the mTORC1 complex in mice by the liver-specific deletion of TSC1 (TSC1L-/-) is sufficient to suppress PPARα signaling and therefore ketogenesis in the fasted state. We found that the activation of mTORC1 in the fasted state is not sufficient to repress PPARα-responsive genes or ketogenesis. Furthermore, we examined whether the activation of the anabolic program mediated by mTORC1 complex activation in the fasted state could suppress the robust catabolic programming and enhanced PPARα transcriptional response of mice with a liver-specific defect in mitochondrial long-chain fatty acid oxidation using carnitine palmitoyltransferase 2 (Cpt2L-/-) mice. We generated Cpt2L-/-; Tsc1L-/- double-KO mice and showed that the activation of mTORC1 by deletion of TSC1 could not suppress the catabolic PPARα-mediated phenotype of Cpt2L-/- mice. These data demonstrate that the activation of mTORC1 by the deletion of TSC1 is not sufficient to suppress a PPARα transcriptional program or ketogenesis after fasting.


Assuntos
Jejum/metabolismo , Fígado/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Proteína 1 do Complexo Esclerose Tuberosa/genética , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
8.
Mol Genet Metab ; 133(2): 182-184, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34020866

RESUMO

Carnitine palmitoyl transferase II (CPT II) catalyzes the release of activated long-chain fatty acids from acylcarnitines into mitochondria for subsequent fatty acid oxidation. Depending on residual enzyme activity, deficiency of this enzyme leads to a spectrum of symptoms from early onset hypoglycemia, hyperammonemia, cardiomyopathy and death to onset of recurrent rhabdomyolysis in adolescents and young adults. We present a case of successful orthotopic heart transplantation in a patient with severe infantile onset cardiomyopathy due to CPT II deficiency identified through newborn screening. Excellent cardiac function is preserved 12 years post-transplantation; however, the patient has developed intermittent episodes of hyperammonemia and rhabdomyolysis later in childhood and early adolescence readily resolved with intravenous glucose. Successful heart transplant in this patient demonstrates the feasibility of this management option in patients with even severe forms of long chain fatty acid oxidation disorders.


Assuntos
Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Transplante de Coração/métodos , Coração/fisiopatologia , Erros Inatos do Metabolismo/terapia , Adolescente , Adulto , Idade de Início , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/terapia , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos/metabolismo , Humanos , Hiperamonemia/genética , Hiperamonemia/patologia , Hiperamonemia/terapia , Hipoglicemia/genética , Hipoglicemia/patologia , Hipoglicemia/terapia , Recém-Nascido , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Triagem Neonatal , Rabdomiólise/genética , Rabdomiólise/patologia , Rabdomiólise/terapia , Adulto Jovem
9.
Biomed Res Int ; 2021: 6657476, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33954193

RESUMO

Objective: It is aimed at investigating the mechanism of palmitic acid (PA) on myocardial contractility in hypertensive rats and its relationship with myocardial neural nitric oxide synthase (nNOS) protein. Methods: The rats were randomly divided into sham operation group and hypertensive group, with thirty rats in each group, to prepare angiotensin II-induced hypertensive model rats. The blood pressure of rats was measured by the multianimal multichannel tail cuff noninvasive blood pressure system of Kent Coda, USA. The Ionoptix single-cell contraction detection system was used to detect myocardial cells. ATP level of left ventricular cardiomyocytes was determined by luminescence method, and protein was measured by Western blot. Results: Compared with the sham group, systolic blood pressure and diastolic blood pressure were increased in the hypertensive group over 4 weeks; PA increased the contractility of left ventricular cardiomyocytes in normal rats, but not in hypertensive rats, and PA increased the intracellular ATP level of rats in the sham group but not in the hypertension group. In the hypertension group, the expression of nNOS in the cardiomyocytes was significantly increased, and specific nNOS inhibitor S-methyl-L-thiocitrulline (SMTC) was found to restore the positive inotropic effect of PA in the myocardium of the hypertension group. PA was supplemented after using CPT-1 inhibitor etomoxir (ETO); it was found that ETO inhibited the positive inotropic effect of PA on left ventricular cardiomyocytes in the sham group, and PA was supplemented after using SMTC and ETO, it was found that SMTC + ETO could inhibit the positive inotropic effect of PA on left ventricular cardiomyocytes in myocardium of hypertensive rats. Conclusion: PA could increase the contractility of healthy cardiomyocytes, but had no obvious positive effect on the cardiomyocytes of hypertensive rats, PA enhanced the contractility of cardiomyocytes by increasing ATP level in them, and the inhibitory effect of PA on myocardial contractility in hypertensive rats may be related to the increased nNOS and CPT-1 in cardiomyocytes.


Assuntos
Contração Muscular/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Óxido Nítrico Sintase Tipo I/metabolismo , Ácido Palmítico/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/metabolismo , Compostos de Epóxi/farmacologia , Hipertensão/fisiopatologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos Endogâmicos SHR , Ratos Sprague-Dawley
10.
FEBS Lett ; 595(14): 1920-1932, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34008174

RESUMO

Deficiency of polyunsaturated fatty acids (PUFAs) is known to induce hepatic steatosis. However, it is not clearly understood which type of PUFA is responsible for the worsening of steatosis. This study observed a marked accumulation of hepatic triacylglycerol and cholesterol in fatty acid desaturase 2 knockout (FADS2-/- ) mice lacking both C18 and ≥ C20 PUFAs that were fed a PUFA-depleted diet. Hepatic triacylglycerol accumulation was associated with enhanced sterol regulatory element-binding protein (SREBP)-1-dependent lipogenesis and decreased triacylglycerol secretion into the plasma via very-low-density lipoprotein (VLDL). Furthermore, upregulation of cholesterol synthesis contributed to increased hepatic cholesterol content in FADS2-/- mice. These results suggest that ≥ C20 PUFAs synthesized by FADS2 are important in regulating hepatic triacylglycerol and cholesterol accumulation during PUFA deficiency.


Assuntos
Colesterol/biossíntese , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Insaturados/deficiência , Fígado Gorduroso/genética , Triglicerídeos/biossíntese , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Dieta/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos Dessaturases/deficiência , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Fígado Gorduroso/enzimologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Expressão Gênica , Perfilação da Expressão Gênica , Lipogênese/genética , Lipoproteínas VLDL/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
11.
BMC Cancer ; 21(1): 409, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33858374

RESUMO

BACKGROUND: Carnitine palmitoyl transferase 1A (CPT1A), the key regulator of fatty acid oxidation, contributes to tumor metastasis and therapeutic resistance. We aimed to identify its clinical significance as a biomarker for the diagnosis and prediction of breast cancer. METHODS: Western blot, ELISA and in silico analysis were used to confirm CPT1A levels in breast cancer cell lines, cell culture medium and breast cancer tissues. Four hundred thirty breast cancer patients, 200 patients with benign breast disease, and 400 healthy controls were enrolled and randomly divided into a training set and a test set with a 7:3 ratio. Training set was used to build diagnostic models and 10-fold cross validation was used to demonstrate the performance of the models. Then test set was aimed to validate the effectiveness of the diagnostic models. ELISA was conducted to detect individual serum CPT1A levels. Receiver operating characteristic (ROC) curves were generated, and binary logistic regression analyses were performed to evaluate the effectiveness of CPT1A as a biomarker in breast cancer diagnosis. CPT1A levels between post-operative and pre-operative samples were also compared. RESULTS: CPT1A was overexpressed in breast cancer tissues, cell lines and cell culture medium. Serum CPT1A levels were higher in breast cancer patients than in controls and were significantly associated with metastasis, TNM stage, histological grading and molecular subtype. CPT1A levels were decreased in post-operative samples compared with paired pre-operative samples. Moreover, CPT1A exhibited a higher efficacy in differentiating breast cancer patients from healthy controls (training set: area under the curve, AUC, 0.892, 95% CI, 0.872-0.920; test set, AUC, 0.904, 95% CI, 0.869-0.939) than did CA15-3, CEA, or CA125. CONCLUSION: CPT1A is overexpressed in breast cancer and can be secreted out of breast cancer cell. Serum CPT1A is positively associated with breast cancer progression and could serve as an indicator for disease monitoring. Serum CPT1A displayed a remarkably high diagnostic efficiency for breast cancer and could be a novel biomarker for the diagnosis of breast cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/enzimologia , Carnitina O-Palmitoiltransferase/metabolismo , Adulto , Idoso , Doenças Mamárias/diagnóstico , Doenças Mamárias/enzimologia , Neoplasias da Mama/mortalidade , Carnitina O-Palmitoiltransferase/sangue , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Reprodutibilidade dos Testes
12.
J Dairy Sci ; 104(7): 7749-7760, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33838888

RESUMO

Modulatory effects of l-carnitine, acetate, propionate, and 5-tetradecyloxy-2-furoic acid (TOFA; an inhibitor of acetyl-CoA carboxylase) on oxidation and esterification of [1-14C]-palmitate were studied in hepatocytes isolated from phlorizin-treated and control wethers. Our hypotheses were that (1) palmitate oxidation would be greater in hepatocytes from sheep injected with phlorizin; (2) l-carnitine would increase palmitate oxidation more in hepatocytes from sheep injected with phlorizin; and (3) acetate and propionate would decrease oxidation in sheep hepatocytes partly through action of acetyl-CoA carboxylase. Palmitate metabolism did not differ between cells from control and those from phlorizin-treated wethers. Carnitine increased oxidation of palmitate to CO2 and acid-soluble products (ASP; mainly ketone bodies) and decreased esterification of palmitate in isolated hepatocytes from both groups of wethers, but the increase in oxidation to ASP was greater in cells from phlorizin-treated wethers. Propionate increased palmitate oxidation to CO2 in phlorizin-treated wethers. Propionate increased oxidation of palmitate to ASP in control wethers but decreased oxidation to ASP in phlorizin-treated wethers. Propionate increased esterification of palmitate to total esterified products and triglyceride, and the effect was larger in phlorizin-treated wethers. Acetate decreased palmitate esterification to total esterified products in control wethers, but the effect was blunted in phlorizin-treated wethers. Acetate did not affect palmitate oxidation. Addition of TOFA increased production of triglyceride from palmitate in the presence of propionate. The lack of interaction between TOFA and propionate indicates that propionate does not inhibit carnitine palmitoyltransferase I via cytosolic generation of methylmalonyl-CoA by acetyl-CoA carboxylase. In conclusion, although in vivo phlorizin treatment did not affect in vitro metabolism of palmitate by isolated ovine hepatocytes, phlorizin increased the stimulatory effect of carnitine on oxidation of palmitate to ASP and the inhibitory effect of propionate on oxidation of palmitate to ASP. Metabolism of acetate and propionate by acetyl-CoA carboxylase did not affect palmitate oxidation or esterification. Results provide additional insight into control of fatty acid metabolism in hepatocytes.


Assuntos
Carnitina , Propionatos , Acetatos/metabolismo , Animais , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos/metabolismo , Furanos , Hepatócitos , Fígado/metabolismo , Masculino , Oxirredução , Palmitatos/metabolismo , Florizina/metabolismo , Florizina/farmacologia , Propionatos/metabolismo , Ovinos
13.
Aging (Albany NY) ; 13(7): 10158-10174, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33819184

RESUMO

This study examined whether hypoxia-induced microRNA (miRNA) upregulation was related to the inhibition of chondriosome aliphatic acid oxidation in myocardial cells under anoxia. We showed that anoxia induced high expression of hypoxia-inducible factor-1-alpha, muscle carnitine palmitoyltransferase I, and vascular endothelial growth factor in cardiomyocytes. Meanwhile, miR-27 and miR-195 were also upregulated in hypoxia-induced cardiomyocytes. Furthermore, hypoxia induction led to reductions in the adenosine triphosphate (ATP) consumption rate and oxidative metabolism as well as an increase in cardiomyocyte glycolysis. Metabolic reprogramming was reduced by hypoxia, as evidenced by the downregulation of sirtuin 1, forkhead box protein O1, sterol regulatory element-binding protein 1c, ATP citrate lyase, acetyl-coenzyme A carboxylase 2, adiponutrin, adipose triglyceride lipase, and glucose transporter type 4, while miR-27 and miR-195 inhibition partially recovered the expression of these transcription factors. In addition, hypoxia induction reduced cell viability and survival by triggering apoptosis; however, miR-27 and miR-195 inhibition partially increased cell viability. Moreover, miR-27 and miR-195 targeted the 3'untranslated regions of two key lipid-associated metabolic players, peroxisome proliferator-activated receptor gamma and fatty acid synthase. In conclusion, miR-27 and miR-195 are related to hypoxia-mediated ATP levels, glycolysis, oxidation, cell survival, and a cascade of transcription factors that control metabolism in cardiomyocytes.


Assuntos
Trifosfato de Adenosina/metabolismo , Sobrevivência Celular/fisiologia , Metabolismo Energético/fisiologia , Ácido Graxo Sintase Tipo I/metabolismo , Hipóxia/metabolismo , Miócitos Cardíacos/metabolismo , PPAR gama/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
J Physiol Biochem ; 77(2): 249-260, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33730333

RESUMO

Lipid metabolism rewiring in gastric adenocarcinoma (GA) pathogenesis is still not clearly elucidated. This study aimed to describe the role of lipid catabolism in GA patient outcomes and possible therapeutic targets by analyzing the effect of hypoxia-inducible factor-1α (HIF-1α) on fatty acid oxidation (FAO). AGS cell line was cultured in normoxic and hypoxic conditions, and FAO-related genes were analyzed by real-time-PCR and Western-blot. The study group comprised 108 newly diagnosed GA patients and 152 control cases. Serum concentrations of medium and long-chain acyl-CoA dehydrogenases (MCAD and LCAD) proteins were measured using ELISA, and local expression of HIF-1α, carnitine palmitoyl transferase 1 (CPT1A) and peroxisome proliferator-activated receptor γ (PPARγ) was evaluated by immunohistochemistry. In addition, gene expression of PPARγ, CPT1A, LCAD, and MCAD was assessed by real-time-PCR. In vitro findings indicate HIF-1α upregulation and FAO-related genes and proteins reduction in the hypoxic culture of AGS cells. GA patients had significantly lower circulating levels of LCAD compared to controls. Higher protein expression of HIF-1α and downregulated CPT1A and PPARγ were observed in GA tissues versus controls. Gene expression of CPT1A, PPARγ, LCAD, and MCAD were repressed in GA tissues compared to controls. Moreover, reduced expression of CPT1A, PPARγ, and MCAD were correlated with HIF-1α upregulation in GA. Poor patient outcome was associated with lower PPARγ and LCAD expression in GA. HIF-1α upregulation in human GA patients and AGS cells was paralleled by downregulation of lipid catabolism genes potentially via reduced PPARγ-mediated FAO. This metabolic adaptation to hypoxic condition may play a role in GA pathogenesis and might have clinical and therapeutic value in GA patients.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/genética , Acil-CoA Desidrogenase/genética , Adenocarcinoma/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , PPAR gama/genética , Neoplasias Gástricas/genética , Acil-CoA Desidrogenase/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Estudos de Casos e Controles , Hipóxia Celular , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Oxirredução , PPAR gama/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida
15.
Biosci Biotechnol Biochem ; 85(5): 1104-1113, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33751045

RESUMO

Protein malnutrition promotes hepatic lipid accumulation in growing animals. In these animals, fibroblast growth factor 21 (FGF21) rapidly increases in the liver and circulation and plays a protective role in hepatic lipid accumulation. To investigate the mechanism by which FGF21 protects against liver lipid accumulation under protein malnutrition, we determined whether upregulated FGF21 promotes the thermogenesis or secretion of very-low-density lipoprotein (VLDL)-triacylglycerol (TAG). The results showed that protein malnutrition decreased VLDL-TAG secretion, but the upregulation of FGF21 did not oppose this effect. In addition, protein malnutrition increased expression of the thermogenic gene uncoupling protein 1 in inguinal white adipose and brown adipose tissue in an FGF21-dependent manner. However, surgically removing inguinal white adipose tissue did not affect liver triglyceride levels in protein-malnourished mice. These data suggest that FGF21 stimulates thermogenesis under protein malnutrition, but this is not the causative factor underlying the protective role of FGF21 against liver lipid accumulation.


Assuntos
Tecido Adiposo Branco/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Metabolismo dos Lipídeos/genética , Lipoproteínas VLDL/metabolismo , Desnutrição/genética , Termogênese/genética , Triglicerídeos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/cirurgia , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/metabolismo , Dieta com Restrição de Proteínas/efeitos adversos , Fatores de Crescimento de Fibroblastos/deficiência , Regulação da Expressão Gênica , Glicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Virilha , Fígado/metabolismo , Masculino , Desnutrição/metabolismo , Desnutrição/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurregulinas/genética , Neurregulinas/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo
16.
PLoS One ; 16(1): e0245858, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33497399

RESUMO

mir-33a and mir-33b are co-transcribed with the SREBF2 and SREBF1 transcription factors, respectively. The main role of SREBF1 is the regulation of genes involved in fatty acid metabolism, while SREBF2 regulates genes participating in cholesterol biosynthesis and uptake. Our objective was to study the expression of both miR-33a and miR-33b, together with their host SREBF genes, in liver, adipose tissue and muscle to better understand the role of miR-33a/b in the lipid metabolism of pigs. In our study, the expression of miR-33a, miR-33b and SREBF2 in liver, adipose tissue, and muscle was studied in 42 BC1_LD (25% Iberian x 75% Landrace backcross) pigs by RT-qPCR. In addition, the expression of in-silico predicted target genes and fatty acid composition traits were correlated with the miR-33a/b expression. We observed different tissue expression patterns for both miRNAs. In adipose tissue and muscle a high correlation between miR-33a and miR-33b expression was found, whereas a lower correlation was observed in liver. The expression analysis of in-silico predicted target-lipid related genes showed negative correlations between miR-33b and CPT1A expression in liver. Conversely, positive correlations between miR-33a and PPARGC1A and USF1 gene expression in liver were observed. Lastly, positive and negative correlations between miR-33a/b expression and saturated fatty acid (SFA) and polyunsaturated fatty acid (PUFA) content, respectively, were identified. Overall, our results suggested that both miRNAs are differentially regulated and have distinct functions in liver, in contrast to muscle and adipose tissue. Furthermore, the correlations between miR-33a/b expression both with the expression of in-silico predicted target-lipid related genes and with fatty acid composition, opens new avenues to explore the role of miR33a/b in the regulation of lipid metabolism.


Assuntos
Tecido Adiposo/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , MicroRNAs/genética , Músculo Esquelético/metabolismo , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , MicroRNAs/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Suínos , Fatores Estimuladores Upstream/genética , Fatores Estimuladores Upstream/metabolismo
17.
JCI Insight ; 6(2)2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33491665

RESUMO

To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their ß-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL-/-), fatty acid oxidation (Cpt2L-/-), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and ß-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.


Assuntos
Ácidos Graxos/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Triglicerídeos/metabolismo , Animais , Carnitina O-Palmitoiltransferase/deficiência , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Progressão da Doença , Feminino , Hidrólise , Lipase/deficiência , Lipase/genética , Lipase/metabolismo , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética , Oxirredução
18.
Commun Biol ; 4(1): 15, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398077

RESUMO

As a promising novel marine fish model for future research on marine ecotoxicology as well as an animal model of human disease, the genome information of yellowstripe goby (Mugilogobius chulae) remains unknown. Here we report the first annotated chromosome-level reference genome assembly for yellowstripe goby. A 20.67-cM sex determination region was discovered on chromosome 5 and seven potential sex-determining genes were identified. Based on combined genome and transcriptome data, we identified three key lipid metabolic pathways for high-fat accumulation in the liver of yellowstripe goby. The changes in the expression patterns of MGLL and CPT1 at different development stage of the liver, and the expansion of the ABCA1 gene, innate immune gene TLR23, and TRIM family genes may help in balancing high-fat storage in hepatocytes and steatohepatitis. These results may provide insights into understanding the molecular mechanisms of sex determination and high-fat storage in the liver of marine fishes.


Assuntos
Lipogênese , Fígado/metabolismo , Perciformes/genética , Processos de Determinação Sexual , Transportador 1 de Cassete de Ligação de ATP , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Fígado Gorduroso/imunologia , Feminino , Masculino , Monoacilglicerol Lipases/metabolismo , Perciformes/imunologia , Perciformes/metabolismo , Fosfolipídeos/biossíntese , Sequenciamento Completo do Genoma
19.
FASEB J ; 35(2): e21343, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33508151

RESUMO

Most physiological processes in mammals are subjected to daily oscillations that are governed by a circadian system. The circadian rhythm orchestrates metabolic pathways in a time-dependent manner and loss of circadian timekeeping has been associated with cellular and system-wide alterations in metabolism, redox homeostasis, and inflammation. Here, we investigated the expression of clock and clock-controlled genes in multiple tissues (suprachiasmatic nucleus, spinal cord, gastrocnemius muscle, and liver) from mutant hSOD1-linked amyotrophic lateral sclerosis (ALS) mouse models. We identified tissue-specific changes in the relative expression, as well as altered daily expression patterns, of clock genes, sirtuins (Sirt1, Sirt3, and Sirt6), metabolic enzymes (Pfkfb3, Cpt1, and Nampt), and redox regulators (Nrf2, G6pd, and Pgd). In addition, astrocytes transdifferentiated from induced pluripotent stem cells from SOD1-linked and FUS RNA binding protein-linked ALS patients also displayed altered expression of clock genes. Overall, our results raise the possibility of disrupted cross-talk between the suprachiasmatic nucleus and peripheral tissues in hSOD1G93A mice, preventing proper peripheral clock regulation and synchronization. Since these changes were observed in symptomatic mice, it remains unclear whether this dysregulation directly drives or it is a consequence of the degenerative process. However, because metabolism and redox homeostasis are intimately entangled with circadian rhythms, our data suggest that altered expression of clock genes may contribute to metabolic and redox impairment in ALS. Since circadian dyssynchrony can be rescued, these results provide the groundwork for potential disease-modifying interventions.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteínas CLOCK/metabolismo , Superóxido Dismutase-1/genética , Esclerose Amiotrófica Lateral/metabolismo , Animais , Astrócitos/metabolismo , Proteínas CLOCK/genética , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Nicotinamida Fosforribosiltransferase/genética , Nicotinamida Fosforribosiltransferase/metabolismo , Fosfofrutoquinase-2/genética , Fosfofrutoquinase-2/metabolismo , Fosfogluconato Desidrogenase/genética , Fosfogluconato Desidrogenase/metabolismo , Sirtuínas/genética , Sirtuínas/metabolismo
20.
Eur J Pharmacol ; 892: 173755, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33245899

RESUMO

CTRP6, a newly identified adiponectin analogue, has been shown to be involved in inflammation, diabetes and cardiovascular diseases. Recently, increasing evidence has shown that CTRP6 plays a critical role in fibrotic diseases, such as myocardial fibrosis and skin fibrosis. FAO, an important energy source for kidney proximal tubular cells, also participates in the process of fibrosis. Therefore, our study aimed to investigate the effect of CTRP6 on mediating FAO in kidney fibrosis and the underlying associated mechanism. Firstly, the activity of CTRP6 and the key enzymes of FAO (CPT1A, ACOX1) were tested in vivo and vitro. Next, the regulatory effect of CTRP6/AMPK on FAO was accessed in animal models and in cell lines. Additionally, we explored the effect of exogenous recombinant CTRP6 on renal tubular epithelial cell differentiation. Decreased CTRP6 and p-AMPK were detected in UUO-induced kidney fibrosis and in TGF-ß1-treated HK-2 cells. We also observed that defective FAO occurred during kidney fibrosis. Moreover, the human CTRP6 peptide could inhibit the ECM deposition and promote the phosphorylation of AMPK by promoting FAO. However, the inhibitory effects of CTRP6 on TGF-ß1-induced ECM deposition and the protective effects of CTRP6 on FAO could be abolished by compound C, a selective inhibitor of AMPK. Compound C also reversed the CTRP6-mediated upregulation of p-AMPK. The mediation of FAO by CTRP6 plays a key role in kidney fibrosis by regulating TGF-ß1-induced renal tubular epithelial cell differentiation by promoting FAO, which is mediated via AMPK activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipocinas/metabolismo , Colágeno/metabolismo , Ácidos Graxos/metabolismo , Nefropatias/enzimologia , Túbulos Renais Proximais/enzimologia , Acil-CoA Oxidase/genética , Acil-CoA Oxidase/metabolismo , Adipocinas/genética , Animais , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular , Colágeno/genética , Modelos Animais de Doenças , Fibrose , Humanos , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Oxirredução , Fosforilação , Transdução de Sinais , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/complicações
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...