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1.
Cancer Sci ; 112(4): 1457-1470, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33511729

RESUMO

Resident adipocytes under a hypoxic tumor microenvironment exert an increasingly important role in cell growth, proliferation, and invasion in cancers. However, the communication between adipocytes and cancer cells during nasopharyngeal carcinoma (NPC) progression is poorly understood. Here, we demonstrate that hypoxic adipocyte-derived exosomes are key information carriers that transfer low expression of miR-433-3p into NPC cells. In addition, luciferase reporter assays detected that hypoxia inducible factor-1α (HIF-1α) induced miR-433-3p transcription through five binding sites at its promoter region. Concordantly, the low expression of miR-433-3p promoted proliferation, migration, and lipid accumulation in NPC cells via targeting stearoyl-CoA desaturase 1 (SCD1) are suggested by functional studies. Consistent with these findings, in tumor-bearing mice, NPC cells with low HIF-1α expression, high miR-433-3p expression, and low SCD1 expression were equally endowed with remarkably reduced potential of tumorigenesis. Collectively, our study highlights the critical role of the HIF-1α-miR-433-3p-SCD1 axis in NPC progression, which can serve as a mechanism-based potential therapeutic approach.


Assuntos
Adipócitos/patologia , Regulação para Baixo/genética , Exossomos/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Estearoil-CoA Dessaturase/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hipóxia/genética , Hipóxia/patologia , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Regiões Promotoras Genéticas/genética
2.
Artigo em Inglês | MEDLINE | ID: mdl-32920140

RESUMO

A comprehensive molecular mechanistic role of lutein on adipogenesis is not well understood. The present study focused to evaluate the effect of lutein at the early and late phase of adipocyte differentiation in vitro using a 3T3-L1 cell model. The effect of purified carotenoid on the viability of normal and differentiated 3T3-L1 cells was analyzed by WST-1 assay. Oil Red O and Nile red staining were employed to observe lipid droplets in mature adipocytes. The effect of lutein on gene and protein expression of major transcription factors and adipogenic markers was analyzed by RT-PCR and western blotting, respectively. The role of lutein on mitotic clonal expansion was analyzed by flow cytometry. The results showed a significant reduction (p < 0.05) in the accumulation of lipid droplets in lutein-treated (5 µM) cells. Inhibition in lipid accumulation was associated with down-regulated expression of CEBP-α and PPAR-γ at gene and protein levels. Subsequently, lutein repressed gene expression of FAS, FABP4, and SCD1 in mature adipocytes. Interestingly, it blocks the protein expression of CEBP-α and PPAR-γ in the initial stages of adipocyte differentiation. This early-stage inhibition of adipocyte differentiation is linked with repressed phosphorylation AKT and ERK. Further, upregulated cyclin D and down-regulated CDK4 and CDK2 in lutein treated adipocytes enumerate its role in delaying the cell cycle progression at the G0/G1 phase. Our results emphasize that adipogenesis inhibitory efficacy of lutein is potentiated by halting early phase regulators of adipocyte differentiation, which strengthens the competency of lutein besides its inevitable presence in the human body.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Proteínas Estimuladoras de Ligação a CCAAT/genética , Diferenciação Celular/efeitos dos fármacos , Luteína/farmacologia , PPAR gama/genética , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Animais , Proteínas Estimuladoras de Ligação a CCAAT/antagonistas & inibidores , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Ciclina D/genética , Ciclina D/metabolismo , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Dexametasona/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Regulação da Expressão Gênica , Camundongos , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fase de Repouso do Ciclo Celular/genética , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
3.
Artigo em Inglês | MEDLINE | ID: mdl-33010452

RESUMO

Type-1 diabetes mellitus (T1DM) is associated with metabolic changes leading to alterations in glucose and lipid handling. While T1DM-associated effects on many major plasma lipids have been characterised, such effects on plasma free fatty acids (FFA) have not been fully examined. Using gas chromatography-mass spectrometry, we measured the plasma concentrations of FFA species in individuals with T1DM (n = 44) and age/sex-matched healthy controls (n = 44). Relationships between FFA species and various parameters were evaluated. Plasma concentrations of myristate (14:0), palmitoleate (16:1), palmitate (16:0), linoleate (18:2), oleate (18:1c9), cis-vaccenate (18:1c11), eicosapentaenoate (20:5), arachidonate (20:4) and docosahexanoate (22:6) were reduced in the T1DM group (p < 0.0001 for all, except p = 0.0020 for eicosapentaenoate and p = 0.0068 for arachidonate); α-linolenate (18:3) and dihomo-γ-linolenate (20:3) concentrations were unchanged. The saturated/unsaturated FFA ratio, n-3/n-6 ratio, de novo lipogenesis index (palmitate (main lipogenesis product)/linoleate (only found in diet)) and elongase index (oleate/palmitoleate) were increased in the T1DM group (p = 0.0166, p = 0.0089, p < 0.0001 and p = 0.0008 respectively). The stearoyl-CoA desaturase 1 (SCD1) index 1 (palmitoleate/palmitate) and index 2 (oleate/stearate) were reduced in T1DM (p < 0.0001 for both). The delta-(5)-desaturase (D5D) index (arachidonate/dihomo-γ-linolenate) was unchanged. Age and sex had no effect on plasma FFA concentrations in T1DM, while SCD1 index 1 was positively correlated (p = 0.098) and elongase index negatively correlated with age (p = 0.0363). HbA1c was negatively correlated with all plasma FFA concentrations measured except α-linolenate and dihomo-γ-linolenate. Correlations were observed between plasma FFA concentrations and cholesterol and HDL concentrations, but not LDL concentration or diabetes duration. Collectively, these results aid our understanding of T1DM and its effects on lipid metabolism.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 1/sangue , Ácidos Graxos não Esterificados/sangue , Metabolismo dos Lipídeos/genética , Triglicerídeos/sangue , Adolescente , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Jejum/sangue , Ácidos Graxos não Esterificados/classificação , Feminino , Expressão Gênica , Hemoglobina A Glicada/genética , Hemoglobina A Glicada/metabolismo , Humanos , Lipidômica/métodos , Masculino , Albumina Sérica Humana/metabolismo , Estearoil-CoA Dessaturase/sangue , Estearoil-CoA Dessaturase/genética
4.
Artigo em Inglês | MEDLINE | ID: mdl-33049404

RESUMO

A large body of research has demonstrated that human stearoyl-CoA desaturase 1 (SCD1), a universally expressed fatty acid Δ9-desaturase that converts saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), is a central regulator of metabolic and signaling pathways involved in cell proliferation, differentiation, and survival. Unlike SCD1, stearoyl-CoA desaturase 5 (SCD5), a second SCD isoform found in a variety of vertebrates, including humans, has received considerably less attention but new information on the catalytic properties, regulation and biological functions of this enzyme has begun to emerge. This review will examine the new evidence that supports key metabolic and biological roles for SCD5, as well as the potential implication of this desaturase in the mechanisms of human diseases.


Assuntos
Fissura Palatina/genética , Ácidos Graxos Monoinsaturados/metabolismo , Ácidos Graxos/metabolismo , Neoplasias/genética , Doenças Neurodegenerativas/genética , Estearoil-CoA Dessaturase/genética , Sequência de Aminoácidos , Animais , Sobrevivência Celular , Fissura Palatina/enzimologia , Fissura Palatina/patologia , Regulação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Neoplasias/enzimologia , Neoplasias/patologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/patologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Estearoil-CoA Dessaturase/metabolismo
5.
Artigo em Inglês | MEDLINE | ID: mdl-33075494

RESUMO

MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) content and adipogenic gene expression were monitored, global lipidome analysis was carried out, and mechanisms underlying the effects of miR-221-3p were investigated. Finally, cross-talk between miR-221-3p expressing adipocytes and MCF-7 breast carcinoma (BC) cells was studied, and miR-221-3p expression in tumor-proximal adipose biopsies from BC patients analyzed. miR-221-3p overexpression inhibited terminal differentiation of adipocytes, as judged from reduced TG storage and gene expression of the adipogenic markers SCD1, GLUT4, FAS, DGAT1/2, AP2, ATGL and AdipoQ, whereas the miR-221-3p inhibitor increased TG storage. Knockdown of the predicted miR-221-3p target, 14-3-3γ, had similar antiadipogenic effects as miR-221-3p overexpression, indicating it as a potential mediator of mir-221-3p function. Importantly, miR-221-3p overexpression inhibited de novo lipogenesis but increased the concentrations of ceramides and sphingomyelins, while reducing diacylglycerols, concomitant with suppression of sphingomyelin phosphodiesterase, ATP citrate lyase, and acid ceramidase. miR-221-3p expression was elevated in tumor proximal adipose tissue from patients with invasive BC. Conditioned medium of miR-221-3p overexpressing adipocytes stimulated the invasion and proliferation of BC cells, while medium of the BC cells enhanced miR-221-3p expression in adipocytes. Elevated miR-221-3p impairs adipocyte lipid storage and differentiation, and modifies their ceramide, sphingomyelin, and diacylglycerol content. These alterations are relevant for metabolic diseases but may also affect cancer progression.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Gotículas Lipídicas/metabolismo , MicroRNAs/genética , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Adipócitos/patologia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Ceramidas/classificação , Ceramidas/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Lipase/genética , Lipase/metabolismo , Células MCF-7 , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais , Esfingolipídeos/classificação , Esfingolipídeos/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/classificação , Triglicerídeos/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
6.
DNA Cell Biol ; 39(9): 1573-1582, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32678986

RESUMO

Many immune cells participate in the pathogenesis of ulcerative colitis (UC), and fatty acid metabolism (FAM) is reported to supporting their cell-specific functions and proliferation, but the underlying mechanism is unclear. This study aimed to investigate the relationship between FAM and inflammation in colon tissues and identify potential therapeutic targets for regulating immune response. A total of 870 different expression genes (DEGs), 304 immunity-related DEGs, and 11 FAM-related DEGs were obtained, gene ontology analysis results showed that immune DEGs were significantly enriched in neutrophil migration, positive regulation of T cell activation. Fifteen types of immune cells were identified in inflamed colon tissues. Five FAM-related DEGs (ACOX1, ACSL4, ELOVL5, FADS2, and SCD) were highly correlated with immunity-related DEGs, and ACSL4, ELOVL5, and FADS2 were significantly upregulated in immune cells, while SCD is downregulated. Five FAM-related DEGs were highly correlated with immune cells. The study promotes the understanding of the pathogenesis of FAM in UC immune cells.


Assuntos
Colite Ulcerativa/genética , Ácidos Graxos/metabolismo , Redes Reguladoras de Genes , Transcriptoma , Acil-CoA Oxidase/genética , Acil-CoA Oxidase/metabolismo , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Colite Ulcerativa/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Linfócitos/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
7.
Anat Sci Int ; 95(4): 489-497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32361815

RESUMO

Steatohepatitis, fibrosis, and cirrhosis are common pathological features in the progression of hepatic steatosis. In the current work, we investigated the effect of germinated barely on the structure and function of the liver and its regulatory mechanism on SDC1 gene expression in a steatohepatitis rat model. Forty-eight adult male white Wistar rats were randomly divided into four groups: Group I, control; Group II, rats fed a germinated barley diet; Group III, rats fed a high-fat diet (HFD); and Group IV, rats fed both germinated barley (GB) and a high-fat diet for 14 weeks. Biochemical, histopathological, immunohistochemical, and morphometric studies, as well as qRT-PCR, were used to analyze the effect of germinated barley on steatohepatitis. The rats in Group IV had a lower liver index percentage and improved altered lipid profile and liver function tests compared to those in Group III. Supplementation of GB with a HFD ameliorated the histopathological features in the livers of rats fed a HFD, decreased the percentage of CD68-positive macrophages, and lowered the upregulated expression of SDC1. Supplementation of a HFD with GB prohibited the deterioration of liver function, lipid profile, and alteration of liver structure; it also decreased the associated hepatic inflammation and downregulated SDC1 in liver tissue.


Assuntos
Dieta , Regulação para Baixo/efeitos dos fármacos , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Expressão Gênica , Germinação , Hordeum , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Fígado/metabolismo , Macrófagos , Masculino , Ratos Wistar , Sindecana-1
8.
Am J Physiol Endocrinol Metab ; 319(1): E34-E42, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32228319

RESUMO

Nonalcoholic fatty liver disease (NAFLD) amplifies the risk of various liver diseases, ranging from simple steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, and ultimately hepatocellular carcinoma. Accumulating evidence suggests the involvement of aberrant microRNAs (miRNAs or miRs) in the activation of cellular stress, inflammation, and fibrogenesis in hepatic cells at different stages of NAFLD and liver fibrosis. Here, we explored the potential role of miR-130b-5p in the pathogenesis of NAFLD, including lipid accumulation and insulin resistance, as well as the underlying mechanism. Initially, the expression of miR-130b-5p and insulin-like growth factor binding protein 2 (IGFBP2) was examined in the established high-fat diet-induced NAFLD mouse models. Then, the interaction between miR-130b-5p and IGFBP2 was validated using dual luciferase reporter assay. The effects of miR-130b-5p and IGFBP2 on lipid accumulation and insulin resistance, as well as the AKT pathway-related proteins, were evaluated using gain or loss-of-function approaches. miR-130b-5p was upregulated, and IGFBP2 was downregulated in liver tissues of NAFLD mice. miR-130b-5p targeted IGFBP2 and downregulated its expression. MiR-130b-5p inhibition or IGFBP2 overexpression reduced the expression of SREBP-1, LXRα, ChREBP, stearoyl CoA desaturase 1, acetyl CoA carboxylase 1, and fatty acid synthase, and levels of fasting blood glucose, fasting insulin, and homeostasis model assessment-insulin resistance, while increasing the ratio of p-AKT/AKT in NAFLD mice. Overall, downregulation of miR-130b-5p can prevent hepatic lipid accumulation and insulin resistance in NAFLD by activating IGFBP2-dependent AKT pathway, highlighting the potential use of anti-miR-130b-5p as therapeutic approaches for the prevention and treatment of NAFLD.


Assuntos
Dieta Hiperlipídica , Resistência à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Fígado/metabolismo , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/genética , Acetil-CoA Carboxilase/genética , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Glicemia/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Ácido Graxo Sintase Tipo I/genética , Expressão Gênica , Regulação da Expressão Gênica , Insulina/metabolismo , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Metabolismo dos Lipídeos/genética , Receptores X do Fígado/genética , Camundongos , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
9.
Int J Mol Sci ; 21(7)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32244800

RESUMO

Fat deposition, which influences pork production, meat quality and growth efficiency, is an economically important trait in pigs. Numerous studies have demonstrated that stearoyl-CoA desaturase (SCD), a key enzyme that catalyzes the conversion of saturated fatty acids into monounsaturated fatty acids, is associated with fatty acid composition in pigs. As SCD was observed to be significantly induced in 3T3-L1 preadipocytes differentiation, we hypothesized that it plays a role in porcine adipocyte differentiation and fat deposition. In this study, we revealed that SCD is highly expressed in adipose tissues from seven-day-old piglets, compared to its expression in tissues from four-month-old adult pigs. Moreover, we found that SCD and lipogenesis-related genes were induced significantly in differentiated porcine adipocytes. Using CRISPR/Cas9 technology, we generated SCD-/- porcine embryonic fibroblasts (PEFs) and found that the loss of SCD led to dramatically decreased transdifferentiation efficiency, as evidenced by the decreased expression of known lipid synthesis-related genes, lower levels of oil red O staining and significantly lower levels of triglyceride content. Our study demonstrates the critical role of SCD expression in porcine adipocyte differentiation and paves the way for identifying it as the promising candidate gene for less fat deposition in pigs.


Assuntos
Adipócitos/enzimologia , Tecido Adiposo/metabolismo , Diferenciação Celular/genética , Genes Essenciais/genética , Estearoil-CoA Dessaturase/genética , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/citologia , Tecido Adiposo/crescimento & desenvolvimento , Animais , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Lipogênese/genética , Carne , Camundongos , Estearoil-CoA Dessaturase/metabolismo , Suínos , Triglicerídeos/metabolismo
10.
Per Med ; 17(2): 111-119, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32125933

RESUMO

Aim: Metabolic syndrome (MetS) diagnosed in the dialysis patients is increasingly reported which worsens the prognosis of the renal diseases. The relationship of SCD1 with MetS is largely unknown. The purpose of this study was to investigate the relationship between SCD1 polymorphism and MetS in dialysis patients. Methods: A cross-sectional study was conducted on 323 Chinese dialysis patients, and the correlation between the seven SNPs of SCD1 gene (rs10883465, rs2060792, rs1502593, rs522951, rs3071, rs3978768 and rs1393492) and MetS was analyzed. Results: One tag-SNP (rs1393492) has significantly associated with the prevalence of MetS. Dialysis patients with rs1393492 AA genotype of SCD1 are more prone to MetS (p = 0.021). Conclusion: This study shows that the rs1393492 variations of SCD1 gene are related with the development of MetS in Chinese dialysis patients.


Assuntos
Nefropatias/terapia , Síndrome Metabólica/epidemiologia , Polimorfismo de Nucleotídeo Único , Estearoil-CoA Dessaturase/genética , Adulto , Idoso , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Masculino , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Prevalência , Diálise Renal
11.
PLoS One ; 15(3): e0229322, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32176696

RESUMO

Tetradecylthioacetic acid (TTA) is a synthetic fatty acid with a sulfur substitution in the ß-position. This modification renders TTA unable to undergo complete ß-oxidation and increases its biological activity, including activation of peroxisome proliferator activated receptors (PPARs) with preference for PPARα. This study investigated the effects of TTA on lipid and lipoprotein metabolism in the intestine and liver of mice fed a high fat diet (HFD). Mice receiving HFD supplemented with 0.75% (w/w) TTA had significantly lower body weights compared to mice fed the diet without TTA. Plasma triacylglycerol (TAG) was reduced 3-fold with TTA treatment, concurrent with increase in liver TAG. Total cholesterol was unchanged in plasma and liver. However, TTA promoted a shift in the plasma lipoprotein fractions with an increase in larger HDL particles. Histological analysis of the small intestine revealed a reduced size of lipid droplets in enterocytes of TTA treated mice, accompanied by increased mRNA expression of fatty acid transporter genes. Expression of the cholesterol efflux pump Abca1 was induced in the small intestine, but not in the liver. Scd1 displayed markedly increased mRNA and protein expression in the intestine of the TTA group. It is concluded that TTA treatment of HFD fed mice leads to increased expression of genes involved in uptake and transport of fatty acids and HDL cholesterol in the small intestine with concomitant changes in the plasma profile of smaller lipoproteins.


Assuntos
HDL-Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Lipoproteínas/metabolismo , PPAR alfa/agonistas , Sulfetos/administração & dosagem , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Sulfetos/farmacologia , Triglicerídeos/sangue
12.
Biochem Biophys Res Commun ; 524(3): 716-722, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32035613

RESUMO

MicroRNAs are well acknowledged as key mediators in the development of chronic metabolic diseases, including NAFLD. However, their roles in hepatic lipid metabolism and fatty liver still remain well elucidated. Here, we found that miR-103 represses de novo lipogenesis (DNL) and dampens the development of obesity/diet-induced fatty liver through targeting at Fasn and Scd1 in mouse liver. miR-103, robustly amplified in obese livers, inhibits the expression of Fasn and Scd1 via directly interacting with their mRNA 3' untranslated regions. Upregulated miR-103 sufficiently reduces the expression of Fasn and Scd1 and blocks the lipid accumulation in oleate-incubated hepatocytes. Furthermore, specifically overexpressing miR-103 in mouse liver by adenovirus significantly inhibits hepatic DNL to repress HCD-promoted hepatic lipid contents as well as NAFLD development. Meanwhile, enforced expression of hepatic miR-103 also alleviates obesity-associated fatty liver via reducing Fasn and Scd1 in db/db mice. Together, our study reveals a critical role of miR-103 in lipid homeostasis of liver and pathogenesis of NAFLD.


Assuntos
Ácido Graxo Sintases/metabolismo , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , MicroRNAs/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Estearoil-CoA Dessaturase/metabolismo , Animais , Sequência de Bases , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Lipogênese/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Ácido Oleico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/genética
13.
Proc Natl Acad Sci U S A ; 117(5): 2462-2472, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953260

RESUMO

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.


Assuntos
Complexo II de Transporte de Elétrons/metabolismo , Gorduras/metabolismo , Obesidade/enzimologia , Estearoil-CoA Dessaturase/genética , Ácido Succínico/metabolismo , Adipócitos Bege/citologia , Adipócitos Bege/metabolismo , Adipogenia , Animais , Metabolismo Energético , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Estearoil-CoA Dessaturase/metabolismo , Termogênese
14.
PLoS One ; 15(1): e0226070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31923252

RESUMO

Conjugated linoleic acid (CLA) is known for its multiple benefits including improvement of growth, increasing lean mass, and anti-carcinogenic effects. However, when used in long-term supplementations CLA does not improve semen parameters in boar and bull and reduces fertility in Japanese quails. The content of unsaturated fatty acids in dietary lipids plays a significant role in spermatogenesis owning the high proportion of unsaturated fatty acids in plasma membrane of sperms. Whether CLA plays a role in testicular tissue and epididymal fat is still unknown. Therefore, in this study we hypothesize that long-term supplementation of equal proportion of CLA isomer mix (c9,t11-CLA and t10,c12- CLA) in rabbit bucks might alter male reproductive potentials. Twelve V-Line weaned male rabbits were used in 26 weeks trial, rabbits were individually raised and randomly allocated into three dietary groups. Control group (CON) received a basal diet, a group received 0.5% CLA (CLA 0.5%), and a group received 1% CLA (CLA 1%). Rabbits were euthanized at the end of the trial and several parameters were evaluated related to growth, semen quality, and testicular and epididymal tissue histopathology and transcriptome. The long-term supplementation of CLA increased feed intake by 5% and body weight by 2-3%. CLA 1% decreased sperm progressive motility. In testicular tissue L-carnitine and α-tocopherol were decreased by CLA supplementation. In epididymal fat, CLA tended to decrease concentration of polyunsaturated fatty acids, the expression of SCD5 gene was upregulated by CLA 1% and CASP3 gene was upregulated by CLA 0.5%. Transcription of PPARG was downregulated by CLA. Feeding 1% CLA also decreased testicular epithelial thickness. Long-term supplementation of CLA modestly enhanced male rabbit growth, but negatively impacted male reproduction, especially at high dose of CLA.


Assuntos
Apoptose/efeitos dos fármacos , Ácidos Linoleicos Conjugados/farmacologia , Motilidade Espermática/efeitos dos fármacos , Espermatozoides/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Carnitina/metabolismo , Suplementos Nutricionais , Regulação para Baixo/efeitos dos fármacos , Epididimo/metabolismo , Epididimo/patologia , Ácidos Graxos Insaturados/metabolismo , Masculino , PPAR gama/genética , PPAR gama/metabolismo , Coelhos , Análise do Sêmen , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Testículo/metabolismo , Testículo/patologia , Testosterona/sangue , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
15.
Chem Biol Interact ; 316: 108917, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838050

RESUMO

Stearoyl-CoA desaturase (SCD) generates monounsaturated fatty acids (MUFAs) which contribute to cell growth, survival, differentiation, metabolic regulation and signal transduction. Overexpression of SCD is evident and implicated in metabolic diseases such as diabetes and non-alcoholic fatty liver disease. SCD also stimulates canonical Wnt pathway and YAP activation in support of stemness and tumorigenesis. SCD facilitates metabolic reprogramming in cancer which is mediated, at least in part, by regulation of AKT, AMPK, and NF-kB via MUFAs. Our research has revealed the novel positive loop to amplify Wnt signaling through stabilization of LRP5/6 in both hepatic stellate cells and liver tumor-initiating stem cell-like cells. As such, this loop is pivotal in promoting liver fibrosis and liver tumor development. This review summarizes the mechanisms of SCD-mediated tumor promotion described by recent studies and discusses the future prospect for SCD-mediated signaling crosstalk as a potential therapeutic target for cancer.


Assuntos
Carcinogênese , Estearoil-CoA Dessaturase/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Estearoil-CoA Dessaturase/genética , Via de Sinalização Wnt
16.
Environ Toxicol ; 35(3): 404-413, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31738477

RESUMO

Cadmium (Cd) is one of the major contaminants in aquatic ecosystem. Stearoyl-coenzyme A desaturase 1 (Scd1) has been implicated in adaptive responses to environmental stressors. The objectives of this study are (a) to characterize scd1 mRNA from silver pomfret (Pampus argenteus); (b) to investigate the expression and activity of Scd1 in silver pomfret exposed to Cd; and (c) to investigate how Cd modifies scd1 gene transcription in silver pomfret. Results indicated that Scd1 was generally conserved across fish species and scd1 mRNA level was higher by far in the brain and liver, followed by the kidney and intestine. Exposure to Cd led to significant changes of the expression and activity of Scd1 in in the liver and intestine. The liver mRNA abundance of scd1 was significantly lower in the Cd-treated groups than in the control group. The 10 days treatment with 1 mg/L Cd significantly upregulated the intestinal scd1 mRNA level, an approximately 9-fold higher in the 1 mg/L Cd-treated group as compared with the control group. Accordingly, Scd1 activity indices (18:1n-9/18:0) in the liver were significantly decreased in the 0.5 mg/L group compared with the control group, while Scd1 activity indices in the intestine were significantly increased in the 1 mg/L group compared with the control group. Moreover, overexpression of sterol regulatory element binding transcription factor 1 (Srebp1) and peroxisome proliferator-activated receptor γ (Pparγ )in HEK 293T cells produced a 2-fold increment in the activity of the scd1 promoter. Furthermore, srebp1 had a similar expression pattern to scd1 in the liver and intestine of silver pomfret exposed to Cd. These results indicated that Cd could regulate scd1 expression, possibly through the transcriptional factor Srebp1.


Assuntos
Cádmio/farmacologia , Peixes/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Estearoil-CoA Dessaturase/genética , Transcrição Genética/efeitos dos fármacos , Poluentes Químicos da Água/farmacologia , Animais , Peixes/metabolismo , Células HEK293 , Humanos , Fígado/metabolismo , PPAR gama/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
17.
J Cell Physiol ; 235(2): 1129-1140, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31241768

RESUMO

Stearoyl-CoA desaturase (SCD) is a rate-limiting enzyme that catalyzes the synthesis of monounsaturated fatty acids. It plays an important role in regulating skeletal muscle metabolism. Lack of the SCD1 gene increases the rate of fatty acid ß-oxidation through activation of the AMP-activated protein kinase (AMPK) pathway and the upregulation of genes that are related to fatty acid oxidation. The mechanism of AMPK activation under conditions of SCD1 deficiency has been unclear. In the present study, we found that the ablation/inhibition of SCD1 led to AMPK activation in skeletal muscle through an increase in AMP levels whereas muscle-specific SCD1 overexpression decreased both AMPK phosphorylation and the adenosine monophosphate/adenosine triphosphate (AMP/ATP) ratio. Changes in AMPK phosphorylation that were caused by SCD1 down- and upregulation affected NAD+ levels following changes in NAD+ -dependent deacetylase sirtuin-1 (SIRT1) activity and histone 3 (H3K9) acetylation and methylation status. Moreover, mice with muscle-targeted overexpression of SCD1 were more susceptible to high-fat diet-induced lipid accumulation and the development of insulin resistance compared with wild-type mice. These data show that SCD1 is involved in nucleotide (ATP and NAD+ ) metabolism and suggest that the SCD1-dependent regulation of muscle steatosis and insulin sensitivity are mediated by cooperation between AMPK- and SIRT1-regulated pathways. Altogether, the present study reveals a novel mechanism that links SCD1 with the maintenance of metabolic homeostasis and insulin sensitivity in skeletal muscle.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Nucleotídeos de Adenina/metabolismo , Histonas/metabolismo , Músculo Esquelético/metabolismo , Sirtuína 1/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Acetilação , Animais , Linhagem Celular , Dieta Hiperlipídica , Regulação para Baixo , Regulação da Expressão Gênica , Histonas/genética , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Knockout , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Sirtuína 1/genética , Estearoil-CoA Dessaturase/genética
18.
FEBS Lett ; 594(3): 530-539, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31557308

RESUMO

Elevated fatty acid (FA) levels contribute to severe metabolic diseases. Unbalanced oversupply of saturated FAs is particularly damaging, which renders stearoyl-CoA desaturase (SCD1) activity an important factor of resistance. A SCD1-related oxidoreductase protects cells against palmitate toxicity, so we aimed to test whether desaturase activity is limited by SCD1 itself or by the associated electron supply. Unsaturated/saturated FA ratio was markedly elevated by SCD1 overexpression while it remained unaffected by the overexpression of SCD1-related electron transfer proteins in HEK293T cells. Electron supply was not rate-limiting either in palmitate-treated cells or in cells with enhanced SCD1 expression. Our findings indicate the rate-limiting role of SCD1 itself, and that FA desaturation cannot be facilitated by reinforcing the electron supply of the enzyme.


Assuntos
Ácidos Graxos/metabolismo , Transfecção , Transporte de Elétrons/efeitos dos fármacos , Expressão Gênica , Células HEK293 , Humanos , Cinética , Ácido Palmítico/farmacologia , Estearoil-CoA Dessaturase/genética
19.
Am J Physiol Gastrointest Liver Physiol ; 318(1): G174-G188, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31630534

RESUMO

Progressive fibrosis, functional liver failure, and cancer are the central liver-related outcomes of nonalcoholic steatohepatitis (NASH) but notoriously difficult to achieve in mouse models. We performed a direct, quantitative comparison of hepatic fibrosis progression in well-defined methionine- and choline-deficient (MCD) and choline-deficient, amino-acid defined (CDAA) diets with increasing fat content (10-60% by calories) in C57Bl/6J and BALB/cAnNCrl mice. In C57Bl/6J mice, MCD feeding resulted in moderate fibrosis at week 8 (up to twofold increase in total hepatic collagen content) and progressive weight loss irrespective of dietary fat. In contrast, CDAA-fed mice did not lose weight and developed progressive fibrosis starting from week 4. High dietary fat in the CDAA diet model induced the lipid metabolism genes for sterol regulatory element-binding protein and stearoyl-CoA desaturase-2 and increased ductular reaction and fibrosis in a dose-dependent manner. Longitudinal analysis of CDAA with 60% fat (HF-CDAA) feeding revealed pronounced ductular reaction and perisinusoidal bridging fibrosis, with a sevenfold increase of hepatic collagen at week 12, which showed limited spontaneous reversibility. At 24 wk, HF-CDAA mice developed signs of cirrhosis with pan-lobular "chicken wire" fibrosis, 10-fold hydroxyproline increase, regenerative nodules, portal hypertension and elevated serum bilirubin and ammonia levels; 80% of mice (8/10) developed multiple glypican-3- and/or glutamine synthetase-positive hepatocellular carcinomas (HCC). High-fat (60%) supplementation of MCD in C57Bl/6J or feeding the HF-CDAA diet fibrosis-prone BALB/cAnNCrl strain failed to result in increased fibrosis. In conclusion, HF-CDAA feeding in C57Bl/6J mice was identified as an optimal model of steatohepatitis with robust fibrosis and ductular proliferations that progress to cirrhosis and HCC within 24 wk. This robust model will aid the testing of interventions and drugs for severe NASH.NEW & NOTEWORTHY Via quantitative comparison of several dietary models, we report HF-CDAA feeding in C57Bl/6 mice as an excellent model recapitulating several key aspects of fibrotic NASH: 1) robust, poorly reversible liver fibrosis, 2) prominent ductular reaction, and 3) progression to cirrhosis, portal hypertension, and liver cancer within 24 wk. High fat dose-dependently activates SREBP2/SCD2 genes and drives liver fibrosis in e HF-CDAA model. These features qualify the model as a robust and practical tool to study mechanisms and novel treatments addressing severe human NASH.


Assuntos
Proliferação de Células , Deficiência de Colina/complicações , Dieta Hiperlipídica , Cirrose Hepática Experimental/etiologia , Neoplasias Hepáticas/etiologia , Fígado/patologia , Metionina/deficiência , Hepatopatia Gordurosa não Alcoólica/etiologia , Ração Animal , Animais , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Progressão da Doença , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Fígado/metabolismo , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Fatores de Tempo
20.
J Med Food ; 23(3): 305-311, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31663815

RESUMO

The metabolic syndrome (MS) underlies metabolic disorders considered risk factors for the development of diabetes and cardiovascular diseases, which are major causes of morbidity and mortality in most of the world. Sterculic acid has been proposed as a potential tool for the treatment of MS since it inhibits the activity of the stearoyl-CoA desaturase-1 (SCD1), a central enzyme in lipid metabolism. We analyzed the effect of sterculic oil (SO) co-administration with 30% fructose in drinking water on the development of MS in male Wistar rats. After 8 weeks, 0.4% SO exerted a protective effect from MS development since parameters altered by fructose (blood pressure, insulin resistance, serum glucose and triglycerides, steatosis, and adiposity) were similar to those of control rats.


Assuntos
Frutose/efeitos adversos , Síndrome Metabólica/dietoterapia , Óleos Vegetais/administração & dosagem , Animais , Glicemia/metabolismo , Modelos Animais de Doenças , Humanos , Insulina/sangue , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Ratos , Ratos Wistar , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Sterculia/química , Sterculia/metabolismo , Triglicerídeos/sangue
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