Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.065
Filtrar
1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 156-158, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034744

RESUMO

OBJECTIVE: To explore the genetic basis for a Chinese neonate with lipoprotein lipase deficiency. METHODS: Targeted capture and next-generation sequencing (NGS) were carried out to detect variants of genes associated with inborn errors of metabolism. Suspected variants were validated by Sanger sequencing. RESULTS: Genetic testing revealed novel complex heterozygous variants, namely c.347G>C (p.Arg116Pro) and c.472T>G (p.Tyr158Asp), of the LPL gene, which were respectively inherited from his father and mother. CONCLUSION: Compound heterozygous variants c.347G>C and c.472T>G of the LPL gene probably underlie the lipoprotein lipase deficiency in this child.


Assuntos
Hiperlipoproteinemia Tipo I , Lipase Lipoproteica/genética , Grupo com Ancestrais do Continente Asiático , Testes Genéticos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperlipoproteinemia Tipo I/genética , Recém-Nascido , Mutação
2.
Acta Biochim Biophys Sin (Shanghai) ; 52(1): 84-90, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31828306

RESUMO

KLF7, one of candidate genes in neurotherapy and metabolic syndrome, has been studied in adipogenesis of mammalian species and birds. However, the effect of the third C2H2 zinc finger of KLF7 for its transcriptional regulation in adipogenesis has not been well understood. Here, the wild-type chicken KLF7 (KLF7) overexpression plasmid, pCMV-myc-KLF7, and two plasmids of chicken KLF7 mutants, i.e. pCMV-myc-KLF7m1 with half of the third zinc finger (KLF7m1) and pCMV-myc-KLF7m2 without the third zinc finger (KLF7m2), were constructed. Luciferase reporter assay in DF1 cells showed that the effect of chicken KLF7 overexpression on the promoter activity of LPL was greater than those of KLF7m1 and KLF7m2 (P < 0.05). There was no significant difference among the overexpression of KLF7, KLF7m1 and KLF7m2 on the promoter activities of FASN, C/EBPα and FABP4 (P > 0.05). Additionally, the effects of KLF7, KLF7m1 and KLF7m2 overexpression on the promoter activity of PPARγ were different. KLF7 overexpression had no significant effect on the PPARγ promoter activity (P > 0.05), KLF7m1 overexpression suppressed PPARγ promoter activity (P < 0.05), while KLF7m2 overexpression facilitated the promoter activity of PPARγ (P < 0.05), consistent with the results of western blot analysis. Our results suggested that the third zinc finger of chicken KLF7 may play a role in its transcriptional regulation of LPL and PPARγ but has no effect on its regulation of C/EBPα, FASN and FABP4. The third zinc finger of KLF7 might be a target for the treatment of metabolic disorder in chicken.


Assuntos
Tecido Adiposo/metabolismo , Dedos de Zinco CYS2-HIS2 , Fatores de Transcrição Kruppel-Like/química , Fatores de Transcrição Kruppel-Like/genética , Transcrição Genética/genética , Adipogenia , Animais , Sítios de Ligação , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Linhagem Celular , Galinhas , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Proteínas Mutantes/genética , PPAR gama/genética , PPAR gama/metabolismo , Plasmídeos/genética , Regiões Promotoras Genéticas/genética , Análise de Sequência , Transfecção
3.
Yonsei Med J ; 60(12): 1187-1194, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31769250

RESUMO

PURPOSE: Adipogenic differentiation of adipose tissue-derived mesenchymal stem cells (AMSCs) is critical to many disease-related disorders, such as obesity and diabetes. Studies have demonstrated that miRNA-138 (miR-138) is closely involved in adipogenesis. However, the mechanisms affected by miR-138 remain unclear. This work aimed to investigate interactions between miR-138 and lipoprotein lipase (LPL), a key lipogenic enzyme, in AMSCs. MATERIALS AND METHODS: Human AMSCs (hAMSCs) isolated from human abdomen tissue were subjected to adipogenic differentiation medium. Quantitative real-time polymerase chain reaction and Western blot assay were applied to measure the expressions of miR-138, LPL, and the two adipogenic transcription factors cytidine-cytidine-adenosine-adenosine-thymidine enhancer binding protein alpha (C/EBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). The relationship between miR-138 and LPL was predicted utilizing the miRTarBase database and validated by dual luciferase reporter assay. RESULTS: Showing increases in C/EBPα and PPARγ expression levels, hAMSCs were induced into adipogenic differentiation. During adipogenesis of hAMSCs, miR-138 expression was significantly downregulated. Overexpression of miR-138 by transfection inhibited hAMSCs adipogenic differentiation in vitro. Mechanically, LPL was a target of miR-138. LPL expression was upregulated during adipogenesis of hAMSCs, and this upregulation was reversed by miR-138 overexpression. Functionally, silencing of LPL by transfection exerted similar inhibition of the expressions of C/EBPα and PPARγ. Meanwhile, LPL ectopic expression was able to partly abolish the suppressive effect of miR-138 overexpression on adipogenic differentiation of hAMSCs. CONCLUSION: Upregulation of miR-138 inhibits adipogenic differentiation of hAMSCs by directly downregulating LPL.


Assuntos
Adipogenia , Tecido Adiposo/citologia , Lipase Lipoproteica/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Sequência de Bases , Células Cultivadas , Regulação para Baixo/genética , Inativação Gênica , Humanos , Lipase Lipoproteica/genética , MicroRNAs/genética , Regulação para Cima/genética
4.
Molecules ; 24(18)2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31533306

RESUMO

Adipogenesis is a complex biological process and the main cause of obesity. Recently, microRNAs (miRNAs), a class of small endogenous non-coding RNAs, have been proven to play an important role in adipogenesis by the post-transcriptional regulation of target genes. In this current study, we observed an increment of miR-152 expression during the process of 3T3-L1 cell audiogenic differentiation. A functional analysis indicated that the overexpression of miR-152 inhibited pre-adipocyte proliferation and suppressed the expression of some cell cycle-related genes. Moreover, the overexpression of miR-152 promoted lipid accumulation in 3T3-L1 preadipocytes accompanied by increase of the expression of some pro-audiogenic genes. Additionally, a dual-luciferase reporter assay demonstrated lipoprotein lipase (LPL) was a direct target gene of miR-152 during preadipocyte differentiation. Further analysis showed that miR-152 was positively correlated with adipogenesis and intramuscular fat formation in vivo. Taken together, our findings suggest that miR-152 could suppress 3T3-L1 preadipocyte proliferation, whereas it could promote 3T3-L1 preadipocyte differentiation by negatively regulating LPL. The findings indicate that miR-152 might have a therapeutic significance for obesity and obesity-related metabolic syndrome.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Adipogenia/genética , Diferenciação Celular/genética , MicroRNAs/genética , Células 3T3-L1 , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Regulação da Expressão Gênica , Lipase Lipoproteica/genética , Camundongos , Modelos Biológicos , Interferência de RNA
5.
Lipids Health Dis ; 18(1): 151, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286991

RESUMO

BACKGROUND: Free fatty acid (FFA) accumulation in proximal tubules plays a fundamental role in the progress of kidney disease. Here, we reported a rare case with undetectable serum FFAs and further evaluated the changes of serum FFAs in patients with chronic renal failure (CRF). METHODS: We analyzed the clinical data of a rare case and 574 CRF patients. The mRNA expression of lipoprotein lipase (LPL), hepatic lipase (HL) and fatty acid synthase (FASN) were determined in the rare case and 30 age-matched healthy males with qPCR. RESULTS: This rare case had serious proteinuria, hyperglycemia, lipid disorders and bilateral renal glomerular filtration dysfunction. Compared with healthy males, this case showed a 1.49-fold increase of LPL expression (P < 0.01), a 3.38-fold reduction of HL expression (P < 0.001), and no significant change of FASN expression (P > 0.05). In total, 21.6% of CRF patients showed abnormal FFAs. Biochemical parameters such as blood urea nitrogen (BUN) and creatinine (CREA) significantly differed among groups with low-, normal- or high-level-FFAs. Moreover, serum FFAs was found to be associated with BUN. FFAs decreased in the group with higher BUN (> 17.4 mmol/L) and in the group with lower estimated glomerular filtration rate (eGFR) (< 15 mL/min/1.73m2). CONCLUSIONS: The proteinuria, HL low expression and renal function failure may contribute to the FFA reduction, which might imply that the renal function is severely damaged.


Assuntos
Ácidos Graxos não Esterificados/sangue , Falência Renal Crônica/sangue , Adulto , Idoso , Análise Química do Sangue , Estudos de Casos e Controles , Ácido Graxo Sintase Tipo I/genética , Feminino , Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/fisiopatologia , Lipase/genética , Transtornos do Metabolismo dos Lipídeos/sangue , Transtornos do Metabolismo dos Lipídeos/etiologia , Lipase Lipoproteica/genética , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Proteinúria/etiologia
6.
Int J Mol Sci ; 20(12)2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208038

RESUMO

Hyperglycaemia and type 2 diabetes (T2D) are associated with impaired insulin secretion and/or insulin action. Since few studies have addressed the relation between DNA methylation patterns with elaborated surrogates of insulin secretion/sensitivity based on the intravenous glucose tolerance test (IVGTT), the aim of this study was to evaluate the association between DNA methylation and an insulin sensitivity index based on IVGTT (calculated insulin sensitivity index (CSi)) in peripheral white blood cells from 57 non-diabetic female volunteers. The CSi and acute insulin response (AIR) indexes, as well as the disposition index (DI = CSi × AIR), were estimated from abbreviated IVGTT in 49 apparently healthy Chilean women. Methylation levels were assessed using the Illumina Infinium Human Methylation 450k BeadChip. After a statistical probe filtering, the two top CpGs whose methylation was associated with CSi were cg04615668 and cg07263235, located in the catenin delta 2 (CTNND2) and lipoprotein lipase (LPL) genes, respectively. Both CpGs conjointly predicted insulin sensitivity status with an area under the curve of 0.90. Additionally, cg04615668 correlated with homeostasis model assessment insulin-sensitivity (HOMA-S) and AIR, whereas cg07263235 was associated with plasma creatinine and DI. These results add further insights into the epigenetic regulation of insulin sensitivity and associated complications, pointing the CTNND2 and LPL genes as potential underlying epigenetic biomarkers for future risk of insulin-related diseases.


Assuntos
Cateninas/genética , Metilação de DNA , Resistência à Insulina/genética , Insulina/metabolismo , Leucócitos/metabolismo , Lipase Lipoproteica/genética , Adulto , Fatores Etários , Biomarcadores , Ilhas de CpG , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética , Feminino , Teste de Tolerância a Glucose , Humanos , Curva ROC , Fatores Sexuais , Transdução de Sinais , Adulto Jovem
7.
Pharmacol Biochem Behav ; 184: 172738, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31229467

RESUMO

The anti-depressant effect of repetitive transcranial magnetic stimulation (rTMS), a clinically-useful treatment for depression, is associated with changes to the endocannabinoid system (ECS). However, it is currently unknown whether different frequencies of rTMS alter the ECS differently. To test this, rats exposed to chronic unpredictable stress (CUS) were treated with rTMS at two different frequencies (5 (high) or 1 Hz (low), 1.26 Tesla) for 7 consecutive days. Twenty-four hours after the final rTMS treatment, we evaluated depressive-like behaviors and the expression of several synaptic proteins and ECS-related proteins in the hippocampus. In addition, we knocked-down diacylglycerol lipase alpha (DAGLα) and cannabinoid type 1 receptor (CB1R), two important components of the ECS, and measured depressive-like behaviors and synaptic protein expression following rTMS. Furthermore, we measured the expression levels of several components of the ECS system in hippocampal-derived astrocytes and neurons exposed to repetitive magnetic stimulation (rMS) with different parameters (5 or 1 Hz, 0.84 or 1.26 Tesla). Interestingly, we found that only high-frequency rTMS ameliorated depressive-like behaviors and normalized the expression of hippocampal synaptic proteins in CUS-treated rats; this effect was eliminated by knockdown of DAGLα or CB1R. Moreover, we found that rMS at 5 Hz increased the expression of DAGLα and CB1R in hippocampal astrocytes and neurons. Collectively, our results suggest that high-frequency rTMS exerts its anti-depressant effect by up-regulating DAGLα and CB1R.


Assuntos
Depressão/terapia , Endocanabinoides/metabolismo , Hipocampo/metabolismo , Lipase Lipoproteica/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Estresse Fisiológico , Sinapses/metabolismo , Estimulação Magnética Transcraniana/métodos , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Comportamento Animal , Endocanabinoides/genética , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Lipase Lipoproteica/genética , Masculino , Neurônios/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/genética
8.
Eur J Pharmacol ; 858: 172492, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31233750

RESUMO

Lipoprotein lipase (LPL) is the rate-controlling enzyme for the accumulation of triacylglycerol into adipocytes, which acts by digesting it into glycerol and fatty acids. In this study, we found that treatment with (+)-JQ1, an inhibitor of the bromodomain and extra-terminal (BET) family proteins, for 4 days from the end of stimulation to induce adipocyte differentiation reduced binding of BRD4, a BET family member, within the gene body of Lpl. This eventually downregulated the expression of Lpl in 3T3-L1 adipocytes. Longer treatment for 8 days reduced the acetylation of histones H3 and H4 within the gene body of Lpl and subsequent Lpl expression. Lpl expression in mesenteric adipose tissues was lower in Brd4+/- heterozygous mice at 14 days after birth than in wild-type mice at the same age. Furthermore, treatment with an inducer of insulin resistance, tumor necrosis factor-α, reduced BRD4 binding and histone acetylation in the gene body of Lpl and its expression. These results indicate that transcriptional elongation of Lpl controlled by BRD4 may be associated with adipocyte differentiation, and that its suppression is potentially associated with insulin resistance of adipocytes.


Assuntos
Adipócitos/citologia , Diferenciação Celular/genética , Epigênese Genética , Resistência à Insulina/genética , Lipase Lipoproteica/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Células 3T3-L1 , Acetilação/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Tecido Adiposo/citologia , Tecido Adiposo/efeitos dos fármacos , Animais , Azepinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/genética , Heterozigoto , Histonas/metabolismo , Camundongos , Triazóis/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
9.
J Ethnopharmacol ; 240: 111952, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31100436

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rosa rugosa Thunb. is a traditional Chinese medicine that was used in the treatment of cardiovascular diseases and relative risk factors such as diabetes, hyperlipidemia, hypertension, and inflammation. Rosa rugosa flavonoids (RRFs) are the main components in Rosa rugosa Thunb. Several studies have demonstrated that RRFs can regulate plasma lipid contents, but the related mechanism of which has not yet been elucidated clearly. AIM OF THE STUDY: The goal of this study was to clarify the effects of RRFs on triglyceride metabolism and its related mechanisms. MATERIALS AND METHODS: RRFs were obtained by ethanol extraction from Rosa rugosa Thunb.. Transgenic mice expressing human Apolipoprotein C3 (ApoC3) were used as a mouse model of hypertriglyceridemia. Fenofibrate (FNB), a PPARα agonist, was used as a positive control drug of decreasing high triglyceride. FNB (100 mg/kg) or RRFs (300 mg/kg) were given to the mice by gavage daily. Two weeks later, the changes of plasma lipid levels in the mice were measured by commercial kits, the clearance of triglyceride was evaluated by oral fat load test, and expression of the genes related to lipid ß-oxidation and synthesis was detected in the mice livers by real time PCR. RESULTS: RRFs, as well as FNB, were found to significantly reduce plasma triglyceride (TG) levels in ApoC3 transgenic mice after administration of the drug for two weeks. Plasma lipid clearance rate was increased and lipid content in the mice livers was reduced after administration of RRF. Treatment with RRFs up-regulated mRNA expression of PPARα and its downstream gene of ACOX, while down-regulated mRNA expression of the genes related to fatty acid synthesis (FASN, SREBP-1c, and ACC1). The expression of LPL was raised, while the expression of ApoC3 was decreased, and Foxo1 was inhibited by RRFs in the mice livers. CONCLUSION: RRFs can reduce plasma TG levels by repressing the expression of ApoC3 and inducing the expression of LPL in liver. RRFs could also reduce triglyceride in hepatocytes through increasing ß-oxidation and decreasing synthesis of the lipids. These findings show the potency of further clinical application of RRFs as a hypolipidemic drug for treatment of cardiovascular diseases.


Assuntos
Flavonoides/uso terapêutico , Hipertrigliceridemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , PPAR alfa/agonistas , Rosa , Animais , Apolipoproteína C-III/genética , Colesterol/metabolismo , Flavonoides/farmacologia , Hipertrigliceridemia/metabolismo , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipase Lipoproteica/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Triglicerídeos/metabolismo
10.
Gene ; 706: 13-18, 2019 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-31034941

RESUMO

BACKGROUND: Metabolic syndrome is a cluster of conditions that increase risk of cardiovascular morbidity and mortality. Among genetic factors that contributed to incidence of metabolic syndrome, Polymorphisms of Lipoprotein lipase (LPL) are major candidates especially because of their effect on obesity and dyslipidemia. S447X (rs328) and Hind III (rs320) Polymorphisms of LPL gene have been reported to change LPL activity, resulting in altered triglyceride (TG) and high density lipoprotein Cholesterol (HDL-C) levels. This study investigates the effects of these gene polymorphisms on factors affecting metabolic syndrome in northern population of Iran. METHODS: Studied population included 223 adults consisting 90 women and 133 men with body mass index (BMI) ≥ 30 kg/m2 as obese subjects, and 156 healthy participants as a control group with BMI <25 that included 68 women and 88 men. All factors causing metabolic syndrome were evaluated. Also DNA was extracted from blood samples and HindIII and S447X LPL gene polymorphisms were screened by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). CONCLUSIONS: The present study proves that some genotypes of S447X were associated with a reduced risk of developing low HDL-C only in men, while the protective effects of HindIII on hypertriglyceridemia were only seen in women [corrected]. The point is that this relation is affected by the weight profile of the participants. It can be concluded that there is a gender-related relation between the polymorphisms of LPL gene and the risk factors for incidence of metabolic syndrome in the northern population of Iran.


Assuntos
Lipase Lipoproteica/genética , Síndrome Metabólica/genética , Adulto , Índice de Massa Corporal , Dislipidemias/genética , Feminino , Predisposição Genética para Doença/genética , Genótipo , Humanos , Hipertrigliceridemia/genética , Irã (Geográfico) , Lipídeos/sangue , Lipase Lipoproteica/fisiologia , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Obesidade/sangue , Polimorfismo de Nucleotídeo Único/genética , Fatores Sexuais , Triglicerídeos/sangue
11.
Lipids Health Dis ; 18(1): 84, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947712

RESUMO

BACKGROUND: Two important regulators for circulating lipid metabolisms are lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). In relation to this, glycosylphosphatidylinositol anchored high-density lipoprotein binding protein 1 (GPIHBP1) has been shown to have a vital role in LPL lipolytic processing. However, the relationships between skeletal muscle mass and lipid metabolism, including LPL, GPIHBP1, and HTGL, remain to be elucidated. Demonstration of these relationships may lead to clarification of the metabolic dysfunctions caused by sarcopenia. In this study, these relationships were investigated in young Japanese men who had no age-related factors; participants included wrestling athletes with abundant skeletal muscle. METHODS: A total of 111 young Japanese men who were not taking medications were enrolled; 70 wrestling athletes and 41 control students were included. The participants' body compositions, serum concentrations of lipoprotein, LPL, GPIHBP1 and HTGL and thyroid function test results were determined under conditions of no extreme dietary restrictions and exercises. RESULTS: Compared with the control participants, wrestling athletes had significantly higher skeletal muscle index (SMI) (p < 0.001), higher serum concentrations of LPL (p < 0.001) and GPIHBP1 (p < 0.001), and lower fat mass index (p = 0.024). Kruskal-Wallis tests with Bonferroni multiple comparison tests showed that serum LPL and GPIHBP1 concentrations were significantly higher in the participants with higher SMI. Spearman's correlation analyses showed that SMI was positively correlated with LPL (ρ = 0.341, p < 0.001) and GPIHBP1 (ρ = 0.309, p = 0.001) concentration. The serum concentrations of LPL and GPIHBP1 were also inversely correlated with serum concentrations of triglyceride (LPL, ρ = - 0.198, p = 0.037; GPIHBP1, ρ = - 0.249, p = 0.008). Serum HTGL concentration was positively correlated with serum concentrations of total cholesterol (ρ = 0.308, p = 0.001), low-density lipoprotein-cholesterol (ρ = 0.336, p < 0.001), and free 3,5,3'-triiodothyronine (ρ = 0.260, p = 0.006), but not with SMI. CONCLUSIONS: The results suggest that increased skeletal muscle mass leads to improvements in energy metabolism by promoting triglyceride-rich lipoprotein hydrolysis through the increase in circulating LPL and GPIHBP1.


Assuntos
Lipase/sangue , Lipase Lipoproteica/sangue , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Receptores de Lipoproteínas/sangue , Adolescente , Adulto , Atletas , LDL-Colesterol/sangue , Metabolismo Energético/genética , Exercício Físico/fisiologia , Feminino , Estudos de Associação Genética , Humanos , Lipase/genética , Metabolismo dos Lipídeos/genética , Lipase Lipoproteica/genética , Fígado/metabolismo , Masculino , Músculo Esquelético/fisiologia , Doenças Musculares/sangue , Doenças Musculares/patologia , Receptores de Lipoproteínas/genética , Testes de Função Tireóidea , Triglicerídeos/sangue , Adulto Jovem
12.
BMJ Case Rep ; 12(4)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30948399

RESUMO

A 44-year-old woman was admitted with pancreatitis caused by hypertriglyceridaemia (fasting triglycerides 28 mmol/L). She used oral contraceptives and ezetimibe 10 mg. She was overweight (body mass index 29.7 kg/m2). Diabetes mellitus was ruled out, as were nephrotic syndrome, alcohol abuse, hypothyroidism and dysbetalipoproteinaemia. Genetic analysis revealed mutations in two genes involved in triglyceride metabolism (apolipoprotein A5 and lipoprotein lipase [LPL]). The LPL activity was 45% compared with pooled healthy controls. The post-heparin triglyceride reduction was 6%, compared with a normal reduction of >20%. The patient was initially treated with gemfibrozil, but this was discontinued due to side effects. Dietary triglyceride restriction and discontinuation of the oral contraceptives lowered the plasma triglycerides within 2 weeks to 3.4 mmol/L. Hypertriglyceridaemia is a risk factor for pancreatitis and cardiovascular disease, and has a broad differential diagnosis including genetic causes. Patients can achieve near-normal triglyceride values with a low-fat diet only.


Assuntos
Apolipoproteína A-V/genética , Hiperlipoproteinemia Tipo I/genética , Hipertrigliceridemia/genética , Lipase Lipoproteica/genética , Pancreatite/genética , Adulto , Feminino , Humanos , Lipase Lipoproteica/deficiência , Mutação
13.
J Agric Food Chem ; 67(16): 4623-4631, 2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-30950260

RESUMO

Propiconazole is a triazole fungicide that has been widely used in agriculture and has been detected in the aquatic environment. This study aimed to investigate the effects of propiconazole exposure on lipid metabolism in the early life stages of zebrafish for 120 h postfertilization (hpf). Using the early life stages of zebrafish to address scientific questions is lower in cost, more efficient, and suitable to meeting current legislation than those in other traditional fish species. Exposure to propiconazole significantly inhibited the development of zebrafish embryos and larvae. This exposure also caused reduced locomotor activities in zebrafish. Furthermore, total cholesterol levels, lipoprotein lipase, and fatty acid synthase activities were significantly decreased. The expression levels of genes involved in lipid metabolism were significantly up-regulated in response to propiconazole exposure. GC-MS/MS analysis revealed that fatty acids were significantly decreased. Together, the findings indicate the potential environmental risks of propiconazole exposure in the aquatic ecosystem.


Assuntos
Fungicidas Industriais/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Triazóis/toxicidade , Peixe-Zebra/embriologia , Animais , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
14.
Exp Oncol ; 41(1): 39-45, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30932419

RESUMO

AIM: The IGHV mutational status is one of the most important markers for chronic lymphocytic leukemia (CLL) prognostication. Lipoprotein lipase (LPL) gene expression was found to correlate with IGHV status and was suggested as its surrogate marker. Recent data reported that LPL expression might be influenced by pivotal signalling pathways in CLL. This study aimed to assess LPL gene expression in relation to key immunogenetic and molecular markers of CLL, including IGHV mutational status, B-cell receptor (BCR) stereotypy, TP53, NOTCH1, and SF3B1 gene mutations. Materials and Methods: Expression of LPL mRNA was measured in peripheral blood mononuclear cells of 73 CLL patients by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). IGHV, NOTCH1, TP53, and SF3B1 gene mutation analysis was performed by PCR amplification and direct sequencing. RESULTS: 44 of 73 (60%) CLL cases were categorized as LPL-positive based on the cut-off value established by ROC (receiver operating characteristic) curve analysis. LPL expression was significantly associated with IGHV mutation status (r = 0.684; p < 0.0001) and tended to correlate with presence of NOTCH1 gene mutations (p = 0.113). BCR stereotyped cases showed higher LPL expression values in comparison to unstereotyped cases in the LPL-positive group of patients (p = 0.041). LPL expression was associated with a shorter overall survival in the entire СLL group (median 107 vs 143, p = 0.048) as well as in Binet A patients, albeit with borderline significance (median 139 vs not reached, p = 0.086). CONCLUSION: LPL expression was found to be closely correlated with IGHV gene mutational status and overall survival, proving LPL as prognostic marker in CLL. Our results also indicate a possible relationship between aberrant expression of LPL and BCR- and NOTCH1-dependent signalling pathways.


Assuntos
Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/genética , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Rearranjo Gênico do Linfócito B , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico
15.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1567-1578, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905785

RESUMO

OBJECTIVE: Hypovitaminosis D is common in the obese population and patients suffering from obesity-associated disorders such as type 2 diabetes and fatty liver disease, resulting in suggestions for vitamin D supplementation as a potential therapeutic option. However, the pathomechanistic contribution of the vitamin D-vitamin D receptor (VDR) axis to metabolic disorders is largely unknown. METHODS: We analyzed the pathophysiological role of global and intestinal VDR signaling in diet-induced obesity (DIO) using global Vdr-/- mice and mice re-expressing an intestine-specific human VDR transgene in the Vdr deficient background (Vdr-/- hTg). RESULTS: Vdr-/- mice were protected from DIO, hepatosteatosis and metabolic inflammation in adipose tissue and liver. Furthermore, Vdr-/- mice displayed a decreased adipose tissue lipoprotein lipase (LPL) activity and a reduced capacity to harvest triglycerides from the circulation. Intriguingly, all these phenotypes were partially reversed in Vdr-/- hTg animals. This clearly suggested an intestine-based VDR activity on systemic lipid homeostasis. Scrutinizing this hypothesis, we identified the potent LPL inhibitor angiopoietin-like 4 (Angptl4) as a novel transcriptional target of VDR. CONCLUSION: Our study suggests a VDR-mediated metabolic cross-talk between gut and adipose tissue, which significantly contributes to systemic lipid homeostasis. These results have important implications for use of the intestinal VDR as a therapeutic target for obesity and associated disorders.


Assuntos
Proteína 4 Semelhante a Angiopoietina/genética , Fígado Gorduroso/genética , Mucosa Intestinal/metabolismo , Lipase Lipoproteica/genética , Fígado/metabolismo , Receptores de Calcitriol/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Estudos de Coortes , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação , Mucosa Intestinal/patologia , Metabolismo dos Lipídeos/genética , Lipase Lipoproteica/antagonistas & inibidores , Lipase Lipoproteica/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Pessoa de Meia-Idade , Receptores de Calcitriol/deficiência , Transdução de Sinais , Transcrição Genética , Transgenes , Triglicerídeos/metabolismo
16.
Cancer Res ; 79(9): 2136-2151, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30862716

RESUMO

Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumor nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS, which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacologic response. SIGNIFICANCE: These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.


Assuntos
Ácidos Graxos/metabolismo , Glicerofosfolipídeos/metabolismo , Melanócitos/patologia , Melanoma/patologia , Peixe-Zebra/metabolismo , Animais , Metabolismo Energético , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Humanos , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Melanoma/metabolismo , Metabolômica , Fator de Transcrição Associado à Microftalmia/genética , Transcriptoma , Células Tumorais Cultivadas , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas ras/genética , Proteínas ras/metabolismo
17.
Anim Sci J ; 90(4): 493-503, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706583

RESUMO

This study was designed to estimate dietary energy level on intramuscular fat (IMF) deposition in Simmental × Yellow breed cattle. Results showed that ultimate weight and average daily gain in high and medium energy groups were significantly higher than low-energy group, yet feed conversion ratio was significantly lower. IMF content was significantly increased by dietary energy increasing, whereas longissimus muscle shear force significantly decreased. Serum-free fatty acids, triglycerides and glucose significantly increased by dietary energy increasing, whereas growth hormone (GH) significantly decreased. Enzyme activities of lipoprotein lipase (LPL), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) significantly increased by dietary energy increasing, whereas hormone-sensitive lipase (HSL) and carnitine palmitoyltransferase-1 (CPT-1) significantly diminished. Peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein 1, stearoyl-CoA desaturase, adipocyte-fatty acid-binding proteins, ACC, LPL, and FAS gene or protein expression significantly increased by dietary energy increasing, whereas HSL, CPT-1, and GH gene or protein expression significantly decreased. These results indicated that high dietary energy promoting IMF deposition is mainly by downregulating pituitary GH gene expression, decreasing serum GH concentration, increasing lipogenic genes levels of mRNA, enzyme activities and protein expression, and decreasing lipolytic genes levels of mRNA, enzyme activities, and protein expression.


Assuntos
Tecido Adiposo/metabolismo , Cruzamento , Bovinos/genética , Bovinos/metabolismo , Dieta/veterinária , Ingestão de Energia/fisiologia , Expressão Gênica , Hormônio do Crescimento/genética , Hormônio do Crescimento/metabolismo , Músculo Esquelético/metabolismo , Animais , Regulação para Baixo , Ingestão de Energia/genética , Lipogênese/genética , Lipólise/genética , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ganho de Peso
18.
Mol Cell Probes ; 44: 29-36, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30703449

RESUMO

In this study, the potential functions of miR-224 in regulating adipogenic differentiation were explored in bovine preadipocytes. Comparative transcriptome analysis between castrated male cattle with increased intramuscular fat (IMF) and intact male cattle revealed that miR-224 and LPL were abnormally expressed, correlating negatively, and LPL was a predicted target of miR-224. A dual luciferase reporter assay confirmed the negative targeting regulatory relationship between miR-224 and LPL. When miR-224 was either overexpressed or silenced, qRT-PCR showed a negative regulatory effect on LPL. mRNA expression levels of the fat-formation-related biomarkers C/EBPα, C/EBPß, PPARγ, FASN and PLIN1 decreased when miR-224 was overexpressed, while the opposite effect occurred and adipogenic differentiation followed when miR-224 was inhibited. Oil Red O staining. Triglyceride (TG) levels and immunostaining revealed that the accumulation of lipid droplets decreased or increased accordingly. Taken together, our data demonstrated that miR-224 regulated the adipogenic differentiation of bovine preadipocytes by targeting LPL. This provides insight into the molecular basis of IMF deposition in beef cattle.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Lipase Lipoproteica/metabolismo , MicroRNAs/metabolismo , Adipócitos/citologia , Animais , Sequência de Bases , Bovinos , Células HEK293 , Humanos , Metabolismo dos Lipídeos/genética , Lipase Lipoproteica/genética , Luciferases/metabolismo , Masculino , MicroRNAs/genética , Plasmídeos/metabolismo
19.
JAMA ; 321(4): 364-373, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30694319

RESUMO

Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.


Assuntos
Apolipoproteínas B/sangue , LDL-Colesterol/sangue , Doença das Coronárias/genética , Predisposição Genética para Doença , Variação Genética , Lipase Lipoproteica/genética , Receptores de LDL/genética , Triglicerídeos/sangue , Estudos de Casos e Controles , Doença das Coronárias/sangue , Feminino , Humanos , Lipase Lipoproteica/metabolismo , Mutação com Perda de Função , Masculino , Análise da Randomização Mendeliana , Redes e Vias Metabólicas , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
20.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1226-1240, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30660685

RESUMO

Erectile dysfunction (ED) is a common comorbidity in males with diabetes. In this study, we aimed to investigate how lncRNA-MIAT affects ED in diabetes and the involved mechanism. Microarray analysis was performed to screen ED-related differentially expressed genes, regulatory microRNA (miR) and long noncoding RNA (lncRNA). Highly expressed lipoprotein lipase (LPL) was identified, and subsequently miR-328a-5p and lncRNA-MIAT were determined. Diabetes was induced by streptozotocin in rats, and diabetic rats with ED were selected. Vascular smooth muscle cells (VSMCs) and vascular endothelial cells (VECs) were cocultured. The siRNA against lncRNA-MIAT, miR-328a-5p mimic and overexpression vector of LPL were transfected to investigate the specific effects of miR-328a-5p, lncRNA-MIAT and LPL on ED in diabetes. The expression of LPL, lncRNA-MIAT and miR-328a-5p in the serum of diabetic patients was measured. Increased LPL and lncRNA-MIAT and reduced miR-328a-5p were observed in diabetic patients. In addition, ED led to upregulated LPL and lncRNA-MIAT and downregulated miR-328a-5p in serum of diabetic patients and VSMCs of diabetic rats, especially in those with ED. LncRNA-MIAT directly regulated miR-328a-5p, which directly targeted LPL. LncRNA-MIAT upregulated LPL by acting as a ceRNA of miR-328a-5p. Silencing of lncRNA-MIAT and LPL or miR-328a-5p overexpression reduced VEC apoptosis and increased cell proliferation. In addition, an increased intracavernosal pressure (ICP)/mean arterial pressure (MAP) ratio was noted in the corpus cavernosum of rats and inhibited VEC injury. Taken together, our data demonstrated that depleted lncRNA-MIAT suppressed LPL by increasing miR-328a-5p, thereby inhibiting VEC injury to attenuate ED in diabetic rats.


Assuntos
Diabetes Mellitus Experimental/genética , Disfunção Erétil/genética , Lipase Lipoproteica/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Animais , Células Cultivadas , Técnicas de Cocultura , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Regulação para Baixo , Células Endoteliais/citologia , Disfunção Erétil/complicações , Disfunção Erétil/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Lipase Lipoproteica/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/citologia , Ratos Sprague-Dawley
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA