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1.
J Enzyme Inhib Med Chem ; 35(1): 96-108, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31690133

RESUMO

A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
2.
Biomed Pharmacother ; 117: 109176, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387185

RESUMO

BACKGROUND/AIMS: Hyperlipidaemia is a major risk factor for cardiovascular and cerebrovascular diseases. Daming capsule (DMC), a medicine for lowering blood lipids, is marketed in China; however, its mechanism is unclear. The present study aimed to investigate the mechanism by which DMC reduces blood lipids. METHODS AND RESULTS: A rat model of hyperlipidaemia was established by feeding rats a high-fat diet (HFD), and the serum lipid levels were detected with an automatic biochemical analyser. DMC (162 mg/kg) and atorvastatin calcium (10 mg/kg) were orally administered to the hyperlipidaemic rats for 4 weeks. HFD feeding markedly induced increases in the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-c); however, DMC treatment significantly decreased the levels of TC, TG, and LDL-c in rats serum. Meanwhile, the hepatic TC and TG levels, liver weight/body weight ratio, and body weight were significantly lower in the DMC-treated rats than in the HFD rats. Moreover, DMC significantly alleviated hepatomegaly, hepatic lipid deposition, and hepatic steatosis. The protein expression level of phospho-adenosine monophosphate-activated protein kinase (p-AMPK) (Thr172) in HFD rat livers was lower than that in normal rat livers, whereas it increased in the liver of the DMC-treated rats; however, the protein expression level of total-AMPK in the liver was not different among the groups. The AMPK-activating effect of DMC was blocked by Compound C (a specific AMPK inhibitor) in HepG2 cells. Additionally, DMC considerably increased peroxisome proliferator-activated receptor-alpha (PPARα) protein expression and lipoprotein lipase (LPL) transcription and concentration in the liver. This effect of DMC was also inhibited by Compound C in HepG2 cells. DMC also promoted LDL receptor (LDLR) protein expression by activating AMPK. We further found that DMC reduced the levels of TC and TG in oleic acid-treated HepG2 cells, and it restored the expression levels of p-AMPK, PPARα, LPL, and LDLR compared to the decreased levels observed in oleic acid-treated HepG2 cells. CONCLUSION: DMC lowered lipids in serum and the liver by activating AMPK. On the one hand, the activation of AMPK enhanced PPARα expression and LPL transcription to lead to the hydrolysis of TG; on the other hand, it increased LDLR protein expression to promote lipid metabolism.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , China , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/metabolismo , Lipase Lipoproteica/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ácido Oleico/metabolismo , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de LDL/metabolismo , Triglicerídeos/sangue
3.
Nutrients ; 11(7)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284400

RESUMO

This study evaluates the progressive participation of enzymes involved in lipolysis and lipogenesis, leading to adipocyte hypertrophy in a metabolic syndrome (MS) rat model caused by chronic consumption of 30% sucrose in drinking water. A total of 70 male Wistar rats were divided into two groups: C and MS. Each of these groups were then subdivided into five groups which were sacrificed as paired groups every month from the beginning of the treatment until 5 months. The intra-abdominal fat was dissected, and the adipocytes were extracted. Lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), protein kinases A (PKA), and perilipin A expressions were determined. The LPL and HSL activities were evaluated by spectrophotometry. Histological staining was performed in adipose tissue. Significant increases were observed in blood pressure, HOMA-IR, leptin, triglycerides, insulin, intra-abdominal fat, and number of fat cells per field (p = 0.001) and in advanced glycosylation products, adipocyte area, LPL, HSL activities and/or expression (p ≤ 0.01) in the MS groups progressively from the third month onward. Lipogenesis and lipolysis were increased by LPL activity and HSL activity and/or expression. This was associated with hyperinsulinemia and release of non-esterified fatty acids causing a positive feedback loop that contributes to the development of adipocyte hypertrophy.


Assuntos
Gordura Abdominal/metabolismo , Lipogênese , Lipólise , Síndrome Metabólica/metabolismo , Gordura Abdominal/patologia , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Sacarose na Dieta , Modelos Animais de Doenças , Progressão da Doença , Ácidos Graxos não Esterificados/metabolismo , Retroalimentação Fisiológica , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Hipertrofia , Lipase Lipoproteica/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/patologia , Perilipina-1/metabolismo , Ratos Wistar , Transdução de Sinais , Esterol Esterase/metabolismo , Fatores de Tempo
4.
Zhonghua Gan Zang Bing Za Zhi ; 27(7): 533-540, 2019 Jul 20.
Artigo em Chinês | MEDLINE | ID: mdl-31357780

RESUMO

Objective: To analyze non-alcoholic steatohepatitis (NASH)-related differentially expressed genes (DEGs) by bioinformatics methods to find key pathways and potential therapeutic targets for NASH. Methods: GSE61260 chip was downloaded from the public microarray database and liver biopsy samples from 24 NASH cases and 38 healthy controls were included. The Limma software package in R language was used to screen DEGs under the condition of difference multiple > 1.5 and adj. P < 0.05. The clusterProfiler software package was used for GO analysis and KEGG analysis. The STRING online database was used for protein-protein interaction analysis, and the L1000 and DrugBank databases were used for drug prediction. Results: Compared with healthy control group, 857 DEGs were screened out in NASH group including 167 up-regulated genes and 690 down-regulated genes. GO analysis showed that DEGs were mainly involved in inflammation and cholesterol metabolism. KEGG analysis showed that DEGs were mainly enriched in PPAR, non-alcoholic fatty liver disease, oxidative phosphorylation and other signaling pathways. Among them, eight genes of ACSL4, CYP7A1, FABP4, FABP5, lipoprotein lipase, ME1, OLR1 and PLIN1 were enriched in PPAR signaling pathway, and 165 interaction nodes were formed with 47 DEGs-encoded proteins. Lipoprotein lipase interacted with 21 DEGs, and its up-regulated expression had improved lipid metabolism, insulin resistance and anti-inflammatory effects. Four drugs (gemfibrozil, bezafibrate, omega-3 carboxylic acid and glycyrrhizic acid) were screened by L1000 and DrugBank to activate lipoprotein lipase. Presently, these four drugs are clinically used to treat hypertriglyceridemia or to improve inflammation. In this regard, we speculated that the pharmacological effects of these four drugs had improved NASH by activating lipoprotein lipase to promote liver lipid metabolism and alleviate inflammation. Conclusion: PPAR signaling pathway is closely associated to the occurrence and development of NASH, and thereby lipoprotein lipase agonist is a new attempt to treat NASH.


Assuntos
Ativadores de Enzimas/farmacologia , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Bezafibrato/farmacologia , Biópsia , Ácidos Carboxílicos/farmacologia , Estudos de Casos e Controles , Biologia Computacional , Genfibrozila/farmacologia , Ácido Glicirrízico/farmacologia , Humanos , Hepatopatia Gordurosa não Alcoólica/enzimologia , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Depuradores Classe E
5.
Ecotoxicol Environ Saf ; 181: 353-361, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31207574

RESUMO

Fatty liver is widely observed during Takifugu fasciatus production, but the mechanisms underlying fatty liver formation remain unknown. The present study was conducted to determine the potential effects of copper (Cu) on hepatic lipid deposition and metabolism in T. fasciatus after 21 days of exposure to Cu (levels: 0, 20 and 100 µg/L). Copper exposure decreased the weight gain rate (WG) in T. fasciatus, but increased the values of the viscerosomatic index (VSI) and hepatosomatic index (HSI) compared with the control. The time-dependent Cu accumulation in tissues increased as the Cu concentration increased. The order of Cu accumulation was liver > intestine > muscle. The lipid content, triglyceride (TG) content and lipoprotein lipase (LPL) activity increased after Cu exposure compared with the control. In addition, more lipid droplets and greater vacuolization were observed in the liver after exposure to 20 µg/L Cu than after 100 µg/L Cu. The expression of genes involved in lipogenesis (g6pd, 6pgd, lpl, fas and acc), lipolysis (hsl and cpt 1) and transcription (ppar α and ppar ©) was dependent on Cu. An analysis of the intestinal microbiome community showed that the highest values of the Chao 1 index, ACE, Shannon index and Simpson index were obtained in fish exposed to 20 µg/L Cu, whereas the lowest values were obtained after the 100 µg/L Cu treatment. The Principal Coordinates Analysis (PCoA) plots of the data revealed structural differences in the groups treated with Cu compared with the control group. At the phylum level, the intestinal microbiota in the Cu-treated and control fish were dominated by Proteobacteria and Bacteroidetes. The higher Firmicutes to Bacteroidetes ratio was observed in fish treated with 20 µg/L Cu compared with other groups, while the lowest ratio was observed in fish exposed to 100 µg/L Cu. Our study revealed the mechanisms by which Cu exposure altered (i) lipid deposition in the body and (ii) the intestinal microbiome, which may contribute to maintain the health status of T. fasciatus for the aquaculture.


Assuntos
Cobre/toxicidade , Fígado Gorduroso/veterinária , Doenças dos Peixes/induzido quimicamente , Takifugu , Poluentes Químicos da Água/toxicidade , Animais , Cobre/farmacocinética , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Doenças dos Peixes/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/genética , Lipase Lipoproteica/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculos/metabolismo , Takifugu/crescimento & desenvolvimento , Takifugu/metabolismo , Triglicerídeos/metabolismo , Poluentes Químicos da Água/farmacocinética
6.
Ann Intern Med ; 170(9): 626-634, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31035285

RESUMO

The chylomicronemia syndrome occurs when triglyceride levels are severely elevated (usually >16.95 mmol/L [1500 mg/dL]) and is characterized by such clinical features as abdominal pain, acute pancreatitis, eruptive xanthomas, and lipemia retinalis. It may result from 1 of 3 conditions: the presence of secondary forms of hypertriglyceridemia concurrent with genetic causes of hypertriglyceridemia, termed multifactorial chylomicronemia syndrome (MFCS); a deficiency in the enzyme lipoprotein lipase and some associated proteins, termed familial chylomicronemia syndrome (FCS); or familial partial lipodystrophy. Most chylomicronemia syndrome cases are the result of MFCS; FCS is very rare. In all these conditions, triglyceride-rich lipoproteins accumulate because of impaired plasma clearance. This review describes the 3 major causes of the chylomicronemia syndrome; their consequences; and the approaches to treatment, which differ considerably by group.


Assuntos
Hiperlipoproteinemia Tipo I/etiologia , Hiperlipoproteinemia Tipo I/terapia , Algoritmos , Angiopoietinas/metabolismo , Apolipoproteínas/antagonistas & inibidores , Apolipoproteínas/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Quilomícrons/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Fíbricos/uso terapêutico , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemia Tipo I/metabolismo , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/terapia , Hipolipemiantes/uso terapêutico , Lipodistrofia Parcial Familiar/complicações , Lipase Lipoproteica/metabolismo , Mutação , Oligonucleotídeos/uso terapêutico , Pancreatite/etiologia , Pancreatite/prevenção & controle , Receptores de Lipoproteínas/genética , Fatores de Risco
7.
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
8.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(7): 1061-1071, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30844432

RESUMO

Very low-density lipoprotein (VLDL) is the main plasma carrier of triacylglycerol that is elevated in pathological conditions such as diabetes, metabolic syndrome, obesity and dyslipidemia. How variations in triacylglycerol levels influence structural stability and remodeling of VLDL and its metabolic product, low-density lipoproteins (LDL), is unknown. We applied a biochemical and biophysical approach using lipoprotein remodeling by lipoprotein lipase and cholesterol ester transfer protein, along with thermal denaturation that mimics key aspects of lipoprotein remodeling in vivo. The results revealed that increasing the triacylglycerol content in VLDL promotes changes in the lipoprotein size and release of the exchangeable apolipoproteins. Similarly, increased triacylglycerol content in LDL promotes lipoprotein remodeling and fusion. These effects were observed in single-donor lipoproteins from healthy subjects enriched in exogenous triolein, in single-donor lipoproteins from healthy subjects with naturally occurring differences in endogenous triacylglycerol, and in LDL and VLDL from pooled plasma of diabetic and normolipidemic patients. Consequently, triacylglycerol-induced destabilization is a general property of plasma lipoproteins. This destabilization reflects a direct effect of triacylglycerol on lipoproteins. Moreover, we show that TG can act indirectly by increasing lipoprotein susceptibility to oxidation and lipolysis and thereby promoting the generation of free fatty acids that augment fusion. These in vitro findings are relevant to lipoprotein remodeling and fusion in vivo. In fact, fusion of LDL and VLDL enhances their retention in the arterial wall and, according to the response-to-retention hypothesis, triggers atherosclerosis. Therefore, enhanced fusion of triacylglycerol-rich lipoproteins suggests a new causative link between elevated plasma triacylglycerol and atherosclerosis.


Assuntos
Lipoproteínas LDL/química , Lipoproteínas VLDL/química , Triglicerídeos/farmacologia , Aterosclerose/etiologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Humanos , Lipase Lipoproteica/metabolismo , Lipoproteínas/metabolismo , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Estrutura Molecular , Desnaturação Proteica
9.
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
10.
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
12.
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
13.
Am J Physiol Renal Physiol ; 316(3): F558-F571, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698048

RESUMO

Activity of lipoprotein lipase (LPL) is high in mouse kidney, but the reason is poorly understood. The aim was to characterize localization, regulation, and function of LPL in kidney of C57BL/6J mice. We found LPL mainly in proximal tubules, localized inside the tubular epithelial cells, under all conditions studied. In fed mice, some LPL colocalized with the endothelial markers CD31 and GPIHBP1 and could be removed by perfusion with heparin, indicating a vascular location. The role of angiopoietin-like protein 4 (ANGPTL4) for nutritional modulation of LPL activity was studied in wild-type and Angptl4-/- mice. In Angptl4-/- mice, kidney LPL activity remained high in fasted animals, indicating that ANGPTL4 is involved in suppression of LPL activity on fasting, like in adipose tissue. The amount of ANGPTL4 protein in kidney was low, and the protein appeared smaller in size, compared with ANGPTL4 in heart and adipose tissue. To study the influence of obesity, mice were challenged with high-fat diet for 22 wk, and LPL was studied after an overnight fast compared with fasted mice given food for 3 h. High-fat diet caused blunting of the normal adaptation of LPL activity to feeding/fasting in adipose tissue, but in kidneys this adaptation was lost only in male mice. LPL activity increases to high levels in mouse kidney after feeding, but as no difference in uptake of chylomicron triglycerides in kidneys is found between fasted and fed states, our data confirm that LPL appears to have a minor role for lipid uptake in this organ.


Assuntos
Dieta Hiperlipídica , Rim/metabolismo , Lipase Lipoproteica/metabolismo , Obesidade/metabolismo , Tecido Adiposo/metabolismo , Proteína 4 Semelhante a Angiopoietina/genética , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Estado Nutricional , Fatores Sexuais
14.
Eur J Pharmacol ; 843: 177-189, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30439364

RESUMO

Recent studies showed that coiled-coil domain-containing 80 (CCDC80) has a positive link with atherosclerosis and that plasma CCDC80 levels are positively correlated with the levels of fasting plasma triglycerides (TG) in obese individuals. The underlying mechanisms, however, are unclear. Using Hematoxylin-eosin (H&E) and Oil Red O staining, we found that CCDC80 overexpression in vivo significantly increased plasma lipid contents, decreased the expression and activity of lipoprotein lipase (LPL), and accelerated the development of atherosclerosis. Conversely, knockdown of CCDC80 decreased plaque lesions area. In vitro, qRT-PCR and western blot results showed that CCDC80 overexpression significantly decreased, while CCDC80 knockdown increased, LPL expression in cultured vascular smooth muscle cells (VSMCs). Further, we found that CCDC80 reduced LPL expression via inhibiting the phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) and also increased the methylation of LPL promoter via down-regulating Tet methylcytosine dioxygenase 2 (TET2). Our results also revealed that CCDC80 significantly down-regulated TET2 expression through decreasing the phosphorylation of ERK1/2. In addition, we found that CCDC80 decreased binding of TET2 to forkhead box O3 (FOXO3a) but had no effect on FOXO3a expression. On the other hand, and that FOXO3a was partially involved in TET2-regulated LPL expression. CCDC80 down-regulated ERK1/2 phosphorylation and decreased expression of TET2 and its interaction with FOXO3a, leading to a reduction of LPL expression and acceleration of atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipase Lipoproteica/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Metilação de DNA , Proteínas da Matriz Extracelular , Proteína Forkhead Box O3/metabolismo , Lipase Lipoproteica/genética , Masculino , Camundongos Knockout para ApoE , Músculo Liso Vascular/citologia , Fosforilação , Triglicerídeos/sangue
15.
Biochem Biophys Res Commun ; 508(1): 97-101, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30471854

RESUMO

Nobiletin has protective effects on cardiovascular diseases, but the mechanism is not clear. In this study, we examined whether nobiletin affects the expression of miR-590/LPL and its relative effects on lipid accumulation and pro-inflammatory cytokine secretion in human THP-1 macrophages. RT-qPCR analysis showed that nobiletin increased the expression of miR-590. Western blot analysis showed that nobiletin-suppressed LPL expression was enhanced by miR-590 mimic and abrogated by miR-590 inhibitor. Oil Red O staining and high-performance liquid chromatography assays showed that nobiletin attenuated lipid accumulation in macrophages. Treatment with nobiletin and miR-590 mimic decreased cellular lipid accumulation, whereas treatment with miR-590 inhibitor increased cellular lipid accumulation. ELISA illustrated that nobiletin alleviated pro-inflammatory cytokine secretion in macrophages as measured by, which was reduced by miR-590 mimic and increased by miR-590 inhibitor. In conclusion, nobiletin may alleviate lipid accumulation and secretion of pro-inflammatory cytokines by enhancing the inhibitory effect of miR-590 on LPL expression, suggesting a promising strategy for potential drug development for atherosclerosis.


Assuntos
Flavonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipase Lipoproteica/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Cardiotônicos/farmacologia , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Desenvolvimento de Medicamentos , Humanos , Mediadores da Inflamação/metabolismo , Lipase Lipoproteica/antagonistas & inibidores , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células THP-1 , Regulação para Cima/efeitos dos fármacos
16.
Anim Sci J ; 90(2): 214-221, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30556368

RESUMO

The aim of this study was to determine the effects of isonitrogenous and isocaloric diets containing different qualities of forages and concentrate content on milk fat composition and genes that encode mammary lipogenic enzymes in dairy cows. A total of 20 Holstein cows were assigned to 1 of 2 treatment diets composed of either mixed forages (MF, starch : 21.50%) or corn stover forage (CS, starch : 25.39%). Mammary tissue biopsies were performed to analyze the mRNA expression of lipogenic enzymes. Dry matter intake, body weight, milk protein, and lactose were not affected by treatments. The milk yield, fat content and saturated fatty acid (SFA) and short- and medium-chain fatty acid (SMFA) contents in milk were lower in the CS diet than in the MF diet, but the unsaturated FA and long-chain FA contents were higher. Genes involved in de novo FA synthesis, FA uptake and transport, and Δ9-desaturation were lower in the CS treatment than in the MF treatment. No effects on the nuclear transcription factors were observed between the two treatments. The data indicated that corn stover diet reduced the milk yield, fat content, SMFA, and SFA contents in milk, as well as the gene expression of mammary lipogenic enzymes in dairy cows.


Assuntos
Ração Animal , Bovinos/metabolismo , Bovinos/fisiologia , Dieta/veterinária , Ácidos Graxos/metabolismo , Lactação , Lipogênese/genética , Glândulas Mamárias Humanas/enzimologia , Glândulas Mamárias Humanas/metabolismo , Leite/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Ração Animal/análise , Animais , Coenzima A Ligases/genética , Coenzima A Ligases/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Proteína 3 Ligante de Ácido Graxo/metabolismo , Ácidos Graxos/biossíntese , Feminino , Expressão Gênica , Humanos , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Proteínas do Leite/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Amido , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Zea mays
17.
Toxicol Lett ; 302: 35-41, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30553937

RESUMO

Environmental tobacco smoke (ETS) exposure during brain development has been associated with several disorders, such as depression, anxiety, sudden infant death syndrome, and the predisposition to addiction. The endocannabinoid system plays an essential role in neuronal development. We investigated the effects of early postnatal ETS exposure on the endocannabinoid system in different brain regions. C57BL/6 J mice were exposed to ETS that was generated from 3R4F cigarettes from postnatal day 3 (P3) to P14. Receptors and enzymes of the endocannabinoid system were assessed in infancy, adolescence, and adulthood by Western blot. In the brainstem, ETS exposure decreased cannabinoid 1 (CB1) receptor, CB2 receptor, N-arachidonoyl phosphatidyl ethanol-specific phospholipase D (NAPE-PLD), and fatty acid amino hydrolase (FAAH) levels and increased in diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) levels during infancy and decreased CB2 and FAAH levels during adulthood. In the striatum, ETS decreased in the NAPE-PLD and MAGL levels and increased FAAH levels during infancy, increased FAAH levels during adolescence, and decreased NAPE-PLD levels during adulthood. The present findings indicate that exposure to ETS during a critical period of brain development can disturb the endocannabinoid system in the brainstem and striatum, regions that are involved in the pathogenesis of sudden infant death syndrome and the susceptibility to addiction.


Assuntos
Tronco Encefálico/efeitos dos fármacos , Fumar Cigarros/efeitos adversos , Corpo Estriado/efeitos dos fármacos , Endocanabinoides/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Amidoidrolases/metabolismo , Animais , Animais Recém-Nascidos , Tronco Encefálico/crescimento & desenvolvimento , Tronco Encefálico/metabolismo , Corpo Estriado/crescimento & desenvolvimento , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Lipase Lipoproteica/metabolismo , Camundongos Endogâmicos C57BL , Monoacilglicerol Lipases/metabolismo , Fosfolipase D/metabolismo , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/efeitos dos fármacos , Receptor CB2 de Canabinoide/metabolismo
18.
Proc Natl Acad Sci U S A ; 116(5): 1723-1732, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30559189

RESUMO

Lipoprotein lipase (LPL) is responsible for the intravascular processing of triglyceride-rich lipoproteins. The LPL within capillaries is bound to GPIHBP1, an endothelial cell protein with a three-fingered LU domain and an N-terminal intrinsically disordered acidic domain. Loss-of-function mutations in LPL or GPIHBP1 cause severe hypertriglyceridemia (chylomicronemia), but structures for LPL and GPIHBP1 have remained elusive. Inspired by our recent discovery that GPIHBP1's acidic domain preserves LPL structure and activity, we crystallized an LPL-GPIHBP1 complex and solved its structure. GPIHBP1's LU domain binds to LPL's C-terminal domain, largely by hydrophobic interactions. Analysis of electrostatic surfaces revealed that LPL contains a large basic patch spanning its N- and C-terminal domains. GPIHBP1's acidic domain was not defined in the electron density map but was positioned to interact with LPL's large basic patch, providing a likely explanation for how GPIHBP1 stabilizes LPL. The LPL-GPIHBP1 structure provides insights into mutations causing chylomicronemia.


Assuntos
Lipase Lipoproteica/metabolismo , Plasma/metabolismo , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Animais , Células CHO , Capilares/metabolismo , Linhagem Celular , Cricetulus , Cristalografia por Raios X/métodos , Células Endoteliais/metabolismo , Humanos , Hidrólise , Hipertrigliceridemia/metabolismo
19.
Int J Obes (Lond) ; 43(2): 276-284, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29907844

RESUMO

BACKGROUND: Obesity and insulin resistance are characterized by metabolic inflexibility, a condition described as an inability to switch from fat oxidation during fasting to carbohydrate oxidation during hyperinsulinemia. The purpose of this study was to examine predictors of metabolic flexibility in 103 obese (37-59% fat), sedentary (VO2max: 19.4 ± 0.5 ml/kg/min), postmenopausal (45-76 years) women, and changes in metabolic flexibility with exercise and weight loss interventions. METHODS: Insulin sensitivity (M) and metabolic flexibility via an 80 mU/m2/min hyperinsulinemic-euglycemic clamp, VO2max, and body composition were measured. Metabolic flexibility was measured after 6-months aerobic training + weight loss (AEX + WL: n = 43) or weight loss (WL: n = 31). Basal and insulin-stimulated vastus lateralis skeletal muscle samples were available from a subset of these women (n = 45). RESULTS: Metabolic flexibility correlated inversely with glucose120 min of OGTT, fasting insulin, and the percent change (insulin-basal) in lipoprotein lipase (LPL) activity and positively with M, but not with VO2max, total body fat, visceral fat, or subcutaneous abdominal fat. Skeletal muscle acyl-CoA synthase and citrate synthase activities decreased during hyperinsulinemia. Metabolic flexibility increased after AEX + WL but not WL, and the percent change in metabolic flexibility was inversely related to the percent change in insulin's effect on LPL activity. CONCLUSION: Metabolic flexibility is related to insulin sensitivity and insulin's action on LPL. Furthermore, metabolic flexibility and insulin suppression of skeletal muscle LPL activity increase with AEX + WL in overweight and obese, sedentary older women.


Assuntos
Exercício/fisiologia , Resistência à Insulina/fisiologia , Músculo Esquelético , Pós-Menopausa , Perda de Peso/fisiologia , Idoso , Glicemia/metabolismo , Glicemia/fisiologia , Ácidos Graxos/metabolismo , Feminino , Técnica Clamp de Glucose , Humanos , Insulina/sangue , Insulina/metabolismo , Lipase Lipoproteica/metabolismo , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Pós-Menopausa/metabolismo , Pós-Menopausa/fisiologia
20.
J Biol Chem ; 294(8): 2678-2689, 2019 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-30591589

RESUMO

Cardiovascular disease has been the leading cause of death throughout the world for nearly 2 decades. Hypertriglyceridemia affects more than one-third of the population in the United States and is an independent risk factor for cardiovascular disease. Despite the frequency of hypertriglyceridemia, treatment options are primarily limited to diet and exercise. Lipoprotein lipase (LPL) is an enzyme responsible for clearing triglycerides from circulation, and its activity alone can directly control plasma triglyceride concentrations. Therefore, LPL is a good target for triglyceride-lowering therapeutics. One approach for treating hypertriglyceridemia may be to increase the amount of enzymatically active LPL by preventing its inhibition by angiopoietin-like protein 4 (ANGPTL4). However, little is known about how these two proteins interact. Therefore, we used hydrogen-deuterium exchange MS to identify potential binding sites between LPL and ANGPTL4. We validated sites predicted to be located at the protein-protein interface by using chimeric variants of LPL and an LPL peptide mimetic. We found that ANGPTL4 binds LPL near the active site at the lid domain and a nearby α-helix. Lipase lid domains cover the active site to control both enzyme activation and substrate specificity. Our findings suggest that ANGPTL4 specifically inhibits LPL by binding the lid domain, which could prevent substrate catalysis at the active site. The structural details of the LPL-ANGPTL4 interaction uncovered here may inform the development of therapeutics targeted to disrupt this interaction for the management of hypertriglyceridemia.


Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Inibidores Enzimáticos/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Proteína 4 Semelhante a Angiopoietina/genética , Animais , Bovinos , Ativação Enzimática , Células HEK293 , Humanos , Lipase Lipoproteica/metabolismo , Conformação Proteica , Especificidade por Substrato
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