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1.
BMC Res Notes ; 14(1): 315, 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404457

RESUMO

OBJECTIVES: Breast cancer cell growth and proliferation requires lipids for energy production, cell membrane synthesis, or as signaling molecules. Lipids can be delivered to cells by lipoprotein lipase (LPL), an extracellular lipase that hydrolyzes triacylglycerols and phospholipids from lipoproteins, that is expressed by adipose tissue and some breast cancer cell lines. Studies have shown that lipoprotein hydrolysis products induce pro-inflammatory cytokine secretion by endothelial cells. Thus, our objective was to determine if hydrolysis products generated by LPL from total lipoproteins can also promote pro-inflammatory cytokine secretion from breast cancer cells. RESULTS: Using cytokine arrays, we found that MDA-MB-231 cells increased secretion of seven cytokines in response to treatment with lipoprotein hydrolysis products. In contrast, MCF-7 cells showed decreased secretion of two cytokines. Expanding the analysis to additional cell lines by ELISA, we found increased secretion of TNF-α and IL-6 by MDA-MB-468 cells, and increased secretion of IL-4 by MDA-MB-468 and SKBR3 cells. The changes to cytokine secretion profiles of the breast cancer cell types examined, including the non-cancerous MCF-10a breast cells, were independent of increased cell metabolic activity. These results provide information on how lipoprotein hydrolysis products within the tumor microenvironment might affect breast cancer cell viability and progression.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Citocinas , Células Endoteliais , Feminino , Humanos , Hidrólise , Lipase Lipoproteica , Macrófagos , Microambiente Tumoral
2.
Biomolecules ; 11(7)2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34356640

RESUMO

Ninety percent of plasma fatty acids (FAs) are contained within lipoprotein-triglyceride, and lipoprotein lipase (LPL) is robustly expressed in the heart. Hence, LPL-mediated lipolysis of lipoproteins is suggested to be a key source of FAs for cardiac use. Lipoprotein clearance by LPL occurs at the apical surface of the endothelial cell lining of the coronary lumen. In the heart, the majority of LPL is produced in cardiomyocytes and subsequently is translocated to the apical luminal surface. Here, vascular LPL hydrolyzes lipoprotein-triglyceride to provide the heart with FAs for ATP generation. This article presents an overview of cardiac LPL, explains how the enzyme works, describes key molecules that regulate its activity and outlines how changes in LPL are brought about by physiological and pathological states such as fasting and diabetes, respectively.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Ácidos Graxos/metabolismo , Lipase Lipoproteica/metabolismo , Miocárdio/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Diabetes Mellitus/enzimologia , Cardiomiopatias Diabéticas/patologia , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos , Lipase Lipoproteica/genética , Miocárdio/enzimologia , Processamento de Proteína Pós-Traducional
3.
Int J Sports Med ; 42(11): 953-966, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34374040

RESUMO

The widespread benefits of physical activity in enhancing health and lowering the risk of non-communicable chronic diseases are well established across populations globally. Nevertheless, the prevalence of several lifestyle-related chronic diseases, including cardiovascular disease, varies markedly across countries and ethnicities. Direct ethnic comparative studies on the health benefits of physical activity are sparse and evidence-based physical activity guidelines are not ethnicity-specific. Indeed, physical activity guidelines in some Asian countries were developed primarily based on data from Western populations even though the magnitude of potential benefit may not be the same among different ethnic groups. Unfavorable diurnal perturbations in postprandial triglycerides and glucose are risk factors for cardiovascular disease. This narrative review summarizes differences in these risk factors primarily between individuals of Asian and white European descent but also within different Asian groups. Moreover, the variable effects of physical activity on mitigating risk factors among these ethnic groups are highlighted along with the underlying metabolic and hormonal factors that potentially account for these differences. Future ethnic comparative studies should include investigations in understudied ethnic groups, such as those of East Asian origin, given that the effectiveness of physical activity for ameliorating cardiovascular disease varies even among Asian groups.


Assuntos
Grupo com Ancestrais do Continente Asiático , Exercício Físico , Período Pós-Prandial , Triglicerídeos/metabolismo , Glucose/metabolismo , Fatores de Risco de Doenças Cardíacas , Humanos , Insulina/metabolismo , Resistência à Insulina , Lipase Lipoproteica/metabolismo , Triglicerídeos/sangue
4.
Enzyme Microb Technol ; 149: 109849, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34311886

RESUMO

A lipase from Malassizia globose, named SMG1, is highly desirable for industrial application due to its substrate specificity towards mono- and diacylglycerol. To improve its thermostability, we constructed a mutant library using an error-prone polymerase chain reaction, which was screened for both initial and residual enzymatic activity. Selected mutants were further studied using purified proteins for their kinetic thermostability at 45 ℃, T50 (the temperature at which the enzyme loses half of its activity), and the optimal reaction temperature. Results showed that the majority of mutations with improved thermostability were on the protein surface. D245N and L270P showed the most significant thermostability enhancement with an approximately 3 ℃ increase in T50 compared to wild-type (WT). In addition, combining these two mutations resulted in an increase of T50 by 5 °C. Also, the optimal reaction temperatures of L270P and this double mutant are 10 ℃ higher than WT. The double mutant showed an approximately 100-fold increase in half-life at 45 ℃ and higher enzymatic activities at 30 ℃ and above compared to WT. High-temperature unfolding molecular dynamics simulation suggested that the double mutant stabilized a flexible loop in the catalytic pocket.


Assuntos
Basidiomycota/enzimologia , Lipase Lipoproteica , Estabilidade Enzimática , Cinética , Simulação de Dinâmica Molecular , Mutação , Temperatura
5.
Clin Chim Acta ; 521: 264-271, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34324844

RESUMO

The aim of this study was to investigate the clinical features and genetic causes of two family cases with familial chylomicronemia syndrome (FCS). Clinical manifestations of proband 1 and her families, and also proband 2 showed severe hypertriglyceridemia, especially the triglycerides levels of two probands were extremely high. Gene sequencing results showed that the LPL genes in each of the two probands had a new mutation site. For the proband 1, a compound heterozygous mutation at c.429 (c.429 + 1G > T) was detected in the LPL gene, which was splicing mutation and inherited from her mother. Homozygous mutation was detected in the LPL gene of proband 2, the nucleotide mutation at c.802 (c.802C > T) exhibited missense mutation, his parents and brother had a heterozygous mutation at the same site. It was confirmed that the conservative lipoprotein lipase superfamily domain changed an amino acid from histidine to tyrosine at p. 268 (p. His268Tyr). Flow cytometry confirmed the deficient expression of LPL protein in two families. These results indicated that the mutation in LPL gene might be the cause of familial chylomicronemia syndrome.


Assuntos
Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , China , Feminino , Humanos , Hiperlipoproteinemia Tipo I/genética , Lipase Lipoproteica/genética , Masculino , Mutação
6.
Clin Chim Acta ; 521: 85-89, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34242636

RESUMO

BACKGROUNDS AND AIM: Lipoprotein lipase (LPL) deficiency is a genetic disorder with a defective gene for lipoprotein lipase, leading to very high triglycerides. In the daily practice it is much more common to come across severely hypertriglyceridemia without homozygous or compound heterozygous LPL deficiency (SHTG). METHODS: We investigated on how to screen homozygous or compound heterozygous LPL deficiency using lipid parameters by meta-analyzing past 20 subjects on this genetic disease reported by Japanese investigators. As a comparison with LPL deficiency, 21 subjects with SHTG from recent two studies were included in this study. RESULTS: Serum HDL-C levels were significantly lower in LPL deficiency than in SHTG (0.38 ± 0.13 vs 0.94 ± 0.28 mmol/L (mean ± SD), p < 0.001), whereas other serum lipids did not differ between the two groups. The ROC curve ± standard error for serum HDL-C for discriminating the two groups was 0.97 ± 0.019. Sensitivity and specificity for distinguishing the two groups were 90% and 95%, respectively when serum HDL-C 0.62 mmol/L was adopted as cut point. CONCLUSION: We found for the first time that serum HDL-C is an extremely useful marker for discriminating LPL deficiency from SHTG in Japanese population.


Assuntos
Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , Homozigoto , Humanos , Hiperlipoproteinemia Tipo I/genética , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/genética , Japão , Lipase Lipoproteica/genética , Triglicerídeos
7.
Nutrients ; 13(7)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202167

RESUMO

In a recent study, we showed that konjac glucomannan (KGM) inhibits rice gruel-induced postprandial increases in plasma glucose and insulin levels. To extend this research, we investigated the effects of KGM addition to rice gruel on pre- and postprandial concentrations of circulating lipoprotein lipase (LPL), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), hepatic triglyceride lipase (HTGL), free fatty acids (FFA), and triglycerides (TG). A total of 13 Japanese men, without diabetes, dyslipidemia, or gastrointestinal diseases, interchangeably ingested rice gruel containing no KGM (0%G), rice gruel supplemented with 0.4% KGM (0.4%G), and rice gruel supplemented with 0.8% KGM (0.8%G), every Sunday for 3 weeks. Blood samples were obtained at baseline and at 30, 60, and 120 min after ingestion to measure the abovementioned lipid parameters. Lipid parameters showed small, but significant, changes. Significant reductions were found in circulating FFA levels among all participants. Circulating TG levels significantly declined at 30 min and then remained nearly constant in the 0.8%G group but exhibited no significant difference in the 0%G and 0.4%G groups. Although circulating levels of LPL and GPIHBP1 significantly decreased in the 0%G and 0.4%G groups, they increased at 120 min in the 0.8%G group. Participants in the 0%G and 0.4%G groups showed significant decreases in circulating HTGL levels, which was not observed in the 0.8%G group. Our results demonstrate the novel pleiotropic effects of KGM. Supplementation of rice gruel with KGM powder led to TG reduction accompanied by LPL and GPIHBP1 elevation and HTGL stabilization, thereby attenuating TG metabolism.


Assuntos
Suplementos Nutricionais , Grão Comestível , Mananas , Oryza , Triglicerídeos/sangue , Adulto , Estudos Cross-Over , Método Duplo-Cego , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipase Lipoproteica/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/efeitos dos fármacos , Pós , Receptores de Lipoproteínas/sangue
8.
Clin Chim Acta ; 521: 19-24, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34153276

RESUMO

Atherosclerosis, as a chronic inflammatory disease within the arterial wall, is a leading cause of morbidity and mortality worldwide due to its role in myocardial infarction, stroke and peripheral artery disease. Additional evidence is emerging that the angiopoietin-like (ANGPTL) family of proteins participate in the pathology of this disease process via endothelial dysfunction, inflammation, dyslipidemia, calcification, foam cell formation and platelet activation. This review summarizes current knowledge on the ANGPTL family of proteins in atherosclerosis related pathological processes. Moreover, the potential value of ANGPTL family proteins as predictive biomarkers in atherosclerosis is discussed. Given the attractive role of ANGPTL3, ANGPTL4, ANGPTL8 in atherosclerotic dyslipidemia via regulation of lipoprotein lipase (LPL), antisense oligonucleotide or/and monoclonal antibody-based inactivation of these proteins represent potential atherosclerotic therapies.


Assuntos
Aterosclerose , Dislipidemias , Hormônios Peptídicos , Proteínas Semelhantes a Angiopoietina , Biomarcadores , Humanos , Lipase Lipoproteica
9.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066911

RESUMO

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


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Músculo Esquelético/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Sinvastatina/farmacologia , Animais , Transporte Biológico/efeitos dos fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Colesterol/sangue , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/sangue , Glucose/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/ultraestrutura , Tamanho do Órgão/efeitos dos fármacos , Perilipina-5/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
10.
Biol Psychiatry ; 90(4): 263-274, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34099188

RESUMO

BACKGROUND: Diacylglycerol lipase α (DAGLα), a major biosynthetic enzyme for endogenous cannabinoid signaling, has emerged as a risk gene in multiple psychiatric disorders. However, its role in the regulation of dendritic spine plasticity is unclear. METHODS: DAGLα wild-type or point mutants were overexpressed in primary cortical neurons or human embryonic kidney 293T cells. The effects of mutated variants on interaction, dendritic spine morphology, and dynamics were examined by proximity ligation assay or fluorescence recovery after photobleaching. Behavioral tests and immunohistochemistry were performed with ankyrin-G conditional knockout and wild-type male mice. RESULTS: DAGLα modulated dendritic spine size and density, but the effects of changes in its protein level versus enzymatic activity were different, implicating either a 2-arachidonoylglycerol (2-AG)-dependent or -independent mechanism. The 2-AG-independent effects were mediated by the interaction of DAGLα with ankyrin-G, a multifunctional scaffold protein implicated in psychiatric disorders. Using superresolution microscopy, we observed that they colocalized in distinct nanodomains, which correlated with spine size. In situ proximity ligation assay combined with structured illumination microscopy revealed that DAGLα phosphorylation upon forskolin treatment enhanced the interaction with ankyrin-G in spines, leading to increased spine size and decreased DAGLα surface diffusion. Ankyrin-G conditional knockout mice showed significantly decreased DAGLα-positive neurons in the forebrain. In mice, ankyrin-G was required for forskolin-dependent reversal of depression-related behavior. CONCLUSIONS: Taken together, ANK3 and DAGLA, both neuropsychiatric disorder genes, interact in a complex to regulate spine morphology. These data reveal novel synaptic signaling mechanisms and potential therapeutic avenues.


Assuntos
Anquirinas , Lipase Lipoproteica , Animais , Espinhas Dendríticas/metabolismo , Humanos , Masculino , Camundongos , Fosforilação , Transdução de Sinais
11.
Stem Cell Res ; 53: 102313, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34087978

RESUMO

In this study, peripheral blood monouclear cells (PBMCs) were donated from a boy suffering from familial combined hyperlipidemia confirmed by clinical and genetic diagnosis, which carried compound heterozygous mutations of lipoprotein lipase (LPL) gene. The induced pluripotent stem cell (iPSC) was generated with non-integrated episomal vectors carrying OCT4, SOX2, KLF4, BCL-XL and C-MYC. The iPSCs presented the morphology of pluripotent cells, highly expressed mRNA and protein of pluripotent markers, excellent differentiation potency in vitro and normal karyotype, and bore LPL gene mutations.


Assuntos
Hiperlipidemia Familiar Combinada , Hiperlipidemias , Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Heterozigoto , Humanos , Lipase Lipoproteica/genética , Masculino , Mutação
12.
Nutr Metab Cardiovasc Dis ; 31(8): 2490-2506, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34172319

RESUMO

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


Assuntos
Colesterol/biossíntese , Ácidos Dicarboxílicos/farmacologia , Ácidos Graxos/biossíntese , Hepatócitos/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Lipogênese/efeitos dos fármacos , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Colesterol/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/sangue , Ácidos Graxos/farmacologia , Hepatócitos/enzimologia , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/enzimologia , Lipase Lipoproteica/metabolismo , Masculino , Mesocricetus , Perilipina-1/metabolismo , Proteínas Quinases/metabolismo , Coelhos , Ratos Wistar
13.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34128469

RESUMO

Although tissue uptake of fatty acids from chylomicrons is primarily via lipoprotein lipase (LpL) hydrolysis of triglycerides (TGs), studies of patients with genetic LpL deficiency suggest additional pathways deliver dietary lipids to tissues. Despite an intact endothelial cell (EC) barrier, hyperchylomicronemic patients accumulate chylomicron-derived lipids within skin macrophages, leading to the clinical finding eruptive xanthomas. We explored whether an LpL-independent pathway exists for transfer of circulating lipids across the EC barrier. We found that LpL-deficient mice had a marked increase in aortic EC lipid droplets before and after a fat gavage. Cultured ECs internalized chylomicrons, which were hydrolyzed within lysosomes. The products of this hydrolysis fueled lipid droplet biogenesis in ECs and triggered lipid accumulation in cocultured macrophages. EC chylomicron uptake was inhibited by competition with HDL and knockdown of the scavenger receptor-BI (SR-BI). In vivo, SR-BI knockdown reduced TG accumulation in aortic ECs and skin macrophages of LpL-deficient mice. Thus, ECs internalize chylomicrons, metabolize them in lysosomes, and either store or release their lipids. This latter process may allow accumulation of TGs within skin macrophages and illustrates a pathway that might be responsible for creation of eruptive xanthomas.


Assuntos
Aorta/metabolismo , Quilomícrons/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Gotículas Lipídicas/metabolismo , Triglicerídeos/metabolismo , Xantomatose/metabolismo , Animais , Aorta/patologia , Quilomícrons/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Gotículas Lipídicas/patologia , Lipase Lipoproteica/deficiência , Lipase Lipoproteica/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Triglicerídeos/genética , Xantomatose/genética , Xantomatose/patologia
14.
Atherosclerosis ; 329: 1-8, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34130222

RESUMO

Lipids released from circulating lipoproteins by intravascular action of lipoprotein lipase (LpL) reach parenchymal cells in tissues with a non-fenestrated endothelium by transfer through or around endothelial cells. The actions of LpL are controlled at multiple sites, its synthesis and release by myocytes and adipocytes, its transit and association with the endothelial cell luminal surface, and finally its activation and inhibition by a number of proteins and by its product non-esterified fatty acids. Multiple pathways mediate endothelial transit of lipids into muscle and adipose tissues. These include movement of fatty acids via the endothelial cell fatty acid transporter CD36 and movement of whole or partially LpL-hydrolyzed lipoproteins via other apical endothelial cell receptors such as SR-B1and Alk1. Lipids also likely change the barrier function of the endothelium and operation of the paracellular pathway around endothelial cells. This review summarizes in vitro and in vivo support for the key role of endothelial cells in delivery of lipids and highlights incompletely understood processes that are the focus of active investigation.


Assuntos
Células Endoteliais , Ácidos Graxos não Esterificados , Endotélio , Ácidos Graxos , Humanos , Lipase Lipoproteica , Lipoproteínas , Triglicerídeos
15.
Poult Sci ; 100(7): 101159, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34077847

RESUMO

The objective of this study was to determine the effects of angiopoietin-like protein 4 (ANGPTL4) on breast muscle lipid metabolism in broilers. In experiment 1, 36 thirty-five-day-old male Arbor Acres broilers were randomly allocated into 6 treatment groups with 6 birds in a completely randomized design. The broilers were subjected to intravenous injection of His-SUMO-ANGPTL4 at the dose of 0 (injection of normal saline [NS]), 20, 100, 500, 2,500, or 12,500 ng/kg BW, respectively. The results showed that broilers at 30 min after His-SUMO-ANGPTL4 at the level of 12,500 ng/kg BW intravenous injection had higher (P < 0.05) concentrations of triglyceride and non-esterified fatty acid in the serum, higher (P < 0.05) adipose triglyceride lipase and carnitine palmitoyltransferase 1 mRNA expression in the breast muscle, but lower (P < 0.05) lipoprotein lipase (LPL) mRNA expression in the breast muscle. In experiment 2, 18 thirty-five-day-old male Arbor Acres broilers were randomly allocated into 3 treatment groups with 6 birds in a completely randomized design. The broilers were subjected to intravenous injection of NS, His-SUMO, or His-SUMO-ANGPTL4 (12,500 ng/kg BW) in order to rule out the effect of His-SUMO tag. It's confirmed that ANGPTL4 could increase (P < 0.05) concentrations of triglyceride and non-esterified fatty acid in the serum, enhance (P < 0.05) adipose triglyceride lipase mRNA expression in the breast muscle, and decrease (P < 0.05) LPL mRNA expression in the breast muscle. In experiment 3 and 4, co-culture experiments of chicken primary myoblasts and NS, His-SUMO, or His-SUMO-ANGPTL4 (250 pg/mL, physiological dose) were set up to monitor the cytotoxicity of ANGPTL4 and the changes of lipid metabolism-related genes expression. It was found that cell viability was not affected but LPL mRNA expression in chicken primary myoblasts was highly reduced (P < 0.05) by ANGPTL4. In conclusion, ANGPTL4 could promote lipodieresis and inhibit LPL in the breast muscle of broilers.


Assuntos
Galinhas , Metabolismo dos Lipídeos , Proteína 4 Semelhante a Angiopoietina/metabolismo , Animais , Galinhas/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Músculos/metabolismo
17.
Atherosclerosis ; 328: 144-152, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34053745

RESUMO

BACKGROUND AND AIMS: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles. METHODS: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference. RESULTS: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. CONCLUSIONS: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.


Assuntos
Lipase , Lipase Lipoproteica , Alelos , LDL-Colesterol/genética , Lipase Lipoproteica/genética , Lipoproteínas , Países Baixos , Triglicerídeos
18.
Food Chem Toxicol ; 152: 112216, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33865937

RESUMO

Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as substitutes for bisphenol A (BPA), an endocrine disrupting chemical (EDC) with obesogenic activity. We investigated the in vitro effects of BPS and BPF on the adipogenesis of human adipose-derived stem cells (hASCs) exposed to different doses (0.01, 0.1, 1, 10 and 25 µM), stopping the adipogenic process at 7 or 14 days. Intracellular lipid accumulation was quantified by the Oil Red O assay, gene expression of peroxisome proliferator-activated receptor gamma (PPARγ), CCAT/enhancer-binding protein (C/EBPα), lipoprotein-lipase (LPL) and fatty acid binding protein 4 (FABP4), by quantitative real-time polymerase chain reaction (qRT-PCR) and protein levels by Western Blot. hASCs with BPF or BPS produced a linear dose-response increase in intracellular lipid accumulation and in gene expression of the adipogenic markers, confirmed by protein levels. Co-treatment ICI 182,780 significantly inhibited BPF- but not BPS-induced lipid accumulation. Given the affinity of bisphenols for diverse nuclear receptors, their obesogenic effects may result from a combination of pathways rather than a single mechanism. Further research is warranted on the manner in which chemicals interfere with adipogenic differentiation. To our best knowledge, this report shows for the first time the obesogenic potential of BPF in hASCs.


Assuntos
Adipogenia/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Fenóis/toxicidade , Sulfonas/toxicidade , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Relação Dose-Resposta a Droga , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Lipase Lipoproteica/metabolismo , PPAR gama/metabolismo
19.
Atherosclerosis ; 324: 1-8, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33798922

RESUMO

BACKGROUND AND AIMS: While low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a well-established cardiovascular risk factor, extremely high HDL-C is paradoxically associated with elevated cardiovascular risk, resulting in the U-shape relationship with cardiovascular disease. Free cholesterol transfer to HDL upon lipolysis of triglyceride-rich lipoproteins (TGRL) was recently reported to underlie this relationship, linking HDL-C to triglyceride metabolism and atherosclerosis. In addition to free cholesterol, other surface components of TGRL, primarily phospholipids, are transferred to HDL during lipolysis. It remains indeterminate as to whether such transfer is linked to HDL-C and cardiovascular disease. METHODS AND RESULTS: When TGRL was labelled with fluorescent phospholipid 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), time- and dose-dependent transfer of DiI to HDL was observed upon incubations with lipoprotein lipase (LPL). The capacity of HDL to acquire DiI was decreased by -36% (p<0.001) in low HDL-C patients with acute myocardial infarction (n = 22) and by -95% (p<0.001) in low HDL-C subjects with Tangier disease (n = 7), unchanged in low HDL-C patients with Type 2 diabetes (n = 17) and in subjects with high HDL-C (n = 20), and elevated in subjects with extremely high HDL-C (+11%, p<0.05) relative to healthy normolipidemic controls. Across all the populations combined, HDL capacity to acquire DiI was directly correlated with HDL-C (r = 0.58, p<0.001). No relationship of HDL capacity to acquire DiI with both overall and cardiovascular mortality obtained from epidemiological studies for the mean HDL-C levels observed in the studied populations was obtained. CONCLUSIONS: These data indicate that the capacity of HDL to acquire phospholipid from TGRL upon LPL-mediated lipolysis is proportional to HDL-C and does not reflect cardiovascular risk in subjects widely differing in HDL-C levels.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Cardiovasculares/diagnóstico , Colesterol , Fatores de Risco de Doenças Cardíacas , Humanos , Lipólise , Lipase Lipoproteica/metabolismo , Lipoproteínas HDL/metabolismo , Fosfolipídeos , Fatores de Risco , Triglicerídeos
20.
J Agric Food Chem ; 69(18): 5344-5352, 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33929832

RESUMO

Engineering of enzymes on the basis of protein structures are rational and efficient approaches to acquire biocatalysts of desired performances. In this study, we focused on a special mono- and diacylglycerol lipase (MDGL) isolated from the lipolytic enzyme-enriched fungus Aspergillus oryzae and discovered improved variants based on its crystal structure. We first solved the crystal structure of Aspergillus oryzae lipase (AOL) at 1.7 Å resolution. Structure analysis and sequence alignment of AOL and other MDGLs revealed that the residue V269 is of vital importance for catalysis. Replacement of the V269 in AOL with the corresponding residues in other MDGLs has led to noticeable changes in hydrolysis without sacrificing the thermostability and substrate specificity. Among the investigated variants, V269D exhibited about a six-fold higher hydrolysis activity compared to the wild type. Molecular dynamics simulations and protein-ligand interaction frequency analyses revealed that the Asp substitution enhanced the substrate affinity of AOL. Our work sheds light on understanding the catalytic process of AOL and helps tailoring MDGLs with desired catalytic performance to fulfill the demand for biotechnological applications.


Assuntos
Aspergillus oryzae , Lipase Lipoproteica , Aspergillus oryzae/genética , Aspergillus oryzae/metabolismo , Hidrólise , Lipase/genética , Lipase/metabolismo , Lipase Lipoproteica/metabolismo , Especificidade por Substrato
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