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1.
Diabetes ; 70(4): 867-877, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33536195

RESUMO

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.


Assuntos
Lipase Lipoproteica/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Animais , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Lipase Lipoproteica/genética , Masculino , Camundongos , Ratos , Ratos Wistar , Análise de Sequência de RNA , Redução de Peso/fisiologia
2.
Metabolomics ; 17(3): 26, 2021 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-33594546

RESUMO

INTRODUCTION: Overexpression of lipoprotein lipase (LPL) protects against high-fat-diet (HFD)-induced obesity and insulin resistance in transgenic rabbits; however, the molecular mechanisms remain unclear. Skeletal muscle is a major organ responsible for insulin-stimulated glucose uptake and energy expenditure. OBJECTIVES: The main purpose of the current study was to examine the effects of the overexpression of LPL on the skeletal muscle metabolomic profiles to test our hypothesis that the mitochondrial oxidative metabolism would be activated in the skeletal muscle of LPL transgenic rabbits and that the higher mitochondrial oxidative metabolism activity would confer better phenotypic metabolic outcomes. METHODS: Under a HFD, insulin resistance index was measured using the intravenous glucose tolerance test, and total energy expenditure (TEE) was measured by doubly-labeled water in control and LPL transgenic rabbits (n = 12, each group). Serum lipids, such as triglycerides and free fatty acid, were also measured. The skeletal muscle metabolite profile was analyzed using capillary electrophoresis time-of flight mass spectrometry in the two groups (n = 9, each group). A metabolite set enrichment analysis (MSEA) with muscle metabolites and a false discovery rate q < 0.2 was performed to identify significantly different metabolic pathways between the 2 groups. RESULTS: The triglycerides and free fatty acid levels and insulin resistance index were lower, whereas the TEE was higher in the LPL transgenic rabbits than in the control rabbits. Among 165 metabolites detected, the levels of 37 muscle metabolites were significantly different between the 2 groups after false discovery rate correction (q < 0.2). The MSEA revealed that the TCA cycle and proteinogenic amino acid metabolism pathways were significantly different between the 2 groups (P < 0.05). In the MSEA, all four selected metabolites for the TCA cycle (2-oxoglutaric acid, citric acid, malic acid, fumaric acid), as well as eight selected metabolites for proteinogenic amino acid metabolism (asparagine, proline, methionine, phenylalanine, histidine, arginine, leucine, isoleucine) were consistently increased in the transgenic rabbits compared with control rabbits, suggesting that these two metabolic pathways were activated in the transgenic rabbits. Some of the selected metabolites, such as citric acid and methionine, were significantly associated with serum lipids and insulin resistance (P < 0.05). CONCLUSION: The current results suggest that the overexpression of LPL may lead to increased activities of TCA cycle and proteinogenic amino acid metabolism pathways in the skeletal muscle, and these enhancements may play an important role in the biological mechanisms underlying the anti-obesity/anti-diabetes features of LPL overexpression.


Assuntos
Metabolismo Energético/fisiologia , Lipídeos/sangue , Lipase Lipoproteica/metabolismo , Metaboloma , Músculo Esquelético/metabolismo , Animais , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Resistência à Insulina/fisiologia , Masculino , Obesidade/metabolismo , Coelhos , Triglicerídeos/metabolismo
3.
Stem Cell Res Ther ; 8(1): 247, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096714

RESUMO

BACKGROUND: Development of clinical-grade cell preparations is central to meeting the regulatory requirements for cellular therapies under good manufacturing practice-compliant (cGMP) conditions. Since addition of animal serum in culture media may compromise safe and efficient expansion of mesenchymal stem cells (MSCs) for clinical use, this study aimed to investigate the potential of two serum/xeno-free, cGMP culture systems to maintain long-term "stemness" of oral MSCs (dental pulp stem cells (DPSCs) and alveolar bone marrow MSCs (aBMMSCs)), compared to conventional serum-based expansion. METHODS: DPSC and aBMMSC cultures (n = 6/cell type) were established from pulp and alveolar osseous biopsies respectively. Three culture systems were used: StemPro_MSC/SFM_XenoFree (Life Technologies); StemMacs_MSC/XF (Miltenyi Biotek); and α-MEM (Life Technologies) with 15% fetal bovine serum. Growth (population doublings (PDs)), immunophenotypic (flow cytometric analysis of MSC markers) and senescence (ß-galactosidase (SA-ß-gal) activity; telomere length) characteristics were determined during prolonged expansion. Gene expression patterns of osteogenic (ALP, BMP-2), adipogenic (LPL, PPAR-γ) and chondrogenic (ACAN, SOX-9) markers and maintenance of multilineage differentiation potential were determined by real-time PCR. RESULTS: Similar isolation efficiency and stable growth dynamics up to passage 10 were observed for DPSCs under all expansion conditions. aBMMSCs showed lower cumulative PDs compared to DPSCs, and when StemMacs was used substantial delays in cell proliferation were noted after passages 6-7. Serum/xeno-free expansion produced cultures with homogeneous spindle-shaped phenotypes, while serum-based expansion preserved differential heterogeneous characteristics of each MSC population. Prolonged expansion of both MSC types but in particular the serum/xeno-free-expanded aBMMSCs was associated with downregulation of CD146, CD105, Stro-1, SSEA-1 and SSEA-4, but not CD90, CD73 and CD49f, in parallel with an increase of SA-gal-positive cells, cell size and granularity and a decrease in telomere length. Expansion under both serum-free systems resulted in "osteogenic pre-disposition", evidenced by upregulation of osteogenic markers and elimination of chondrogenic and adipogenic markers, while serum-based expansion produced only minor changes. DPSCs retained a diminishing (CCM, StemPro) or increasing (StemMacs) mineralization potential with passaging, while aBMMSCs lost this potential after passages 6-7 under all expansion conditions. CONCLUSIONS: These findings indicate there is still a vacant role for development of qualified protocols for clinical-grade expansion of oral MSCs; a key milestone achievement for translation of research from the bench to clinics.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Meios de Cultura Livres de Soro/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Agrecanas/genética , Agrecanas/metabolismo , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Processo Alveolar/citologia , Processo Alveolar/efeitos dos fármacos , Processo Alveolar/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Condrogênese/genética , Meios de Cultura Livres de Soro/química , Polpa Dentária/citologia , Polpa Dentária/efeitos dos fármacos , Polpa Dentária/metabolismo , Indústria Farmacêutica/legislação & jurisprudência , Expressão Gênica/efeitos dos fármacos , Humanos , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , PPAR gama/genética , PPAR gama/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Homeostase do Telômero , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
4.
Endocrinology ; 158(5): 1252-1259, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28204173

RESUMO

Angiopoietin-like protein (ANGPTL)8 is a negative regulator of lipoprotein lipase-mediated plasma triglyceride (TG) clearance. In this study, we describe a fully human monoclonal antibody (REGN3776) that binds monkey and human ANGPTL8 with high affinity. Inhibition of ANGPTL8 with REGN3776 in humanized ANGPTL8 mice decreased plasma TGs and increased lipoprotein lipase activity. Additionally, REGN3776 reduced body weight and fat content. The reduction in body weight was secondary to increased energy expenditure. Finally, single administration of REGN3776 normalized plasma TGs in dyslipidemic cynomolgus monkeys. In conclusion, we show that blockade of ANGPTL8 with monoclonal antibody strongly reduced plasma TGs in mice and monkeys. These data suggest that inhibition of ANGPTL8 may provide a new therapeutic avenue for the treatment of dyslipidemia with beneficial effects on body weight.


Assuntos
Angiopoietinas/antagonistas & inibidores , Angiopoietinas/imunologia , Anticorpos Monoclonais/administração & dosagem , Metabolismo Energético , Triglicerídeos/sangue , Redução de Peso , Proteína 8 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Anticorpos Monoclonais/uso terapêutico , Dislipidemias/terapia , Humanos , Cinética , Lipase Lipoproteica/metabolismo , Macaca fascicularis , Camundongos , Camundongos Transgênicos
6.
Biosci Rep ; 36(3)2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27013337

RESUMO

Diacylglycerol lipase α (DAGLα) hydrolyses DAG to generate the principal endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the central nervous system. DAGLα dependent cannabinoid (CB) signalling has been implicated in numerous processes including axonal growth and guidance, adult neurogenesis and retrograde signalling at the synapse. Recent studies have implicated DAGLα as an emerging drug target for several conditions including pain and obesity. Activity assays are critical to the drug discovery process; however, measurement of diacylglycerol lipase (DAGL) activity using its native substrate generally involves low-throughput MS techniques. Some relatively high-throughput membrane based assays utilizing surrogate substrates have been reported, but these do not take into account the rate-limiting effects often associated with the ability of a drug to cross the cell membrane. In the present study, we report the development of a live cell assay to measure DAGLα activity. Two previously reported DAGLα surrogate substrates, p-nitrophenyl butyrate (PNPB) and 6,8-difluoro-4-methylumbelliferyl octanoate (DiFMUO), were evaluated for their ability to detect DAGLα activity in live cell assays using a human cell line stably expressing the human DAGLα transgene. Following optimization, the small molecule chromogenic substrate PNPB proved to be superior by providing lower background activity along with a larger signal window between transfected and parental cells when compared with the fluorogenic substrate DiFMUO. The assay was further validated using established DAGL inhibitors. In summary, the live cell DAGLα assay reported here offers an economical and convenient format to screen for novel inhibitors as part of drug discovery programmes and compliments previously reported high-throughput membrane based DAGL assays.


Assuntos
Ensaios Enzimáticos/métodos , Lipase Lipoproteica/metabolismo , Butiratos/metabolismo , Linhagem Celular , Sobrevivência Celular , Avaliação Pré-Clínica de Medicamentos/economia , Avaliação Pré-Clínica de Medicamentos/métodos , Ensaios Enzimáticos/economia , Inibidores Enzimáticos/farmacologia , Halogenação , Humanos , Himecromona/análogos & derivados , Himecromona/metabolismo , Lipase Lipoproteica/antagonistas & inibidores
7.
J Lipid Res ; 57(1): 131-41, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26423520

RESUMO

Lipids are used as cellular building blocks and condensed energy stores and also act as signaling molecules. The glycerolipid/ fatty acid cycle, encompassing lipolysis and lipogenesis, generates many lipid signals. Reliable procedures are not available for measuring activities of several lipolytic enzymes for the purposes of drug screening, and this resulted in questionable selectivity of various known lipase inhibitors. We now describe simple assays for lipolytic enzymes, including adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), sn-1-diacylglycerol lipase (DAGL), monoacylglycerol lipase, α/ß-hydrolase domain 6, and carboxylesterase 1 (CES1) using recombinant human and mouse enzymes either in cell extracts or using purified enzymes. We observed that many of the reported inhibitors lack specificity. Thus, Cay10499 (HSL inhibitor) and RHC20867 (DAGL inhibitor) also inhibit other lipases. Marked differences in the inhibitor sensitivities of human ATGL and HSL compared with the corresponding mouse enzymes was noticed. Thus, ATGListatin inhibited mouse ATGL but not human ATGL, and the HSL inhibitors WWL11 and Compound 13f were effective against mouse enzyme but much less potent against human enzyme. Many of these lipase inhibitors also inhibited human CES1. Results describe reliable assays for measuring lipase activities that are amenable for drug screening and also caution about the specificity of the many earlier described lipase inhibitors.


Assuntos
Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Lipólise/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Hidrolases de Éster Carboxílico/antagonistas & inibidores , Hidrolases de Éster Carboxílico/metabolismo , Ácidos Graxos/metabolismo , Humanos , Lipase/antagonistas & inibidores , Lipase/metabolismo , Lipogênese/fisiologia , Lipólise/fisiologia , Lipase Lipoproteica/antagonistas & inibidores , Lipase Lipoproteica/metabolismo , Camundongos , Monoacilglicerol Lipases/metabolismo , Esterol Esterase/antagonistas & inibidores , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo
8.
PLoS One ; 9(5): e96482, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24788417

RESUMO

BACKGROUND: Determination of lipoprotein lipase (LPL) activity is important for hyperchylomicronemia diagnosis, but remains both unreliable and cumbersome with current methods. Consequently by using human VLDL as substrate we developed a new LPL assay which does not require sonication, radioactive or fluorescent particles. METHODS: Post-heparin plasma was added to the VLDL substrate prepared by ultracentrifugation of heat inactivated normolipidemic human serums, diluted in buffer, pH 8.15. Following incubation at 37°c, the NEFA (non esterified fatty acids) produced were assayed hourly for 4 hours. LPL activity was expressed as µmol/l/min after subtraction of hepatic lipase (HL) activity, obtained following LPL inhibition with NaCl 1.5 mmol/l. Molecular analysis of LPL, GPIHBP1, APOA5, APOC2, APOE genes was available for 62 patients. RESULTS: Our method was reproducible (coefficient of variation (CV): intra-assay 5.6%, inter-assay 7.1%), and tightly correlated with the conventional radiolabelled triolein emulsion method (n = 26, r = 0.88). Normal values were established at 34.8 ± 12.8 µmol/l/min (mean ± SD) from 20 control subjects. LPL activities obtained from 71 patients with documented history of major hypertriglyceridemia showed a trimodal distribution. Among the 11 patients with a very low LPL activity (<10 µmol/l/min), 5 were homozygous or compound heterozygous for LPL or GPIHBP1 deleterious mutations, 3 were compound heterozygous for APOA5 deleterious mutations and the p.S19W APOA5 susceptibility variant, and 2 were free of any mutations in the usual candidate genes. No homozygous gene alteration in LPL, GPIHBP1 and APOC2 genes was found in any of the patients with LPL activity >10 µmol/l/min. CONCLUSION: This new reproducible method is a valuable tool for routine diagnosis and reliably identifies LPL activity defects.


Assuntos
Ensaios Enzimáticos/métodos , Lipase Lipoproteica/metabolismo , Lipoproteínas VLDL/metabolismo , Triglicerídeos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/farmacologia , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Coagulação Sanguínea/efeitos dos fármacos , Análise Mutacional de DNA , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Feminino , Heparina/farmacologia , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/genética , Cinética , Lipólise/genética , Lipase Lipoproteica/sangue , Lipase Lipoproteica/genética , Masculino , Pessoa de Meia-Idade , Receptores de Lipoproteínas/sangue , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Especificidade por Substrato , Adulto Jovem
9.
Physiol Biochem Zool ; 87(2): 245-56, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24642542

RESUMO

Proper adjustments of physiology and behavior are required for small mammals to cope with seasonal climate change. The aim of this study was to examine the role of leptin in the regulation of body mass and energy budget in striped hamsters. We first investigated seasonal changes in body mass, energy budget, and serum leptin levels in hamsters acclimated to outdoor natural daylight and ambient temperature. Then we assessed the effect of leptin administration on energy budget, serum lipoprotein lipase (LPL) and hepatic lipase (HL) activities, and gene expression of uncoupling protein 1 (UCP1) in brown adipose tissue and of hypothalamic neuropeptides associated with the regulation of energy balance in hamsters maintained at 21° and 5°C. Hamsters showed constant body mass throughout the four seasons but significantly increased food intake and thermogenesis in winter, compared to summer. Minimum body fat was observed in winter, and minimum serum leptin was found in autumn. Hamsters housed at 5°C showed higher energy intake, upregulated gene expression of UCP1 and hormone-sensitive lipase, and lower fat content and LPL and HL activity than the animals maintained at 21°C. Leptin administration had no effect on energy intake but increased maximal thermogenic capacity, as indicated by upregulated UCP1 gene expression at both 21° and 5°C. Body fat and activity of LPL and HL were decreased in hamsters treated with leptin. The results suggest that leptin plays an important role in the seasonal regulation of thermogenic capacity and body composition in striped hamsters. Leptin may be involved in increasing maximal thermogenesis in the cold rather than acting as a starvation signal to increase energy intake.


Assuntos
Adiposidade , Peso Corporal , Cricetulus/fisiologia , Metabolismo Energético , Leptina/metabolismo , Estações do Ano , Aclimatação , Tecido Adiposo , Animais , Ingestão de Energia , Regulação da Expressão Gênica , Canais Iônicos/genética , Canais Iônicos/metabolismo , Leptina/sangue , Lipase/metabolismo , Lipase Lipoproteica/metabolismo , Masculino , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Esterol Esterase/genética , Esterol Esterase/metabolismo , Proteína Desacopladora 1
10.
Prog Lipid Res ; 51(1): 11-22, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22123195

RESUMO

Historically, the link between elevated cholesterol and increased risk of cardiovascular disease has been based on fasting measurements. This is appropriate for total, low-density lipoprotein and high-density lipoprotein cholesterol. However, triglyceride concentrations vary considerably throughout the day in response to the regular consumption of food and drink. Recent findings indicate that postprandial triglyceride concentrations independently predict future cardiovascular risk. Potential modulators of postprandial lipidemia include meal composition and physical activity. Early cross sectional studies indicated that physically active individuals had a lower postprandial lipidemic response compared to inactive individuals. However, the effect of physical activity on postprandial lipidemia is an acute phenomenon, which dissipates within 60 h of a single bout of exercise. Total exercise induced energy expenditure, rather than duration or intensity of the physical activity is commonly reported to be a potent modulator of postprandial lipidemia. However, the pooled results of studies in this area suggest that energy expenditure exerts most of its influence on fasting triglyceride concentrations rather than on the incremental change in triglyceride concentrations seen following meal consumption. It seems more likely that energy expenditure is one component of a multifactorial list of mediators that may include local muscle contractile activity, and other yet to be elucidated mechanisms.


Assuntos
Metabolismo Energético , Hiperlipidemias/metabolismo , Lipase Lipoproteica/metabolismo , Atividade Motora , Período Pós-Prandial , Animais , Dieta , Humanos , Hiperlipidemias/enzimologia
11.
Drug Metab Pharmacokinet ; 21(1): 19-28, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16547390

RESUMO

The mRNA levels of human cytochrome P450 (CYP)2Cs and CYP3As in primary cultures of freshly isolated human hepatocytes were assessed after exposure to NO-1886 and rifampicin, a typical inducer of CYP3As. mRNA levels were analyzed by real-time RT-PCR using an ABI PRISM 7700 Sequence Detector system. Exposure to NO-1886 for 24 hr at a concentration of less than 10 microM showed only a tendency to reduce or increase the expression levels of CYP2C8, CYP2C9, CYP2C19, CYP3A4, or CYP3A5 mRNA. A higher concentration (50 microM) of NO-1886 induced an increase in CYP2C8 mRNA and a decrease in CYP2C19 mRNA, and these changes continued after additional culture for 24 hr in fresh medium without NO-1886. The expression level of CYP3A4 mRNA after exposure to NO-1886 for 24 hr at 50 microM was about twice that in controls. Following additional culture for 24 hr in fresh medium without NO-1886, the expression of CYP3A4 mRNA was comparable to that in controls. On the other hand, the expression levels of CYP2C9 and CYP3A5 mRNA showed small and variable changes in each donor even at a high concentration (50 microM) of NO-1886. Furthermore, the pharmacokinetics of NO-1886 during repeated oral administration for 14 days was studied in female rats. The pharmacokinetic parameters of NO-1886 were nearly the same on days 1, 7, and 14 of repeated administration. The hepatic microsomal content of CYP isoforms was not affected by repeated administration for 7 days at a dose of 1 to 30 mg/kg in female rats, although the total CYP content was increased at a dose of 30 mg/kg. The expression levels of CYP1A2, CYP2B2, CYP2C12, and CYP2E1 mRNA in primary cultures of rat hepatocytes were not affected by exposure to NO-1886 at 2, 10, or 50 microM. The expression levels of CYP3A1 mRNA in primary cultures of rat hepatocytes were not affected by exposure to NO-1886 at 2 or 10 microM, but were increased, with large individual variation, by exposure at 50 microM. The mRNA expression levels in rat hepatocytes exposed to concentrations comparable to free plasma levels did not change significantly, which was consistent with the equivalence in the in vivo plasma concentrations observed on days 1 and 14 of repeated administration. These results suggest that repeated administration of NO-1886 at clinical doses does not significantly affect the expression levels of CYP isoforms in human liver, although the mRNA levels of the CYP isoforms involved in the metabolism of NO-1886 were increased by exposure to higher concentrations of NO-1886 in human hepatocytes in vitro.


Assuntos
Benzamidas/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Hepatócitos/enzimologia , Lipase Lipoproteica/metabolismo , Fígado/enzimologia , Compostos Organofosforados/farmacologia , Animais , Western Blotting , Células Cultivadas , Eletroforese em Gel de Poliacrilamida , Indução Enzimática/efeitos dos fármacos , Feminino , Hepatócitos/efeitos dos fármacos , Humanos , Técnicas In Vitro , Isoenzimas/biossíntese , Fígado/efeitos dos fármacos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley
12.
Int J Obes Relat Metab Disord ; 17(6): 343-7, 1993 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8392500

RESUMO

The effect of ephedrine (E) and theophylline (T), administered alone and in combination (E/T), on weight loss, resting energy expenditure and post-heparin lipoprotein lipase activity in plasma (PHLA) and in adipose tissue (ATLP) were investigated in obese over-fed rats, who had been diet restricted (-40% of normal caloric intake) for three weeks. E, T and E/T significantly increased weight loss in all experimental groups as compared to the controls. Weight loss was achieved not only by preventing the adaptive fall in resting energy expenditure associated with diet restriction, but by raising it above basal level. The effect of E/T mixture was no greater than that of E or T alone. E, T and E/T administration increased PHLA in plasma while hypocaloric diet alone did not influence the activity of the enzyme. ATLP in the epididymal fat pads decreased insignificantly in all experimental groups, as well as in the controls. Serum cholesterol levels were not influenced by hypocaloric diet and by drug administration, but serum triglycerides increased significantly in E, T and E/T treated groups. The elevation of PHLA after ephedrine and/or theophylline administration was mostly due to an increase in the hepatic lipase (HL) level. This enzyme contributes to the removal of the atherogenic intermediate density lipoproteins from blood serum. The increased HL activity in drug-treated, diet-restricted obese rats may therefore play a role in the prevention of atherosclerosis.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Efedrina/farmacologia , Lipase Lipoproteica/metabolismo , Obesidade/metabolismo , Teofilina/farmacologia , Redução de Peso/efeitos dos fármacos , Animais , Metabolismo Basal , Colesterol/sangue , Dieta , Ingestão de Energia , Efedrina/administração & dosagem , Masculino , Ratos , Ratos Wistar , Teofilina/administração & dosagem , Triglicerídeos/sangue
13.
J Dairy Sci ; 72(6): 1451-8, 1989 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2760307

RESUMO

Bovine plasma and lipoproteins isolated by gel filtration chromatography were examined for their ability to activate skim milk lipoprotein lipase. Addition of equal amounts of protein from either triglyceride-rich lipoprotein, low density lipoprotein, high density lipoprotein or plasma to a lipoprotein lipase assay resulted in 6.0, 2.2, 2.5, or 1.1% hydrolysis of radiolabelled triglyceride emulsion. Lipoprotein lipase activity in skim milk was evaluated as an indicator of mammary lipid secretory capacity. Skim milk lipoprotein lipase activity was significantly lower immediately prepartum as compared with activity immediately postpartum (.2 vs. 5.4% of substrate hydrolyzed). Skim milk lipoprotein lipase was significantly higher during the final 12 d of lactation than in samples obtained 12 d after machine milking was terminated (5.6 vs. less than 1% of substrate hydrolyzed). Although skim milk lipoprotein lipase activity appeared positively related to mammary lipid secretory capacity during the time immediately surrounding initiation and cessation of copious milk production, activity between those periods was not correlated to milk fat percentage, milk fat yield, or stage of lactation.


Assuntos
Bovinos/metabolismo , Lipídeos/biossíntese , Lipase Lipoproteica/metabolismo , Lipoproteínas/farmacologia , Glândulas Mamárias Animais/metabolismo , Leite/enzimologia , Animais , Ativação Enzimática , Feminino , Lipoproteínas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas HDL/farmacologia , Lipoproteínas LDL/metabolismo , Lipoproteínas LDL/farmacologia , Glândulas Mamárias Animais/citologia , Triglicerídeos/metabolismo
14.
Am J Clin Nutr ; 30(4): 508-11, 1977 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-851077

RESUMO

The (potential) activities of the two lipases in human milk were determined in breast milk samples collected from Ethiopian and Swedish mothers. The major lipase in human milk is dependent on bile salts for activity and probably participates in intestinal digestion of milk lipids in the newborn. The level of this lipase in the milk did not change with time after parturition, but differed between the groups so that it was higher in the privileged Ethopian mothers than in the nonprivileged Ethiopian mothers, who in turn had a higher level than the Swedish mothers. The other lipase is a serum-stimulated lipase (lipoprotein lipase). The level of this lipase varied between samples from different mothers as well as between different samples from the same mother. It tended to be lower in samples obtained at 4 to 5 days after parturition (Swedish mothers) than in later samples. There were in this case no significant differences between nonprivileged and privileged Ethiopian mothers or between them and Swedish mothers.


Assuntos
Lipase/metabolismo , Lipase Lipoproteica/metabolismo , Leite Humano/enzimologia , Adolescente , Adulto , Etiópia , Feminino , Humanos , Gravidez , Fatores Socioeconômicos , Suécia
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