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1.
Biochimie ; 89(2): 265-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17126471

RESUMO

Sense of taste informs the body about the quality of ingested foods. Five sub-modalities allowing the perception of sweet, salty, sour, bitter, and umami stimuli are classically depicted. However, the inborn attraction of mammals for fatty foods raises the possibility of an additional orosensory modality devoted to fat perception. For a long time, dietary lipids were thought to be detected only by trigeminal (texture perception), retronasal olfactory, and post-ingestive cues. This minireview analyses recent findings showing that gustation also plays a significant role in dietary lipid perception.


Assuntos
Gorduras na Dieta/metabolismo , Paladar/fisiologia , Animais , Humanos , Lipídeos/química , Modelos Biológicos , Transdução de Sinais/fisiologia
2.
Biochim Biophys Acta ; 1735(1): 41-9, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15936983

RESUMO

Peroxisome proliferator-activator receptors (PPAR) are involved in cholesterol homeostasis through the regulation of bile acids synthesis, composition, and reclamation. As ileal bile acid-binding protein (I-BABP) is thought to play a crucial role in the enterohepatic circulation of bile acids, we investigated whether I-BABP gene expression could also be affected by PPAR. Indeed, treatment with the PPARalpha-PPARbeta/delta agonist bezafibrate led to the up-regulation of I-BABP mRNA levels in the human intestine-derived Caco-2 cells. Cotransfections of the reporter-linked human I-BABP promoter (hI-BABP-2769/+44) together with PPAR and RXR expression vectors demonstrated that the fibrate-mediated induction of the I-BABP gene is dependent on PPARalpha or PPARbeta/delta. Using progressive 5' deletions of the hI-BABP promoter and sequence analysis, we identified a putative PPAR-binding site located at the position -198 and -186 upstream of the transcription initiation site. Electrophoretic mobility shift assays showed that the PPAR/RXR heterodimer can specifically bind to this PPRE-like motif. The deletion of the PPRE within the hI-BABP promoter abolished the PPAR-mediated transactivation in transient transfection assays. The regulation of the I-BABP promoter by PPAR appears species-specific, as the mouse I-BABP promoter, which lacks a conserved PPRE, was not responsive to exogenous PPAR expression in the presence of bezafibrate. Our findings show that the I-BABP gene may be a novel target for PPAR in humans and further emphasize the role for PPAR in the control of bile acid homeostasis.


Assuntos
Proteínas de Transporte/genética , Regulação da Expressão Gênica , Íleo/metabolismo , Glicoproteínas de Membrana/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Sequência de Bases , Bezafibrato/farmacologia , Sítios de Ligação , Células CACO-2 , Proteínas de Transporte/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Glicoproteínas de Membrana/biossíntese , Camundongos , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Elementos de Resposta/genética , Especificidade da Espécie
3.
Toxicology ; 357-358: 11-20, 2016 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-27241191

RESUMO

Bisphenol A were removed from consumer products and replaced by chemical substitutes such as Bisphenol S (BPS). Based on their structural similarity, BPS may be obesogen like Bisphenol A in mice. Our objective was to determine the impact of BPS on lipid homeostasis in C57Bl/6 mice after perinatal and chronic exposure. Pregnant mice were exposed to BPS via the drinking water (0.2; 1.5; 50µg/kg bw/d). Treatment began at gestational day 0 and continued in offspring up to 23-weeks old. Then, offspring mice were fed with a standard or high fat diet. The body weight, food consumption, fat mass and energy expenditure were measured. A lipid load test was performed to check the postprandial triglyceridemia. Plasma parameters and mRNA gene expression in adipose tissues were also analysed. BPS induced overweight in male mice offspring fed with a HFD at the two highest doses. There was no change in food intake and energy expenditure. The overweight was correlated to the fat mass, hyperinsulinemia and hyperleptinemia. The plasma triglyceride clearance was significantly increased with BPS and tyloxapol(®) (triglyceride clearance inhibitor) reversed this phenomenon. BPS induced alteration in mRNA expression of marker genes involved in adipose tissue homeostasis: hormone sensitive lipase, PPARγ, insulin receptor, SOCS3 and adiponectin. This is the first time that BPS is described as obesogenic at low doses and after perinatal and chronic exposure in male mice. BPS potentiated the obesity induced by a HFD by inducing the lipid storage linked to faster lipid plasma clearance.


Assuntos
Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Obesidade/etiologia , Sobrepeso/etiologia , Fenóis/toxicidade , Sulfonas/toxicidade , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenóis/administração & dosagem , Polietilenoglicóis/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/metabolismo , Sulfonas/administração & dosagem , Triglicerídeos/sangue
4.
Biochim Biophys Acta ; 1391(2): 204-12, 1998 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-9555014

RESUMO

The effects of glucocorticoids on the regulation of the liver fatty acid-binding protein (L-FABP) were studied in vivo and in primary culture of hepatocytes in rats. No change in L-FABP cytosolic content and mRNA levels occurred after adrenalectomy. By contrast, a twofold decrease in L-FABP expression was found in dexamethasone (Dex) treated rats. In primary culture of rat hepatocytes, insulin did not modify the L-FABP mRNA levels, whereas Dex produced a significant decrease. This down-regulation was independent of specific glucocorticoid receptors, of alteration in the turnover of L-FABP mRNA and did not require a de novo protein synthesis. However, it was totally prevented when 320 microM oleic acid was added in the culture medium. These findings show that the dex-mediated down-regulation of the L-FABP expression found in vivo is not due to a direct endocrine effect, but is likely secondary to changes in cellular lipid metabolism.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Dexametasona/farmacologia , Ácidos Graxos/metabolismo , Glucocorticoides/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Proteína P2 de Mielina/genética , Proteína P2 de Mielina/metabolismo , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Glândulas Suprarrenais/metabolismo , Adrenalectomia , Animais , Sequência de Bases , Células Cultivadas , Primers do DNA/genética , Regulação para Baixo/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Insulina/farmacologia , Ácido Oleico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
5.
Biochim Biophys Acta ; 1299(2): 191-7, 1996 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-8555264

RESUMO

This study was designed to examine whether short- and long-term treatments by a low level of dietary L-carnitine are capable of altering enzyme activities related to fatty acid oxidation in normal Wistar rats. Under controlled feeding, ten days of treatment changed neither body weights nor liver and gastrocnemius weights, but succeeded in reducing the weight of peri-epididymal adipose tissues. Triacylglycerol contents were lowered in liver and ketone body concentrations were found slightly more elevated in blood. In the liver, mitochondrial carnitine palmitoyltransferase I (CPT I) exhibited a slightly higher specific activity and a lower sensitivity to malonyl-CoA inhibition, while peroxisomal fatty acid oxidizing system (PFAOS) was found to be less active. Carnitine supplied for one month reduced the mass of the periepididymal fat tissue, but not those of the other studied organs, and produced a slight but non-significant gain in body weight after ten days of treatment. In the liver, CPTI characteristics were comparable in control and treated groups, while PFAOS activity was less in rats receiving carnitine. Data show that L-carnitine at a low level in the diet exerted two paradoxical effects before and after ten days of treatment. Results are discussed in regard to fatty acid oxidation in mitochondria and peroxisomes, and to the possible altered acyl-CoA/acylcarnitine ratio with increased concentrations of L-carnitine in the liver.


Assuntos
Carnitina/administração & dosagem , Ácidos Graxos/metabolismo , Fígado/metabolismo , Animais , Peso Corporal , Carnitina/farmacocinética , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/metabolismo , Dieta , Corpos Cetônicos/sangue , Corpos Cetônicos/metabolismo , Masculino , Microcorpos/metabolismo , Mitocôndrias/metabolismo , Tamanho do Órgão , Oxirredução , Ratos , Ratos Wistar , Distribuição Tecidual , Triglicerídeos/sangue , Triglicerídeos/metabolismo
6.
Biochim Biophys Acta ; 1436(3): 593-9, 1999 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-9989289

RESUMO

Liver fatty acid-binding protein (L-FABP) is a small cytoplasmic molecule highly expressed in the liver. Since L-FABP exhibits affinities for several biliary components, its presence in bile was explored by Western blotting and competitive ELISA in various mammalian species. A L-FABP-like immunoreactivity was consistently found in both hepatic and gallbladder bile. A close molecular identity between this 14 kDa biliary protein and the purified L-FABP was assessed by immunological analyses and high performance capillary electrophoresis. Pharmacological induction of hepatic L-FABP biosynthesis led to a similar increase in biliary L-FABP levels showing a close relationships between the cytosolic and biliary contents of this protein. Finally, a correlation between the presence of L-FABP in bile and both bile flow and bile acid release was found. These data suggest an output of L-FABP in bile in normal conditions which might be coupled with the physiological release of biliary components.


Assuntos
Bile/metabolismo , Proteínas de Transporte/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Proteína P2 de Mielina/metabolismo , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Proteínas Supressoras de Tumor , Animais , Proteínas de Transporte/química , Proteínas de Transporte/isolamento & purificação , Citosol/metabolismo , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Vesícula Biliar/metabolismo , Humanos , Imunoquímica , Masculino , Camundongos , Peso Molecular , Proteína P2 de Mielina/química , Proteína P2 de Mielina/isolamento & purificação , Ratos , Ratos Wistar
7.
Biochimie ; 87(1): 73-9, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15733740

RESUMO

Conjugated linoleic acids (CLA) are positional and geometric dienoic isomers of linoleic acid. Dietary CLA supplementation leads to a drop in fat mass in various species, including in humans. The t10,c12-CLA isomer is responsible for this anti-obesity effect. The reduction of fat mass is especially dramatic in the mouse, in which it is associated with severe hyperinsulinemia, insulin resistance and massive liver steatosis. The origin of these adverse side effects and putative chronology of events leading to CLA-mediated lipoatrophic syndrome are presented and discussed in this review.


Assuntos
Diabetes Mellitus Lipoatrófica/etiologia , Gorduras na Dieta/farmacologia , Ácidos Linoleicos Conjugados/fisiologia , Tecido Adiposo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Resistência à Insulina/fisiologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ácidos Linoleicos Conjugados/farmacologia , Camundongos
8.
FEBS Lett ; 412(3): 480-4, 1997 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-9276450

RESUMO

The role of retinoic acids (RA) on liver fatty acid-binding protein (L-FABP) expression was investigated in the well differentiated FAO rat hepatoma cell line. 9-cis-Retinoic acid (9-cis-RA) specifically enhanced L-FABP mRNA levels in a time- and dose-dependent manner. The higher induction was found 6 h after addition of 10(-6) M 9-cis-RA in the medium. RA also enhanced further both L-FABP mRNA levels and cytosolic L-FABP protein content induced by oleic acid. The retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR), which are known to be activated, respectively, by 9-cis-RA and long chain fatty acid (LCFA), co-operated to bind specifically the peroxisome proliferator-responsive element (PPRE) found upstream of the L-FABP gene. Our result suggest that the PPAR-RXR complex is the molecular target by which 9-cis-RA and LCFA regulate the L-FABP gene.


Assuntos
Proteínas de Transporte/genética , Ácidos Graxos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Proteína P2 de Mielina/genética , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Tretinoína/farmacologia , Alitretinoína , Animais , Carcinoma Hepatocelular , Proteínas de Transporte/biossíntese , Dimerização , Sinergismo Farmacológico , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Fígado/efeitos dos fármacos , Microcorpos/metabolismo , Proteína P2 de Mielina/biossíntese , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides , Fatores de Transcrição/biossíntese , Fatores de Transcrição/metabolismo , Tretinoína/metabolismo , Células Tumorais Cultivadas
9.
FEBS Lett ; 384(2): 131-4, 1996 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-8612808

RESUMO

Enterocytes actively transport bile acids from the ileal lumen to the portal blood. This physiological process greatly contributes to maintaining the bile acid homeostasis. However, little is known about the molecular mechanisms involved in this transport system. The effect of bile on gene expression of the intestinal bile-acid binding protein (I-BABP) expressed in the enterocytes was studied in vivo, using the by-pass method, and in vitro, using organ culture of ileum explants and Caco-2 cell line. The low cytosolic I-BABP concentration and I-BABP mRNA level found in diverted ileum was totally recovered when bile was added in the ileal lumen. Northern blot analysis of the ileal explants revealed a dose-dependent increase in the I-BABP mRNA in the presence of bile. In Caco-2 cells, the I-BABP transcript was dramatically increased in the presence of human bile while it was undetectable in the control cultures. These data offer the first evidence that biliary components regulate the I-BABP gene expressed in the enterocytes.


Assuntos
Ácidos e Sais Biliares/metabolismo , Bile/fisiologia , Proteínas de Transporte/biossíntese , Colo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroxiesteroide Desidrogenases , Íleo/efeitos dos fármacos , Glicoproteínas de Membrana , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Proteínas Supressoras de Tumor , Animais , Transporte Biológico/genética , Proteínas de Transporte/genética , Colo/metabolismo , Neoplasias do Colo/patologia , DNA/metabolismo , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Humanos , Íleo/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Proteína P2 de Mielina/biossíntese , Proteína P2 de Mielina/genética , Proteínas/metabolismo , RNA/metabolismo , Ratos , Ratos Sprague-Dawley , Células Tumorais Cultivadas
10.
Biochimie ; 79(2-3): 129-33, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9209709

RESUMO

During the last years, the direct involvement of lipidic nutrients in the regulation of genes has been established. Fatty acids may induce or repress the transcription rate of several genes involved in both lipid and carbohydrate metabolisms. Gene up-regulation has been found in various tissues including liver, adipose tissue and small intestine. It is only triggered by saturated and unsaturated long-chain fatty acids or their CoA-derivatives. In contrast, gene down-regulation appears to be restricted to the liver. This negative effect is exerted only by polyunsaturated fatty acids. Long-chain fatty acids are able to regulate the expression of two different genes oppositely in the same cell type. The molecular mechanism of these fatty acid-mediated effects remains unclear. The involvement of members of the peroxisome proliferator-activated receptor is discussed.


Assuntos
Proteínas de Transporte/metabolismo , Ácidos Graxos/metabolismo , Proteína P2 de Mielina/metabolismo , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Adipócitos/fisiologia , Animais , Regulação para Baixo , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Ácidos Graxos Insaturados/fisiologia , Regulação da Expressão Gênica , Fígado/fisiologia , Camundongos , RNA Mensageiro/genética , Transcrição Gênica
11.
Biochem Pharmacol ; 40(9): 2137-43, 1990 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-2242041

RESUMO

Lean Zucker rats were dosed orally for 1 week with fenofibrate (100 mg/kg/day). Liver weights of treated rats, expressed as per cent of body weight, were increased, while protein, DNA and triacylglycerol contents were not changed to any great extent per gram of liver, but increased when expressed per whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly enhanced by fenofibrate, both per gram of liver and per total liver, while urate oxidase activity was slightly depressed when expressed per gram of liver. The activity of cytochrome c oxidase used as a mitochondrial marker was only higher when expressed per total liver. Besides, fenofibrate treatment induced a pronounced increase in the mitochondrial activities of carnitine palmitoyl- and acetyltransferases, of palmitoyl-CoA dehydrogenase and of carnitine-dependent oleate oxidation. Fenofibrate also enhanced significantly the carnitine content in liver and hepatic mitochondria. Malonyl-CoA content per gram of liver was found to be twice as high as in control rats, while the sensitivity of carnitine acyltransferase I to malonyl-CoA inhibition was hardly altered. The drug enhanced the percentage of palmitic acid in lipids of liver, but not in adipose tissues. The present data show that fenofibrate induced greater oxidative activities towards fatty acids, even in the lean animal. This stimulation could be related to the energy used for building new cells. In turn, at the same time of treatment, an enhanced fatty acid synthesis would provide specific fatty acids for the formation of new membranes. This latter effect will eventually disappear and the maintenance of a higher fatty acid oxidation may explain part of the overall hypolipaemic effect of fenofibrate.


Assuntos
Ácidos Graxos/metabolismo , Fenofibrato/farmacologia , Fígado/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Animais , Fígado/anatomia & histologia , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Ratos , Ratos Zucker , Fatores de Tempo
12.
Biochem Pharmacol ; 49(10): 1403-10, 1995 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-7763283

RESUMO

This study was designed to examine whether the depletion of L-carnitine may induce compensatory mechanisms allowing higher fatty acid oxidative activities in liver, particularly with regard to mitochondrial carnitine palmitoyltransferase I activity and peroxisomal fatty acid oxidation. Wistar rats received D-carnitine for 2 days and 3-(2,2,2,-trimethylhydrazinium)propionate (mildronate), a noncompetitive inhibitor of gamma-butyrobetaine hydroxylase, for 10 days. They were starved for 20 hr before being sacrificed. A dramatic reduction in carnitine concentration was observed in heart, skeletal muscles and kidneys, and to a lesser extent, in liver. Triacylglycerol content was found to be significantly more elevated on a gram liver and whole liver basis as well as per mL of blood (but to a lesser extent), while similar concentrations of ketone bodies were found in the blood of D-carnitine/mildronate-treated and control rats. In liver mitochondria, the specific activities of acyl-CoA synthetase and carnitine palmitoyltransferase I were enhanced by the treatment, while peroxisomal fatty acid oxidation was higher per gram of tissue. It is suggested that there may be an enhancement of cellular acyl-CoA concentration, a signal leading to increased liver fatty acid oxidation in acute carnitine deficiency.


Assuntos
Carnitina/deficiência , Ácidos Graxos/metabolismo , Fígado/metabolismo , Oxigenases de Função Mista/antagonistas & inibidores , Animais , Peso Corporal , Carnitina/antagonistas & inibidores , Carnitina/biossíntese , Masculino , Metilidrazinas/farmacologia , Tamanho do Órgão , Oxirredução , Ratos , Ratos Wistar , gama-Butirobetaína Dioxigenase
13.
Lipids ; 29(7): 481-9, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7968269

RESUMO

This study was designed to examine whether n-3 and n-6 polyunsaturated fatty acids at a very low dietary level (about 0.2%) would alter liver activities in respect to fatty acid oxidation. Obese Zucker rats were used because of their low level of fatty acid oxidation, which would make increases easier to detect. Zucker rats were fed diets containing different oil mixtures (5%, w/w) with the same ratio of n-6/n-3 fatty acids supplied either as fish oil or arachidonic acid concentrate. Decreased hepatic triacylglycerol levels were observed only with the diet containing fish oil. In mitochondrial outer membranes, which support carnitine palmitoyltransferase I activity, cholesterol content was similar for all diets, while the percentage of 22:6n-3 and 20:4n-6 in phospholipids was enhanced about by 6 and 3% with the diets containing fish oil and arachidonic acid, respectively. With the fish oil diet, the only difference found in activities related to fatty acid oxidation was the lower sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition. With the diet containing arachidonic acid, peroxisomal fatty acid oxidation and carnitine palmitoyltransferase I activity were markedly depressed. Compared with the control diet, the diets enriched in fish oil and in arachidonic acid gave rise to a higher specific activity of aryl-ester hydrolase in microsomal fractions. We suggest that slight changes in composition of n-3 or n-6 polyunsaturated fatty acids in mitochondrial outer membranes may alter carnitine palmitoyltransferase I activity.


Assuntos
Hidrolases de Éster Carboxílico/metabolismo , Gorduras Insaturadas na Dieta/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Insaturados/farmacologia , Metabolismo dos Lipídeos , Microssomos Hepáticos/enzimologia , Mitocôndrias Hepáticas/metabolismo , Monoaminoxidase/metabolismo , Urato Oxidase/metabolismo , Animais , Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos Ômega-6 , Masculino , Malonil Coenzima A/farmacologia , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Obesidade/enzimologia , Palmitoil Coenzima A/farmacologia , Ratos , Ratos Zucker , Frações Subcelulares/metabolismo
14.
Histochem Cell Biol ; 128(2): 115-23, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17605029

RESUMO

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.


Assuntos
Abetalipoproteinemia/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Mucosa Intestinal/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Síndromes de Malabsorção/metabolismo , Abetalipoproteinemia/genética , Adolescente , Adulto , Criança , Proteínas de Ligação a Ácido Graxo/genética , Feminino , Humanos , Imuno-Histoquímica , Erros Inatos do Metabolismo Lipídico/genética , Síndromes de Malabsorção/genética , Masculino , RNA Mensageiro/metabolismo
15.
Diabetologia ; 48(6): 1059-65, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15868135

RESUMO

AIMS/HYPOTHESIS: Dietary supplementation with conjugated linoleic acids (CLA) has a fat-reducing effect in various species, but induces severe hyperinsulinaemia and hepatic steatosis in the mouse. This study aimed to determine the causes of the deleterious effects of CLA on insulin homeostasis. METHODS: The chronology of adipose and liver weight, hepatic triglyceride accumulation and selected blood parameters, including lipids, insulin, leptin and adiponectin, was determined in C57BL/6J female mice fed a 1% isomeric mixture of CLA for various periods of time ranging from 2 to 28 days. Insulin secretion was measured in 1-h static incubations of pancreatic islets, and pancreas morphometric parameters were determined in mice fed CLA for 28 days. RESULTS: Plasma levels of leptin and adiponectin sharply decreased after 2 days of CLA feeding, although adipose tissue mass only decreased after day 6. Hyperinsulinaemia developed at day 6 and consistently worsened up to day 28, in parallel with increases in hepatic lipid content. Islets from CLA-fed mice displayed three- to four-fold increased rates of glucose-stimulated insulin secretion, both in the absence and presence of isobutyl methylxanthine or carbachol. The increased insulin-releasing capacity of islets from CLA-fed mice was explained by an increase in beta cell mass and number. CONCLUSIONS/INTERPRETATION: The data suggest that CLA supplementation induces a profound reduction of leptinaemia and adiponectinaemia, followed by hyperinsulinaemia due to the increased secretory capacity of pancreatic islets, leading, in turn, to liver steatosis. These observations cast doubt on the safety of dietary supplements containing CLA.


Assuntos
Hiperinsulinismo/induzido quimicamente , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Ilhotas Pancreáticas/patologia , Leptina/sangue , Ácidos Linoleicos Conjugados/efeitos adversos , Adiponectina , Tecido Adiposo/anatomia & histologia , Animais , Peso Corporal , Modelos Animais de Doenças , Feminino , Hiperplasia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Triglicerídeos/metabolismo
16.
Biochem J ; 263(3): 867-73, 1989 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-2597132

RESUMO

The movement of alpha-linolenic acid (C18:3, n-3) through the mitochondrial outer membrane to oxidation sites was studied in rat liver and compared with the movement of linoleic acid (C18:2, n-6) and oleic acid (C18:1, n-9). All differ in the degree of unsaturation, but have the same chain length and the same position of the first double bond when counted from the carboxyl end. The following results were obtained. (1) The overall beta-oxidation in total mitochondria was in the order C18:3, n-3 greater than C18:2, n-6 greater than C18:1, n-9, independent of the amount of albumin in the medium. (2) The rate of formation of acylcarnitine from acyl-CoA was higher with oleoyl-CoA than with linoleoyl-CoA, and remained very low with alpha-linolenoyl-CoA for all concentrations studied. (3) When the formation of acylcarnitines originated from fatty acids (as potassium salts) in a medium containing CoA and ATP, the conversion of alpha-linolenate was greater than that of linoleate, which in turn was greater than that of oleate. (4) Use of a more purified mitochondrial fraction, practically devoid of peroxisomes, did not modify the results obtained with alpha-linolenate. (5) alpha-Linolenoyl-CoA did not inhibit oxidation of labelled alpha-linolenate, whereas the other acyl-CoAs did. (6) Transfer to carnitine of all three fatty acids (as potassium salts) by carnitine palmitoyltransferase-I (CPT-I) was similarly inhibited by increasing concentrations of malonyl-CoA. (7) On using a fraction containing mitochondrial outer membranes, the formation of acylcarnitines from potassium salts of fatty acids was qualitatively and quantitatively similar to that found with whole mitochondria. (8) Our observations show that alpha-linolenoyl-CoA synthesized other than in the mitochondria cannot be used to any great extent by the mitochondria due to its configuration. However when added as the unactivated form, alpha-linolenate appears to be very quickly oxidized, but should first be activated by acyl-CoA synthetase in the mitochondrion itself. Then it is rapidly channelled to CPT-I. These enzymic sites are probably close together in the mitochondrial outer membrane. The different behaviour of the alpha-linolenic group compared with the other acyl groups in the studied pathway can be explained by a different spatial arrangement due to the number and position of the double bonds.


Assuntos
Ácidos Linolênicos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Acil Coenzima A/metabolismo , Animais , Transporte Biológico , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/metabolismo , Técnicas In Vitro , Membranas Intracelulares/metabolismo , Ácido Linoleico , Ácidos Linoleicos/metabolismo , Masculino , Ácido Oleico , Ácidos Oleicos/metabolismo , Oxirredução , Ratos , Ratos Endogâmicos
17.
Biochem J ; 319 ( Pt 2): 483-7, 1996 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-8912685

RESUMO

The role of fatty acids in the expression of the gene for liver fatty acid-binding protein (L-FABP) was investigated in the well-differentiated FAO rat hepatoma cell line. Cells were maintained in serum-free medium containing 40 microM BSA/320 microM oleate. Western blot analysis showed that oleate triggered an approx. 4-fold increase in the cytosolic L-FABP level in 16 h. Oleate specifically stimulated L-FABP mRNA in time-dependent and dose-dependent manners with a maximum 7-fold increase at 16 h in FAO cells. Preincubation of FAO cells with cycloheximide prevented the oleate-mediated induction of L-FABP mRNA, showing that protein synthesis was required for the action of fatty acids. Run-on transcription assays demonstrated that the control of L-FABP gene expression by oleate was, at least in part, transcriptional. Palmitic acid, oleic acid, linoleic acid, linolenic acid and arachidonic acid were similarly potent whereas octanoic acid was inefficient. This regulation was also found in normal hepatocytes. Therefore long-chain fatty acids are strong inducers of L-FABP gene expression. FAO cells constitute a useful tool for studying the underlying mechanism of fatty acid action.


Assuntos
Proteínas de Transporte/metabolismo , Ácidos Graxos/farmacologia , Fígado/metabolismo , Proteína P2 de Mielina/metabolismo , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Regulação para Cima/efeitos dos fármacos , Animais , Proteínas de Transporte/genética , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Masculino , Proteína P2 de Mielina/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/efeitos dos fármacos , Ratos , Ratos Wistar , Células Tumorais Cultivadas
18.
Eur J Biochem ; 227(3): 801-7, 1995 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-7867641

RESUMO

The effect of bezafibrate on cytosolic fatty-acid-binding-protein (FABPc) production along the small intestine has been investigated in mice. This drug increased the intestinal fatty-acid-binding-protein (I-FABPc) and liver fatty-acid-binding-protein (L-FABPc) mRNA levels in the duodenum. The extents of induction in the duodenum and in the liver are similar. However, the degree of stimulation gradually decreases along the length of the gut, no effect being found in the ileum. An efficient absorption of this drug as early as the proximal part of the small intestine may explain this phenomenon. The L-FABPc gene is silent in terminal ileum of mice, but a direct infusion of bezafibrate into the ileum switches it on. We used this original model to follow the time course of induction of the L-FABPc gene by bezafibrate. L-FABPc mRNA was first detected 4 h after fibrate infusion, reached a maximum level at 16 h and subsequently decreased at 24 h. This induction was totally blocked by cycloheximide. Sunflower oil also caused small increases in the L-FABPc mRNA levels. The transcriptional origin of the induction triggered both by bezafibrate and sunflower oil was demonstrated by run-on assays. These data indicate that (a) the transcription of the L-FABPc gene is induced by bezafibrate via de novo protein synthesis and (b) components of sunflower oil can transcriptionally activate the L-FABPc gene. Our results also demonstrate that the mouse terminal ileum is a useful system for studying the regulation of L-FABPc gene expression both in vivo and in vitro.


Assuntos
Bezafibrato/farmacologia , Proteínas de Transporte/genética , Ácidos Graxos/metabolismo , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Animais , Proteínas de Transporte/biossíntese , Cicloeximida/farmacologia , Citosol/metabolismo , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Regulação da Expressão Gênica/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Óleos de Plantas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Óleo de Girassol , Transcrição Gênica/efeitos dos fármacos
19.
Am J Physiol ; 273(2 Pt 1): G289-95, 1997 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9277406

RESUMO

The effects of dietary oil intake and fatty acid infusions on the expression of intestinal and liver fatty acid-binding proteins (I-FABP and L-FABP, respectively) were investigated in the small intestine of mice. A daily force-feeding for 7 days with 0.2 ml sunflower oil specifically increased L-FABP mRNA and protein levels in duodenum and proximal jejunum. This upregulation was mediated in time- and dose-dependent manners by a minute quantity of linoleic acid, the main fatty acid found in sunflower oil. The L-FABP induction was only found with long-chain fatty acids, with the nonmetabolizable, substituted fatty acid alpha-bromopalmitate being far more active. A hormonally mediated effect is unlikely because long-chain fatty acids induced L-FABP mRNA in the Caco-2 cell line cultured in serum-free medium. Therefore, long-chain fatty acids are strong inducers of L-FABP gene expression in the small intestine. In contrast to data found in the rat, I-FABP gene expression appears to be unaffected by a lipid-enriched diet in the mouse.


Assuntos
Proteínas de Transporte/metabolismo , Ácidos Graxos/fisiologia , Intestino Delgado/metabolismo , Proteína P2 de Mielina/metabolismo , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Proteínas Supressoras de Tumor , Animais , Células CACO-2/metabolismo , Proteínas de Transporte/genética , Gorduras Insaturadas na Dieta/farmacologia , Proteína 7 de Ligação a Ácidos Graxos , Proteínas de Ligação a Ácido Graxo , Ácidos Graxos/química , Humanos , Íleo/metabolismo , Masculino , Camundongos , Proteína P2 de Mielina/genética , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo
20.
Biochem J ; 304 ( Pt 2): 577-84, 1994 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-7998995

RESUMO

Liver mitochondrial fractions as normally isolated contain only 10-20% of total mitochondria and may not be representative of the whole mitochondrial population. This study was designed to evaluate the dependence of the sensitivity of carnitine palmitoyl-transferase I (CPT I) to malonyl-CoA inhibition in mitochondrial fractions that are not normally studied. Four fractions prepared from rat liver were found to be contaminated to different extents by microsome vesicles, on the basis of marker-enzyme activities and micrographic data. Purification of mitochondrial fractions on a Percoll gradient decreased to some extent the microsomal contamination, which was due in part to the existence of close bonds between microsomes and the outer membranes of mitochondria. A greater degree of contamination of mitochondrial fractions by microsomes was correlated with a greater sensitivity of CPT I to malonyl-CoA inhibition. Attempts were made to enhance the sensitivity of CPT I to malonyl-CoA with the use of microsomes. Measurements performed by adding mitochondria and microsomes in the same CPT I assay failed to demonstrate any significant enhancement of malonyl-CoA inhibition. However, addition of ATP to a mixture of mitochondria and microsomes was shown to trigger the binding of both particles, as assessed by enzymic and micrographic data, and to increase the sensitivity of CPT I to malonyl-CoA inhibition. These results demonstrated that the binding of microsomes to mitochondria, unlike the simple mixing of both particles, was capable of altering the sensitivity of CPT I to malonyl-CoA. The data also suggest that this process could be of physiological importance, owing to the frequency of contiguous zones between mitochondria and endoplasmic reticulum observed in sections of intact liver cells.


Assuntos
Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Malonil Coenzima A/farmacologia , Microssomos Hepáticos/enzimologia , Mitocôndrias Hepáticas/enzimologia , Trifosfato de Adenosina/farmacologia , Animais , Fracionamento Celular/métodos , Centrifugação com Gradiente de Concentração , Masculino , Microssomos Hepáticos/metabolismo , Mitocôndrias Hepáticas/metabolismo , Ratos , Ratos Wistar
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