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Biomedical subjects

J Fauvel

Publications and source records attributed to J Fauvel.

At least 19 recordsLinked to original sources
PubMed2001

Enterophilins, a new family of leucine zipper proteins bearing a b30.2 domain and associated with enterocyte differentiation.

Enterocyte terminal differentiation occurs at the crypt-villus junction through the transcriptional activation of cell-specific genes, many of which code for proteins of the brush border membrane such as intestinal alkaline phosphatase, sucrase-isomaltase, or the microvillar structural protein villin. Several studies have shown that this sharp increase in specific mRNA levels is intimately associated with arrest of cell proliferation. We isolated several clones from a guinea pig intestine cDNA library. They encode new proteins characterized by an original structure associating a carboxyl-terminal B30.2/RFP-like domain and a long leucine zipper at the amino terminus. The first member of this novel gene family codes for a 65-kDa protein termed enterophilin-1, which is specifically expressed in enterocytes before their final differentiation. Enterophilin-1 is the most abundant in the small intestine but is still present in significant amounts in colonic enterocytes. In Caco-2 cells, a similar 65-kDa protein was recognized by a specific anti-enterophilin-1 antibody, and its expression was positively correlated with cell differentiation status. In addition, transfection of HT-29 cells with enterophilin-1 full-length cDNA slightly inhibited cell growth and promoted an increase in alkaline phosphatase activity. Taken together, these data identify enterophilins as a new family of proteins associated with enterocyte differentiation.

Amino Acid Sequence↗
PubMed2001

Apoprotein c-III and E-containing lipoparticles are markedly increased in HIV-infected patients treated with protease inhibitors: association with the development of lipodystrophy.

Long-term therapy with protease inhibitors (PIs) can induce hypertriglyceridemia and development of a lipodystrophy. To better understand these metabolic alterations, the apoprotein and lipoparticle profile was investigated in male HIV patients under antiretroviral therapy: 49 received PIs, and 14 were given only two reverse transcriptase inhibitors. As controls, 63 male subjects were selected from a population study carried out in the Toulouse, France, area. Fasting glucose, insulin, and C-peptide were also determined. All patients under PIs displayed low levels of plasma glucose and increased insulin. PI administration was associated with moderate hypertriglyceridemia, low high-density cholesterol and apolipoprotein (apo) A-I levels. The most striking changes were a 2- to 3-fold increase in apo E and apo C-III, essentially recovered as associated to apo B-containing lipoparticles. Levels of those lipoparticles were two to eight times above control values. About 50% of PI-treated patients had developed a patent lipodystrophy. Multivariate analysis revealed that, among the investigated parameters, apo C-III was the only one found strongly associated with the occurrence of lipodystrophy (odds ratio, 5.5; P: < 0.015). Finally, 13 PI-receiving subjects with patent hypertriglyceridemia were given fenofibrate and were reevaluated 2 months later. Triglycerides, apo E, apo C-III, and the corresponding lipoparticles had returned to nearly normal levels. These results document the accumulation of potentially atherogenic lipoparticles under PIs. Apo C-III may play a pivotal role in the development of hypertriglyceridemia and lipodystrophy.

Adult↗
PubMed2000

Polymorphism of the 5' untranslated region of NHE1 gene associated with type-I diabetes.

The ubiquitous form of the sodium-hydrogen exchanger, NHE1, is devoted to the regulation of intracellular pH and cell volume. In addition, NHE1 activity is stimulated by growth factors and increased NHE rates are found in both circulating and immortalized cells during diabetes or diabetic nephropathy. In this context, we searched for polymorphisms of the 5'-flanking regulatory region of NHE1 gene in subjects with type-I diabetes. We identified a C/T transition 696 bases upstream the translation initiation start site which disrupts a repeated palindromic GC sequence. The TT genotype was significantly more frequent in type-1 diabetics and may have functional importance. Genetic linkage between NHE1 and diabetes has been previously described in NOD mice strains with consequences on NHE rates. Hence, the polymorphism described hereby may act as a predisposition factor to type-I diabetes or to diabetic complications, and may be useful to investigate the genetic involvement of NHE1 in human pathophysiology.

5' Untranslated Regions↗
PubMed2000

Toxoplasma gondii secretes a calcium-independent phospholipase A(2).

Phospholipases A(2) (PLA(2)) play an important role in Toxoplasma gondii host cell penetration. They are also key enzymes in the host cell response to the parasite invasion. PLA(2) hydrolyse cellular phospholipids, releasing multiple inflammatory lipidic mediators. We have investigated the biochemical characterisation of T. gondii PLA(2) activity in a mouse-cultured tachyzoite homogenate and in the peritoneal exudate from infected mice, using the hydrolysis of a fluorescent phosphatidylglycerol labelled at the sn-2 position. Spectrofluorimetry and thin-layer chromatography showed a PLA(2) activity (about 0.5-2 nmol/min per mg), calcium-independent, secreted into infected mice peritoneal exudate, with a broad pH activity ranging between 6.5 and 9.5 and resistant to a great number of potential PLA(2) inhibitors except dithio-nitrobenzoic acid (1 mM). An associated phospholipase A(1) activity was also displayed. These results suggest that Toxoplasma gondii displays specific phospholipases different from host enzymes and probably involved at critical steps of infectious cycle.

Animals↗
PubMed1999

New developments in phospholipase A2.

Some of the most recent data concerning various phospholipases A2, with special emphasis on secretory, cytosolic, and calcium-independent phospholipases A2 are summarized. Besides their contribution to the production of proinflammatory lipid mediators, the involvement of these enzymes in key cell responses such as apoptosis or tumor cell metastatic potential is also discussed, taking advantage of transgenic models based on gene invalidation by homologous recombination. The possible role of secretory and cytosolic platelet-activating factor acetyl hydrolases is also briefly mentioned. Finally, the ectopic expression in epididymis of an intestinal phospholipase B opens some novel issues as to the possible function of phospholipases in reproduction.

Animals↗
PubMed1999

Angiotensin I-converting enzyme gene polymorphism in a low-risk European population for coronary artery disease.

An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) has been associated with an increased risk of coronary artery disease (CAD) and myocardial infarction (MI). However, this finding has not been fully investigated in European populations with very low CAD risk. In a case-control study on a population from Southern Europe (Toulouse, France), we evaluated the ACE I/D polymorphism in 405 men, aged 35-65 years, who underwent coronary angiography and in 357 representative control men within the same age range. We also explored associations in the patients between this polymorphism and CAD severity. The ACE genotype was not associated with the presence of either CAD or MI. The ACE genotype was not a marker for angiographically assessed CAD severity. In a sample in one of the European populations with the lowest CAD risk, ACE I/D polymorphism was not associated with an increased risk for CAD or MI and did not influence the extent of CAD.

Adult↗
PubMed1999

Carotid intima-media thickness and coronary heart disease risk factors in a low-risk population.

OBJECTIVE: Coronary heart disease (CHD) risk factors have been consistently related to an increase in carotid intima-media thickness (IMT) in selected populations. However, few studies were population-based and furthermore little attention has been given to the influence of CHD risk factors on IMT in low-risk populations for CHD. DESIGN: We examined the association between carotid IMT and CHD risk factors in a large (n = 1013) and representative sample of middle-aged men and women in one of the European populations with the lowest CHD risk. METHODS: High-resolution B-mode ultrasonography of the common carotid arteries was performed. RESULTS: Age, smoking (not significant in women), body mass index, waist to hip ratio, systolic (SBP) and diastolic blood pressure, alcohol consumption, total and low-density lipoprotein cholesterol, triglycerides, glycaemia, fibrinogen (not significant in women), haematocrit (not significant in men) and insulin (not significant in women) were positively and significantly associated with mean IMT. High-density lipoprotein (HDL) cholesterol (not significant in women) was negatively and significantly associated with mean IMT. In a subsample of 355 men, IMT was not associated with angiotensin I-converting enzyme gene polymorphism. Multivariate analyses showed, in men, independent associations between mean IMT (0.61+/-0.11 mm) and age, pack-years, SBP, HDL cholesterol, alcohol and the interaction between age and alcohol. In women, only age and SBP were independently associated with mean IMT (0.58+/-0.09 mm). CONCLUSIONS: We found thinner IMT than those found in high-risk populations, suggesting that an increased IMT might reflect local atherosclerosis. Protective factors such as HDL cholesterol or regular and moderate alcohol consumption are probably important determinants of the early stages of atherosclerosis in these low-risk populations.

Adult↗
PubMed1998

Ectopic epididymal expression of guinea pig intestinal phospholipase B. Possible role in sperm maturation and activation by limited proteolytic digestion.

Guinea pig intestinal phospholipase B is a calcium-independent phospholipase hydrolyzing sequentially the acyl ester bonds at sn-2 and sn-1 positions of glycerophospholipids, promoting the formation of sn-glycero-3-phosphocholine from phosphatidylcholine. This 140-kDa glycoprotein from the brush border membrane of differentiated enterocytes contributes to lipid digestion as an ectoenzyme. The cDNA coding for guinea pig phospholipase B was revealed to be the homologue of AdRab-B, an mRNA appearing in rabbit upon intestine development. The sequence predicts a polypeptide of 1463 amino acids displaying four homologous repeats, two of them containing the lipase consensus sequence GXSXG. A 5-kilobase transcript was particularly abundant in mature ileal and jejunal enterocytes but was also detected in epididymis, where phospholipase B displayed a higher molecular mass (170 kDa versus 140 kDa in intestine), with no obvious evidence for enzyme activity. Trypsin treatment of phospholipase B immunoprecipitated from epididymal membranes reduced its size to 140 kDa, coinciding with the appearance of a significant phospholipase A2 activity. The same results were obtained in COS cells transfected with phospholipase B cDNA. Since sn-glycero-3-phosphocholine present at high concentrations in seminal plasma mainly stems from epididymis, this suggests a possible role of phospholipase B in male reproduction. This novel localization also unravels a mechanism of phospholipase B activation by limited proteolysis involving either trypsin in the intestinal lumen or a trypsin-like endopeptidase in the male reproductive tract.

Amino Acid Sequence↗
PubMed1998

Regulation of secretory type-II phospholipase A2 and of lysophosphatidic acid synthesis.

Secretory non-pancreatic phospholipase A2 (sPLA2), also called type II-PLA2, is produced in large amounts under inflammatory conditions, thus accumulating in inflammatory fluids. Since the enzyme is virtually inactive on phospholipids from intact cells, we have searched for conditions allowing the action of sPLA2 on membrane phospholipids. Based on an in vitro model, our studies suggest that only those membranes where the transverse distribution of phospholipids has been disturbed offer a convenient surface able to interact with the enzyme, which then achieves significant degradation of all glycerophospholipids. This results in the accumulation of various lysophospholipids such as lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine. However, lysophosphatidic acid (LPA) can also be generated under these conditions involving accumulation of phosphatidic acid in the cytoplasmic leaflet of the membrane, followed by its transfer to the outer monolayer. Since LPA is now considered as a novel phospholipid mediator, this pathway deserves further studies concerning mainly platelets, the main source of LPA identified so far.

Animals↗
PubMed1998

[Prevalence and management of major risk factors in 500 men with stable coronary disease].

Management of major risk factors (smoking, hypercholesterolaemia, hypertension), in the context of secondary prevention, has an impact on recurrence and life expectancy. However, there is a delay between the publication of therapeutic trials and their diffusion within the medical community. The objective of this study was to evaluate the prevalence and management of the main risk factors in a sample of 500 men, with a mean age of 55.1 +/- 7.5 years, presenting with stable coronary artery disease. 11% of subjects had a family history of premature myocardial infarction. Smoking was frequent: 21% of smokers, 60% of ex-smokers. Hypercholesterolaemia (LDL-C > 3.4 mmole/l or treatment) was present in 82% of subjects. Only 45% of treated subjects had an LDL-C < 3.4 mmole/l. Hypertension (systolic blood pressure > or = 140 mmHg or diastolic blood pressure > or = 90 mmHg or treatment) was present in 61% of subjects. Only 33% of treated subjects were controlled. Non-insulin-dependent diabetes mellitus (blood glucose > or = 7.7 mmole/l or treatment) was present in 21% of subjects. Only 43% of treated subjects were controlled. Calculation of the distribution of major risk factors (smoking, pathological obesity, hypercholesterolaemia, hypertension, diabetes) showed that 90% of coronary patients presented at least two risk factors. Overall, the prevalence and management of risk factors in patients with stable coronary artery disease is far from optimal.

Adult↗
PubMed1997

Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis.

From very recent studies, including molecular cloning of cDNA coding for membrane receptors, lysophosphatidic acid (LPA) reached the status of a novel phospholipid mediator with various biological activities. Another strong argument supporting this view was the discovery that LPA is secreted from activated platelets, resulting in its appearance in serum upon blood coagulation. The metabolic pathways as well as the enzymes responsible for LPA production are poorly characterized. However, a survey of literature data indicates some interesting issues which might be used as the basis for further molecular characterization of phospholipases A able to degrade phosphatidic acid.

Animals↗
PubMed1996

Increased content of annexin II (p36) and p11 in human placenta brush-border membrane vesicles during syncytiotrophoblast maturation and differentiation.

Annexins are a group of proteins abundant in placental membranes where they may play diverse functional roles. Annexins are expressed in high levels in mature placenta but little is known about their presence at very early stages of gestation and later. We used the model of brush-border membrane vesicles (BBMV) at different stages of gestation to assess precise localization of some of these proteins in syncytiotrophoblast apical membrane and to determine their appearance along the maturation process of placenta. Here we describe annexins type I, II, IV, V and VI which are present all along gestation in BBMV. Annexin II (p36) is present with the S100 like calcium-binding protein p11 in BBMV, where they can constitute heterotetrameric forms of annexin II linked to cytoskeleton structures. No variation of annexins I, IV and VI content was observed in BBMV along pregnancy. Annexin V undergoes significant decrease after 12th week, which could be related to local anticoagulant activity. Levels of annexin II and p11 increased progressively during gestation suggesting that heterotetrameric forms of annexin II play a role in the differentiation process of placenta and in function of the mature microvilli.

Annexin A2↗
PubMed1994

Annexin I as a potential inhibitor of insulin receptor protein tyrosine kinase.

Insulin receptor (IR) purified from human placenta by wheat germ agglutinin affinity chromatography was incubated in the presence of insulin, [gamma-32P]ATP and annexin I. In parallel to its own tyrosine phosphorylation, annexin I promoted a dose-dependent inhibition of IR autophosphorylation (IC50 0.5 microM). This effect was specific for insulin-stimulated tyrosine kinase activity and required the N-terminal end of the protein containing the phosphorylatable Tyr21 residue. A pentadecapeptide encompassing residues 16-30 of human annexin I displayed a similar activity, but at higher concentrations. These data underscore a specific interaction of IR with annexin I, which should be considered as a potential physiological regulator of the effects of insulin on its target tissues.

Adenosine Triphosphate↗
PubMed1994

Virtual lack of annexins in human platelets argues against a role in phospholipase A2 regulation and platelet secretion.

Annexins are calcium-phospholipid binding proteins which share structural similarities and common biochemical properties. These proteins seem to be involved in different pathways of cell activation such as regulation of phospholipase A2 activity, membrane-cytoskeleton interaction, and exocytosis. The aim of this study was to attempt to characterize annexins in human platelets. Our results were based on specific EGTA extraction of proteins from platelet homogenates, immunodetection with specific antibodies raised against annexins I, II, V and VI, and measurement of phospholipase A2 inhibition. Antibodies raised against annexins I, V and VI revealed only trace amounts of these proteins in platelet EGTA extracts which did not promote phospholipase A2 inhibition in an in vitro assay. In addition, upon precipitation of membranes in the presence of calcium followed by EGTA extraction, the main substrate of protein kinase C (40-47-kDa protein) displayed a behaviour strictly different from that of annexins. Although one cannot exclude that a small amount of annexin(s) becomes phosphorylated in activated human platelets, these data argue against a role of annexins in the regulation of intracellular phospholipase A2 or in the processes of exocytosis in activated human platelets.

Annexin A1↗
PubMed1993

Annexin 5 as a potential regulator of annexin 1 phosphorylation by protein kinase C. In vitro inhibition compared with quantitative data on annexin distribution in human endothelial cells.

In vitro phosphorylation of annexin 1 by purified rat brain protein kinase C (PKC) has been studied in the presence of annexin 5, which is not a substrate for PKC. Annexin 5 promoted a dose-dependent inhibition of annexin 1 phosphorylation, which could be overcome by increasing the concentration of phosphatidylserine (PtdSer). In addition, a close relationship was found between the amount of PtdSer uncovered by annexin 5 and the residual phosphorylation of annexin 1. These data fit with the 'surface depletion model' explaining the antiphospholipase activity of annexins. In order to check the possibility that the in vitro effect of annexin 5 could be of some physiological relevance, annexins 1, 2, and 5, as well as the light chain of calpactin 1 (p11), have been quantified in human endothelial cells by measuring the radioactivity bound to the proteins after Western blotting with specific antibodies and 125I-labelled secondary antibody. Our data indicate that annexins 1 and 5, PKC and PtdSer are present in human endothelial cells in relative amounts very similar to those used in vitro under conditions permitting the detection of the inhibitory effect of annexin 5. Since annexin 1 remained refractory to PKC-dependent phosphorylation in intact cells, we suggest that annexin 5 might exert its inhibitory effect towards PKC in vivo, provided that its binding to phospholipids can occur at physiological (micromolar) concentrations of Ca2+. This was previously shown to occur in vitro using phosphatidylethanolamine/phosphatidic acid vesicles [Blackwood and Ernst (1990) Biochem. J. 266, 195-200]. Using identical assay conditions, which also allowed expression of PKC activity, annexin 5 again inhibited annexin 1 phosphorylation without interfering with PKC autophosphorylation. These data suggest that annexins 1 and 5 might interact with each other on the lipid surface, resulting in a specific inhibition of annexin 1 phosphorylation by PKC. Whether a similar mechanism also occurs in vivo remains to be determined.

Adenosine Triphosphate↗