Biomedical subjects
Publications and source records attributed to J Nordmann.
Stimulated exocytotic secretion from nerve endings is initiated by an increase in intracellular free calcium concentration. We summarize here our latest findings regarding the temporal relationship between depolarization, elevation of [Ca2+]i and exocytosis in single vertebrate neuroendocrine nerve endings. In addition, we present surprising findings for a regulatory role of intracellular Na+ on exocytosis.
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Besides ethanol, other aliphatic alcohols such as n-propanol and isopropanol induce a triacylglycerol (TAG) accumulation in the liver. To determine whether a common mechanism is responsible for the effects of these three alcohols on hepatic lipid metabolism, each was administered by gastric tube to female Wistar rats at the dose of 50 mmol/kg body wt. Whichever alcohol was administered, the hepatic triacylglycerol accumulation was found to be related to the duration of elevated blood alcohol concentration. After administration of n-propanol or isopropanol, the liver [14C]palmitate uptake was increased whereas hepatic palmitate oxidation to 14CO2 was impaired and palmitate esterification into TAG enhanced; these perturbations were however more discrete than after ethanol administration. In contrast to ethanol and n-propanol which, at the dose presently used, increase precursor incorporation into blood TAG, isopropanol inhibits this incorporation. Interference with the process of very low density lipoprotein (VLDL) synthesis and/or secretion, which appears only at a late stage of isopropanol intoxication, is probably responsible for the intensity and duration of the fatty liver observed after administration of this alcohol.
The effects of the various naturally occurring amino acids on ethanol oxidation in hepatocytes from starved rats was systematically studied. In order to minimize the non ADH pathways, the ethanol concentration used was 4 mmol/litre, the amino acids being added at the same concentration. In hepatocytes from fasted rats, alanine, arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, hydroxyproline, ornithine and serine increase significantly ethanol consumption. The stimulatory effect of glutamine being much less pronounced than the asparagine one and proline being devoid of action, the influence of ammonium chloride addition on ethanol consumption in the presence of these amino acids was studied. Ammonium chloride determines an enhancement of ethanol oxidation in these conditions, the results showing no apparent correlation between intracellular glutamate concentration and ethanol oxidation rate, contrarily to previous data. In hepatocytes from fed rats, only alanine, asparagine, cysteine, glycine, hydroxyproline, ornithine and serine increase ethanol oxidation, although to a lesser extent than in cells from starved rats.
The effects of the administration of different fatty liver inducing drugs on the serum lipoprotein lipase activating ability was investigated in rats. Addition of serum from 2-mercaptoethanol-, 2-mercaptoacetate-, ethionine- or D-galactosamine- treated rats failed to activate heart and adipose tissue lipoprotein lipase from control rats. The activating effect of serum was only slightly reduced in isopropanol-treated rats, whereas it was found unaffected in ethanol-treated ones. Electrophoresis of the lipoproteins and of the very low density lipoproteins (VLDL) fraction of sera from 2-mercaptoethanol-, 2-mercaptoacetate-, isopropanol-, ethionine- and D-galactosamine-treated rats suggest that the lack of lipoprotein lipase activation ability of these sera is most probably related to the impairing effects of these drugs upon VLDL metabolism, i.e. reduction of VLDL secretion in the case of 2-mercaptoethanol, 2-mercaptoacetate and isopropanol, production of abnormal VLDL in the case of D-galactosamine and both decreased VLDL secretion and production of abnormal VLDL in the case of ethionine.
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2-Mercaptoethanol-induced fatty liver involves an increased free fatty acid mobilization which is primarily due to an inhibition of free fatty acid reesterification in adipose tissue. Furthermore, increased free fatty acid mobilization as well as fatty liver induction are not induced by 2-mercaptoethanol per se but result most probably from 2-mercaptoacetate through oxidation of 2-mercaptoethanol.
Isopropanol and acetone administered to rats in conditions leading to a similar blood acetone level differ markedly in their effects on lipid metabolism. Isopropanol administration determines a fatty liver, which is mainly related to a defect in hepatic lipoprotein synthesis. Acetone administration gives only raise to a slight increase in the liver triacylglycerol level. It does not alter the [1-14C] palmitate, [1-14C] glycerol or [U-14C] leucine incorporation into blood lipoproteins. Acetone does thus not appear to play a preminent role in the isopropanol induced fatty liver which seems to be related mainly to a direct action of the alcohol itself.
The present study is concerned with the effects of L-arginine hydrochloride administration on the disturbances of liver glutamine metabolism following acute ammonia intoxication in the rat. Our results show that arginine administration does not suppress the decrease in the hepatic glutamine level and the marked activation of liver glutaminase I induced by ammonia. These alterations do not therefore appear to be related to the limitation of ammonia detoxication through the urea cycle.
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The effects of some mono-, di- and tricarboxylic substrates (acetate, pyruvate, L-lactate, L-alanine, D,L-beta-hydroxybutyrate, succinate, D,L-malate, alpha-oxoglutarate, L-glutamate and citrate) on the basal lypolytic activity of isolated white adipocytes from fasted rats were investigated "in vitro". At concentrations ranging from 1 to 10 mM, the compounds tested, except lactate, had no influence on the rate of glycerol release but markedly reduced the free fatty acid (FFA) release. Lactate reduced both the glycerol and FFA release. As this "in vitro" lowering effect on FFA release was observed using concentrations occurring "in vivo" in the blood for lactate, beta-hydrobutyrate, and alanine, these results suggest that, besides lactate and beta-hydroxybutyrate, alanine may also assume an important role in the "in vivo" regulation of peripheral FFA mobilization and consequently of ketogenesis.
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The intraperitoneal administration of 2-mercaptoethanol or 2-mercaptoacetate (40 muM/100 g body weight) to the rat induces a fatty liver, a marked and early increase of free fatty acids and a decrease of triacylglycerol and phospholipids in the blood. These changes are accompanied by a decrease of the ketone body level and the beta-hydroxybutyrate/acetoacetate ratio in the liver. Under the same experimental conditions, however, administration of 2-mercaptopropionate fails to induce a fatty liver and does not modify the hepatic ketone body level or the blood triacylglycerol and free fatty acid levels. These results led us to conclude that fatty liver induction is not a general feature of foreign thiols, and suggest that increased peripheral fat mobilization as well as decreased hepatic lipoprotein synthesis and/or release are responsible for the 2-mercaptoethanol- and 2-mercaptoacetate-induced fatty liver.
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When studied at different times following ethanol intubation, the effects of pyrazole, administered to rats prior to ethanol, affects differently the alcohol-induced disturbances in hepatic [1-14C] palmitate oxidation. This peculiar time-course of the pyrazole induced effects supports the relationship between active ethanol oxidation and inhibition of hepatic fatty acid oxidation, but also emphasizes the caution which must be taken when using pyrazole to study "in vivo" the mechanisms involved in the alcohol induced fatty liver.
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