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Biomedical subjects

S Skrede

Publications and source records attributed to S Skrede.

At least 19 recordsLinked to original sources
PubMed2005

Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.

Antipsychotic Agents↗
PubMed2001

[Treatment of acute bacterial meningitis].

BACKGROUND: Acute bacterial meningitis requires immediate antimicrobial therapy. MATERIALS AND METHODS: Guidelines to antimicrobial treatment of children and adults with acute bacterial meningitis are presented. RESULTS: The most common agents causing acute bacterial meningitis are Streptococcus agalactiae in children less than one month of age, and Streptococcus pneumoniae and Neisseria meningitidis in individuals more than one month of age. If the causative bacterial agent is not known, children below one month of age should be given ampicillin and gentamicin, whereas older children and adults should be given benzylpenicillin in combination with either cefotaxime or ceftriaxone. We suggest treatment with specific antibiotic regimens in cases of known aetiology.

Acute Disease↗
PubMed1997

Thia fatty acids, metabolism and metabolic effects.

(1) The chemical properties of thia fatty acids are similar to normal fatty acids, but their metabolism (see below: points 2-6) and metabolic effects (see below: points 7-15) differ greatly from these and are dependent upon the position of the sulfur atom. (2) Long-chain thia fatty acids and alkylthioacrylic acids are activated to their CoA esters in endoplasmatic reticulum. (3) 3-Thia fatty acids cannot be beta-oxidized. They are metabolized by extramitochondrial omega-oxidation and sulfur oxidation in the endoplasmatic reticulum followed by peroxisomal beta-oxidation to short sulfoxy dicarboxylic acids. (4) 4-Thia fatty acids are beta-oxidized mainly in mitochondria to alkylthioacryloyl-CoA esters which accumulate and are slowly converted to 2-hydroxy-4-thia acyl-CoA which splits spontaneously to an alkylthiol and malonic acid semialdehyde-CoA ester. The latter presumably is hydrolyzed and metabolized to acetyl-CoA and CO2. (5) Both 3- and 4-thiastearic acid are desaturated to the corresponding thia oleic acids. (6) Long-chain 3- and 4-thia fatty acids are incorporated into phospholipids in vivo, particularly in heart, and in hepatocytes and other cells in culture. (7) Long-chain 3-thia fatty acids change the fatty acid composition of the phospholipids: in heart, the content of n-3 fatty acids increases and n-6 fatty acids decreases. (8) 3-Thia fatty acids increase fatty acid oxidation in liver through inhibition of malonyl-CoA synthesis, activation of CPT I, and induction of CPT-II and enzymes of peroxisomal beta-oxidation. Activation of fatty acid oxidation is the key to the hypolipidemic effect of 3-thia fatty acids. Also other lipid metabolizing enzymes are induced. (9) Fatty acid- and cholesterol synthesis is inhibited in hepatocytes. (10) The nuclear receptors PPAR alpha and RXR alpha are induced by 3-thia fatty acids. (11) The induction of enzymes and of PPAR alpha and RXR alpha are increased by dexamethasone and counteracted by insulin. (12) 4-Thia fatty acids inhibit fatty acid oxidation and induce fatty liver in vivo. The inhibition presumably is explained by accumulation of alkylthioacryloyl-CoA in the mitochondria. This metabolite is a strong inhibitor of CPT-II. (13) Alkylthioacrylic acids inhibits both fatty acid oxidation and esterification. Inhibition of esterification presumably follows accumulation of extramitochondrial alkylthioacryloyl-CoA, an inhibitor of microsomal glycerophosphate acyltransferase. (14) 9-Thia stearate is a strong inhibitor of the delta 9-desaturase in liver and 10-thia stearate of dihydrosterculic acid synthesis in trypanosomes. (15) Some attempts to develop thia fatty acids as drugs are also reviewed.

Acyl-CoA Dehydrogenase, Long-Chain↗
PubMed1995

Formation of pivaloylcarnitine in heart and brown adipose tissue in the rat.

Both pivaloylesterified antibiotics and pivalic acid cause pivaloylcarnitine excretion into urine in the rat and human. In the present study, the formation of pivaloylcarnitine, expressed as short-chain acylcarnitines has been observed in rats. The carnitine pool of the rats was radiolabeled by injection of L-[3H]butyrobetaine 24 h prior to exposure to pivalic acid injected i.p. or pivampicillin administered orally. The presence of pivaloylcarnitine in liver, heart, kidney, stomach, small intestine, testis, muscle, brown fat, white fat and serum was determined at zero time, 0.5, 2, 8 and 24 h after exposure to pivalic acid. After injection of pivalic acid, pivaloylcarnitine calculated as percent of free carnitine and short-chain acylcarnitines amounted to (mean +/- SD) 1.1 +/- 0, 15.4 +/- 2.5, 33.4 +/- 0.7 and 37.5 +/- 1.5% in the heart and 1.2 +/- 0.2, 20.6 +/- 9.5, 29.8 +/- 7.6 and 22.5 +/- 1.6% in brown fat after 0, 0.5, 2 and 8 h, respectively. 2 h after administration, pivaloylcarnitine calculated as percent of free carnitine and short-chain acylcarnitines was highest in the heart (20.9 +/- 7.6%) and brown fat (19.0 +/- 8.5%) in the pivalic acid-treated rat, and highest in the kidney (12.4 +/- 3.1%) and brown fat (10.2 +/- 2.8%) in the pivampicillin-treated rat. Pivaloylcarnitine percent in the liver was 2.8 +/- 0.6 in the pivalic acid-treated rat, 3.5 +/- 1.2 in the pivampicillin-treated rat and 1.3 +/- 0.4 in the control group. Pivaloylcarnitine concentration, nmol/g and nmol/organ, was highest in the heart and brown fat in both treatment groups. The present study suggests that the heart and the brown fat, but not the liver, play important roles in pivaloylcarnitine formation in the rat.

Adipose Tissue, Brown↗
PubMed1995

Effects of tetradecylthiopropionic acid and tetradecylthioacrylic acid on rat liver lipid metabolism.

Studies of effects of 4-thia-substituted fatty acid analogues on rat liver lipid metabolism are described. With isolated hepatocytes tetradecylthiopropionate was shown to divert [1-14C]oleate from beta-oxidation into esterification, the total amount of [1-14C]oleate metabolized remaining unchanged. Tetradecylthiopropionyl-CoA was a good substrate for mitochondrial carnitine palmitoyltransferases I and II (EC 2.3.1.21), acyl-CoA oxidase (EC 1.3.3.6), for the microsomal (but not mitochondrial) glycerophosphate acyltransferase (EC 2.3.1.15), and for long-chain acyl-CoA dehydrogenase (EC 1.3.99.3). In isolated hepatocytes, its 4-thia-trans-2-enoic derivative, tetradecylthioacrylate, inhibits both beta-oxidation of, and incorporation of, [1-14C]oleate into lipids. In rat liver mitochondria tetradecylthiocrylate inhibited beta-oxidation. The degree of inhibition was not markedly increased by preincubation with tetradecylthioacrylate. Tetradecylthioacrylyl-CoA was a poor substrate for carnitine palmitoyltransferase I, and inhibited carnitine palmitoyltransferase II, microsomal glycerophosphate acyltransferase and acyl-CoA oxidase. It is concluded that the inhibitory effects of tetradecylthiopropionyl-CoA are expressed intramitochondrially, whereas primary sites of inhibition by tetradecylthioacrylyl-CoA are extramitochondrial.

Acrylates↗
PubMed1995

Enhanced oxygen consumption and fatty acid metabolism in rat bone marrow with acute promyelocytic leukaemia.

The metabolism of bone marrow cells during the development of acute promyelocytic leukaemia has only been scarcely characterized, even though such knowledge might improve our understanding of the mechanisms of leukemogenesis as well as of drug treatment failure. We have investigated the in vitro oxygen consumption and the metabolism of palmitate in rat bone marrow cells during development of acute promyelocytic leukaemia. As the leukaemia progressed, the cellular oxygen consumption, the beta-oxidation of palmitate and the incorporation of palmitate into phospholipids all increased markedly. Cyclophosphamide supplement led to a temporary reduction of the palmitate metabolism, but did not lower the increased oxygen consumption. We conclude that the cellular metabolic rate is elevated during the progression of acute promyelocytic leukaemia, and that this might reflect an enhanced proliferative rate of the malignant cells.

Animals↗
PubMed1995

Tetradecylthioacetic acid (a 3-thia fatty acid) decreases triacylglycerol secretion in CaCo-2 cells.

The effects of the hypolipidemic fatty acid analogue tetradecylthioacetic acid (TTA) on synthesis and secretion of lipoproteins in CaCo-2 cells were studied. Radiolabeled tetradecylthioacetic acid was absorbed and metabolized as efficiently as oleic acid, although a discrepancy in the metabolic fate was evident. Whereas tetradecylthioacetic acid was incorporated into cell-associated triacylglycerol to the same extent as normal fatty acids (e.g., oleic acid and palmitic acid), the amount of triacylglycerol secreted from cells incubated with tetradecylthioacetic acid was 8 to 10 times lower than the amount secreted from cells incubated with palmitic acid and oleic acid, respectively. On the other hand, there was an enhanced incorporation of tetradecylthioacetic acid into cell-associated and secreted phospholipids. Despite incorporation of tetradecylthioacetic acid into cellular triacylglycerol, unlike oleic acid, tetradecylthioacetic acid did not stimulate production of triacylglycerol-rich particles. Ultracentrifugation of basolateral media from cells incubated with tetradecylthioacetic acid revealed low amounts of triacylglycerol in the triacylglycerol-rich fraction (p < 1.006 g/ml), suggesting secretion of lipoproteins with a higher density than chylomicrons. However, the present study shows that the stimulated triacylglycerol secretion caused by oleic acid was inhibited in the presence of TTA. The decreased rate of triacylglycerol secretion from these cells was not accompanied by a stimulation of fatty acid oxidation. Based on these findings, we therefore suggest that tetradecylthioacetic acid mainly affects secretion of lipoproteins in CaCo-2 cells.

Cell Line↗
PubMed1994

Dexamethasone and insulin demonstrate marked and opposite regulation of the steady-state mRNA level of the peroxisomal proliferator-activated receptor (PPAR) in hepatic cells. Hormonal modulation of fatty-acid-induced transcription.

Fatty acids and the peroxisomal proliferator, 3-tetradecylthioacetic acid (TTA) stimulate transcription of peroxisomal beta-oxidation enzymes. Recently, we have shown that their actions are markedly modulated by dexamethasone and insulin which show synergistic and inhibitory effects, respectively. In this study, we describe the regulation of the peroxisomal proliferator-activated receptor (PPAR), a member of the steroid-hormone-receptor superfamily, in a similar manner by hormones and fatty acids, supporting the hypothesis that PPAR may act as a ligand-activated transcription factor. Northern-blot analysis of steady-state mRNA levels revealed three different specific transcripts for PPAR of 10.2, 4.6 and 1.8 kb, and the former two being regulated in hepatic tissue, hepatocytes and hepatoma cells. Dexamethasone produced a pronounced overall stimulatory effect (15.3-fold) in rat hepatocytes, while insulin blocked this action completely. Minor inductions of PPAR mRNA (up to twofold induction) were observed when different fatty acids were administrated alone. However, in combination with dexamethasone, additive or synergistic actions, mounting to 24-fold stimulation, were observed, while insulin always exerted an over-riding down-regulatory effect. In non-fasting rats receiving dexamethasone, elevation of serum insulin, a slight increase in serum free fatty acids accompanied by PPAR mRNA level increases of 2.4-fold and stimulation of liver peroxisomal acyl-CoA oxidase mRNA were observed. Our results suggest that PPAR mRNA expression is under strict hormonal control and that the fatty acids and hormones affect PPAR mRNA levels in a manner analogous to the regulation of the peroxisomal beta-oxidation enzymes. The PPAR gene-regulating unit apparently contains hormone-response elements (HRE) for dexamethasone and insulin, which are thus functionally important for PPAR transcription in liver cells, making a significant enhancement or inhibition of the physiological actions of fatty acids possible.

Acyl-CoA Oxidase↗
PubMed1994

Stimulation of fatty acid oxidation by a 3-thia fatty acid reduces triacylglycerol secretion in cultured rat hepatocytes.

The present work shows that when mitochondrial beta-oxidation is stimulated by the hypolipemic, non-beta-oxidizable fatty acid analogue tetradecylthioacetic acid, there is a decrease in the secretion of triacylglycerol in cultured rat hepatocytes. In order to study the effects of tetradecylthioacetic acid in cells with different fatty acid oxidation rates, cells were grown without or with L-carnitine supplement or with addition of the beta-oxidation inhibitor L-aminocarnitine. In cells grown without and with L-carnitine in the medium, the oxidation of [1-14C]oleic acid was stimulated by tetradecylthioacetic acid, whereas it was not significantly changed by palmitic acid. In cells grown with L-aminocarnitine, oxidation of [1-14C]oleic acid was almost abolished both in the absence and in presence of tetradecylthioacetic acid. The effect of tetradecylthioacetic acid and palmitic acid on incorporation of [1-14C]oleic acid into triacylglycerol was similar under all conditions. In the presence of L-carnitine, secretion of oleic acid-labeled triacylglycerol was reduced significantly more by tetradecylthioacetic acid than by palmitic acid. The effects of tetradecylthioacetic acid and palmitic acid on secretion of oleic acid-labeled triacylglycerol were reversed in cells grown with L-aminocarnitine, where palmitic acid was the stronger inhibitor. These results were substantiated by determination of mass of triacylglycerol secreted. It is concluded that tetradecylthioacetic acid reduces secretion of triacylglycerol from rat hepatocytes mainly by acutely stimulating fatty acid oxidation.

Animals↗
PubMed1993

Substrate and hormone regulation of palmitoyl-CoA synthetase in 7800 C1 Morris hepatoma cells and cultured rat hepatocytes.

The effects of tetradecylthioacetic acid (TTA), insulin and dexamethasone on palmitoyl-CoA synthetase activity and its mRNA both in 7800 C1 hepatoma cells and cultured rat hepatocytes were studied. (1) When the hepatoma cells were cultivated in the presence of fatty acids or alkyl thioacetic acids (3-thia fatty acids) palmitoyl-CoA synthetase activity was increased several fold. The stronger effect was obtained with TTA, which also increased long-chain acyl-CoA synthetase mRNA significantly. TTA has no inducing effect on butyryl-CoA synthetase and little effect on octanoyl-CoA synthetase in the same cells. Dexamethasone also had inducing effect on palmitoyl-CoA synthetase in the hepatoma cells. Insulin counteracted the induction given by TTA. All of these regulation actions take place at the pretranslational level. (2) In isolated hepatocytes the activity of palmitoyl-CoA synthetase was much higher than in hepatoma cells, but it was lost rapidly in culture. The loss of the enzyme activity was slowed down in the presence of TTA and insulin, either alone or combined. Dexamethasone combined with TTA reversed the loss of enzyme activity, while dexamethasone alone even increased the loss. Analysis of palmitoyl-CoA synthetase mRNA shows that TTA prevents the loss of the enzyme activity by inducing mRNA of the enzyme, dexamethasone enhances the effect of TTA, while insulin stabilizes the enzyme activity in the cultured cells without increasing the mRNA level.

Animals↗
PubMed1993

Acylcarnitine formation and fatty acid oxidation in hepatocytes from rats treated with tetradecylthioacetic acid (a 3-thia fatty acid).

In livers of rats fed a single morning dose of 100 mg tetradecylthioacetic acid (TTA) total long-chain acyl-CoA increased significantly to 3 times control levels within 6 h, then the level declined almost to control value within the next morning. Hepatic malonyl-CoA was reduced 75% 6 h after TTA treatment. From 6 to 24 h malonyl-CoA increased about 10-fold to about 3 times that of controls. Paradoxically there was nearly a 2-fold higher oxidation of both [1-14C]palmitic acid (0.5 mM) and [1-14C]oleic acid (0.5 mM) in hepatocytes isolated from rats 24 h after TTA treatment compared to controls. After 6 h, when malonyl-CoA was at a minimum in vivo, fatty acid oxidation in cells was not increased. Acylcarnitine formation in digitonin permeabilized hepatocytes isolated 24 h after administration of TTA was increased both in the absence and in the presence of malonyl-CoA. At 24 h peroxisomal palmitoyl-CoA oxidase activity was not increased. The results suggest that an increased CPT activity and increased acylcarnitine formation in the presence of malonyl-CoA is a delayed response to increased acyl-CoA levels. Furthermore, in hepatocytes isolated after 24 h incorporation of [1-14C]oleic acid into triacylglycerols was significantly reduced. The data show that in hepatocytes isolated from rats 24 h after administration of a single dose of TTA, there is a diversion of hepatic acyl-CoA from synthesis of triacylglycerols into beta-oxidation in the mitochondria.

Acyl Coenzyme A↗
PubMed1992

The metabolism of tetradecylthiopropionic acid, a 4-thia stearic acid, in the rat. In vivo and in vitro studies.

The metabolism of [1-14C]tetradecylthiopropionic acid (TTP), a 4-thia stearic acid, and its sulphoxide, [1-14C]texadecylsulphoxypropionic acid (TTP-SO), has been studied in intact rats, in isolated rat hepatocytes, and in rat liver mitochondria. Two pathways of oxidation (beta-oxidation and omega-oxidation) have been demonstrated. TTP is incorporated, in vivo, into tissue triacylglycerol and phospholipids, it is oxidized to CO2, and it is excreted in urine, mainly as carboxypropylsulphoxypropionic acid and a little as carboxymethylsulphoxypropionic acid. TTP-SO is metabolized, in vivo, more rapidly to the same two omega-oxidation products. In hepatocytes TTP is incorporated into triacylglycerol and phospholipids even more rapidly than stearic acid. It is recovered mainly in the 1-position of phosphatidylcholine. Some is oxidized to CO2 and acid-soluble products. TTP-SO is mainly omega-oxidized to the same metabolites as are found in urine. A small fraction is incorporated into phospholipids or oxidized to CO2. In isolated mitochondria [1-14C]TTP is converted into 14CO2, radioactive malonic semialdehyde, and addition products of malonic semialdehyde. In the presence of phenylhydrazine, malonic semialdehyde phenylhydrazone is the dominating product. In soluble extracts of mitochondria [1-14C]malonic semialdehyde is oxidized directly to 14CO2 in the presence of CoA and NAD+, probably by the (methyl)malonic acid semialdehyde dehydrogenase (EC 1.2.1.27).

Animals↗
PubMed1990

The effect of adaptation on the metabolism of dodecylthioacetic acid (a 3-thia fatty acid) in rat tissues.

Dodecylthioacetic acid (DTA) was both omega-hydroxylated and sulfur-oxygenated at about equal rates by the microsomal fraction from liver and kidney. Feeding tetradecylthioacetic acid (TTA) for 4 days increased omega-hydroxylation 4-fold only in the liver. The sulfur oxygenation rate was similar in liver, kidney and lung, barely detectable in heart and absent in intestinal mucosa. In isolated hepatocytes from normal rats the major metabolite from dodecylthioacetic acid was carboxypropylsulfoxyacetic acid. In hepatocytes from adapted rats, the main product was identified as bis(carboxymethyl)sulfide. In kidney perfusion experiments dodecylthioacetic acid was metabolized to carboxypropyl-sulfoxyacetic acid and preferentially excreted in the urine. In hindquarter perfusion experiments no oxidative metabolites were detected. These experiments show that only liver and kidney can metabolize dodecylthioacetic acid completely and that omega-hydroxylation in the liver is the only inducible activity, in addition to the beta-oxidation.

Animals↗
PubMed1990

[Occupational health care, coordination with primary health care].

Occupational health care is a privately financed health service offered to the healthiest part of the population. It is not governed in the same way as primary health care. In this paper we conclude that the present model of organization is inadequate. The entire responsibility for organization of occupational health care should be placed with the Ministry of Health and Social Affairs. This will ensure efficient use of resources.

Cost Control↗
PubMed1989

The effects of alkylthioacetic acids (3-thia fatty acids) on fatty acid metabolism in isolated hepatocytes.

Long-chain alkylthioacetic acids (3-thia fatty acids) inhibit fatty acid synthesis from [1-14C]acetate in isolated hepatocytes, while fatty acid oxidation is nearly unaffected or even stimulated. Desaturation of [1-14C]stearate (delta 9-desaturase) is also unaffected. [1-14C]Dodecylthioacetic acid (a 3-thia fatty acid) is incorporated in triacylglycerol and in phospholipids more efficiently than [1-14C]palmitate in isolated hepatocytes. The metabolism of [1-14C]dodecylthioacetic acid to acid-soluble products (by omega-oxidation) is slow compared to the oxidation of [1-14C]palmitate. In hepatocytes from adapted rats (rats fed tetradecylthioacetic acid for 4 days) the rate of [1-14C]palmitate oxidation is increased and its rate of esterification is decreased. Stearate desaturation is also decreased. The rate of cyanide-insensitive peroxisomal fatty acid beta-oxidation is several-fold increased. The metabolic effects of long-chain 3-thia fatty acids are discussed and it is concluded that they behave essentially like normal fatty acids except for their slow breakdown due to the sulfur atom in the 3 position, which blocks normal beta-oxidation.

Acetates↗
PubMed1989

Thyrotropin-releasing hormone antagonism of ethanol inebriation.

The effect of ethanol [1 g/kg per orally (p.o.) during 1 hr] after thyrotropin-releasing hormone (TRH) pretreatment (five doses of 20 mg p.o. during 30 hr preceding ethanol intake) was studied in a placebo-controlled, double-blind design in 11 healthy subjects. Computerized reaction tests measuring errors and reaction time, as well as clinical testing and a self evaluation (modified Osgood test) were performed before, 75, 150, and 225 min after ethanol intake. TRH treatment did not influence blood ethanol concentrations. The effect of ethanol to produce errors was substantially reduced in all three reaction tests after TRH treatment compared to placebo treatment. The reaction times were slightly increased in simple and four choice reaction tests and up to 20% increased in a complex test in the TRH-ethanol situation compared to the placebo-ethanol situation. The effects caused by ethanol were also significantly reduced in three clinical tests and in two subjective tests of inebriation by TRH treatment compared to placebo treatment. In conclusion the study demonstrated that several acute effects of ethanol intake in humans were reduced by TRH pretreatment which did not interfere with the blood ethanol concentration versus time curve.

Adult↗
PubMed1988

Reduced C27-steroid 26-hydroxylase activity in heterozygotes for cerebrotendinous xanthomatosis.

C27-steroid 26-hydroxylase activity in fibroblasts from two heterozygotes for CTX was determined, using an optimized enzyme assay. With 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, 5 beta-cholestane-3 alpha,7 alpha-diol, 7 alpha-hydroxy-4-cholestane-3-one or 7 alpha-hydroxycholesterol as substrates, the activities were about 50% of those of control cells. The Km for the substrates was not increased in the CTX heterozygotes. These findings support that deficiency of the C27-steroid 26-hydroxylase is the primary enzymatic defect in CTX.

Adult↗