Biomedical subjects

A Aarsland

Publications and source records attributed to A Aarsland.

At least 19 recordsLinked to original sources

PubMed1998

Insulin therapy in burn patients does not contribute to hepatic triglyceride production.

Lipid kinetics were studied in six severely burned patients who were treated with a high dose of exogenous insulin plus glucose to promote protein metabolism. The patients were 20+/-2-yr-old (SD) with 63+/-8% total body surface area burned. They were studied in a randomized order (a) in the fed state on the seventh day of a control period (C) of continuous high-carbohydrate enteral feeding alone, and (b) on the seventh day of enteral feeding plus exogenous insulin (200 pmol/h = 28 U/h) with extra glucose given as needed to avoid hypoglycemia (I+G). Despite a glucose delivery rate approximately 100% in excess of energy requirements, the following lipid parameters were unchanged: (a) total hepatic VLDL triglyceride (TG) secretion rate (0.165+/-0.138 [C] vs. 0.154+/- 0.138 mmol/kg . d-1 [I+G]), (b) plasma TG concentration (1.58+/-0.66 [C] vs. 1. 36+/-0.41 mmol/liter [I+G]), and (c) plasma VLDL TG concentration (0. 68+/-0.79 [C] vs. 0.67+/- 0.63 mmol/liter [I+G]). Instead, the high-carbohydrate delivery in conjunction with insulin therapy increased the proportion of de novo-synthesized palmitate in VLDL TG from 13+/-5% (C) to 34+/-14% (I+G), with a corresponding decreased amount of palmitate from lipolysis. In association with the doubling of the secretion rate of de novo-synthesized fatty acid (FA) in VLDL TG during insulin therapy (P > 0.5), the relative amount of palmitate and stearate increased from 35+/-5 to 44+/-8% and 4+/-1 to 7+/-2%, respectively, in VLDL TG, while the relative concentration of oleate and linoleate decreased from 43+/-5 to 37+/-6% and 8+/-4% to 2+/-2%, respectively. A 15-fold increase in plasma insulin concentration did not change the rate of release of FA into plasma (8.22+/-2.86 [C] vs. 8.72+/-6.68 mmol/kg.d-1 [I+G]. The peripheral release of FA represents a far greater potential for hepatic lipid accumulation in burn patients than the endogenous hepatic fat synthesis, even during excessive carbohydrate intake in conjunction with insulin therapy.

Adolescent↗

PubMed1998

Hepatic secretion of VLDL fatty acids during stimulated lipogenesis in men.

Fatty acids (FA) that are utilized for triglyceride (TG) synthesis in the liver and principally from two sources: FA synthesized de novo in the liver and preformed FA. We have measured the contribution from the two sources to very low density lipoprotein (VLDL) TG synthesis individually for palmitate, oleate, stearate, and linoleate (approximately 98% of the total FA of VLDL TG (VLDL TGFA)) by isotopomer analysis. Five healthy men were studied in the basal state, and 1 (day 1) and 4 days (day 4) after the start of a hypercaloric carbohydrate-enriched diet (approximately 2.5 times energy expenditure). The secretion of de novo palmitate was increased 15- and 43-fold after 1 and 4 days of hyperalimentation (2.6+/-1.2 (basal state), 40.8+/-20.0 (day 1), and 113.3+/-42.0 micromol/kg per d (day 4)). Even though 4 days of hyperalimentation increased the secretion of de novo stearate 43-fold and de novo oleate 70-fold (stearate; 0.2+/-0.2 (basal), 8.6+/-3.3 micromol/kg per d (day 4), oleate; 0.4+/-0.4 (basal), 28.2+/-12.7 micromol/kg per d (day 4)), palmitate accounted for 75-85% of all the de novo VLDL TGFA. One day of carbohydrate hyperalimentation tended to decrease the secretion while 4 days increased the secretion of all preformed FA in VLDL TG. The rate of secretion of preformed palmitate and oleate were almost identical (palmitate; 80.2+/-22.2 (basal), 45.1+/-23.8 (day 1), and 256.2+/-74.1 micromol/kg per d (day 4), oleate; 95.2+/-22.8 (basal), 46.2+/-24.2 (day 1), and 356.8+/-74.1 micromol/kg per d (day 4)) and collectively these two FA accounted for 80-90% of the secretion from the preformed source. Palmitate is the predominant product of acute and prolonged carbohydrate mediated lipogenesis in the human liver. The pathway of further elongation and subsequent desaturation of de novo synthesized palmitate to generate stearate and oleate is inducible but, quantitatively, of minor significance in hepatic lipogenesis.

Dietary Carbohydrates↗

PubMed1997

Hepatic and whole-body fat synthesis in humans during carbohydrate overfeeding.

The magnitude of the capacity to convert carbohydrate to fat in the human body is still controversial, as is the extent to which it takes place in the liver as opposed to the adipose tissue. We calculated whole-body net fat synthesis from indirect calorimetry and substrate balance data from five healthy men in the basal state and after 1 and 4 d on a hyperenergetic carbohydrate diet (approximately 2.5 times energy expenditure). At the same time, the secretion of fatty acids synthesized in the liver was measured to determine the extent to which fat synthesis occurs in the liver in a lipogenic state. The respiratory exchange ratio (RER) was 0.81 +/- 0.01 in the basal state and 0.99 +/- 0.025 and 1.15 +/- 0.022 on days 1 and 4, respectively. Although there was net fat oxidation in the basal state (955 +/- 139 mg.kg-1.min-1), there was net fat synthesis at the whole-body level both during early (day 1; 481 +/- 205 mg.kg-1.min-1) and late (day 4; 2243 +/- 253 mg.kg-1.min-1) carbohydrate overfeeding. Although hepatic secretion of fat synthesized de novo increased approximately 35-fold during the study (basal state, 1.0 +/- 0.3; day 1, 13.8 +/- 6.8; and day 4, 43.3 +/- 16.3 mg.kg-1.min-1) this could only account for a small portion of total fat synthesis. We conclude that the liver plays a quantitatively minor role when surplus carbohydrate energy is converted into fat in the human body. The main site for fat synthesis is likely to be the adipose tissue.

Adult↗

PubMed1997

Mixed muscle protein synthesis and breakdown after resistance exercise in humans.

Mixed muscle protein fractional synthesis rate (FSR) and fractional breakdown rate (FBR) were examined after an isolated bout of either concentric or eccentric resistance exercise. Subjects were eight untrained volunteers (4 males, 4 females). Mixed muscle protein FSR and FBR were determined using primed constant infusions of [2H5]phenylalanine and 15N-phenylalanine, respectively. Subjects were studied in the fasted state on four occasions: at rest and 3, 24, and 48 h after a resistance exercise bout. Exercise was eight sets of eight concentric or eccentric repetitions at 80% of each subject's concentric 1 repetition maximum. There was no significant difference between contraction types for either FSR, FBR, or net balance (FSR minus FBR). Exercise resulted in significant increases above rest in muscle FSR at all times: 3 h = 112%, 24 h = 65%, 48 h = 34% (P < 0.01). Muscle FBR was also increased by exercise at 3 h (31%; P < 0.05) and 24 h (18%; P < 0.05) postexercise but returned to resting levels by 48 h. Muscle net balance was significantly increased after exercise at all time points [(in %/h) rest = -0.0573 +/- 0.003 (SE), 3 h = -0.0298 +/- 0.003, 24 h = -0.0413 +/- 0.004, and 48 h = -0.0440 +/- 0.005], and was significantly different from zero at all time points (P < 0.05). There was also a significant correlation between FSR and FBR (r = 0.88, P < 0.001). We conclude that exercise resulted in an increase in muscle net protein balance that persisted for up to 48 h after the exercise bout and was unrelated to the type of muscle contraction performed.

Adult↗

PubMed1996

Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man.

Triglycerides (TG) are synthesized in the liver principally from two sources of fatty acids (FA): FA synthesized de novo in the liver and preformed FA. We have measured the rate of secretion of de novo synthesized FA and total secretion of FA bound to VLDL-TG in healthy men (n = 5) in the basal state, and after 1 (day 1) and 4 d (day 4) of a hypercaloric carbohydrate diet (approximately 2.5 times energy expenditure) that generated a moderate endogenous hyperinsulinemia (plasma insulin approximately 60 microU/ml). Prolonged carbohydrate hyperalimentation/hyperinsulinemia increased plasma VLDL-TG approximately 10-fold in part due to a 3.4-fold increase in total VLDL-TG secretion rate (basal state = 72+/-23, day 4 = 242+/-78 micromol TG/kg/d). Although the secretion of de novo synthesized FA increased throughout the study (basal state = 1.1+/-0.4, day 1 = 15.9+/-7.9, day 4 = 50.0+/-18.8 micromol TG/ kg/d), the 2.7-fold increase in secretion rate of preformed FA (basal state = 70+/-23, day 4 = 191+/-57 micromol TG/kg/d) quantitatively contributed the most to total VLDL-TG secretion rate. Decreased catabolism of VLDL-TG also contributed to the hypertriglyceridemia as reflected by an approximately fourfold decrease in both fractional turnover rate (basal state = 9.2+/-3.8, day 1 = 2.1+/-0.2, day 4 = 2.1+/-0.3 pools/d) and rate of clearance (basal state = 0.35+/-0.08, day 1 = 0.11+/-0.01, day 4 = 0.09+/-0.01 liter/kg/d) of VLDL-TG. Thus, the primary difference between 1 and 4 d of hyperinsulinemia in conjunction with carbohydrate hyperalimentation is the increase in hepatic secretion of preformed FA into VLDL-TG.

Adult↗

PubMed1996

Beta-blockade lowers peripheral lipolysis in burn patients receiving growth hormone. Rate of hepatic very low density lipoprotein triglyceride secretion remains unchanged.

OBJECTIVE: The purpose of this study was to determine the effect of propranolol on peripheral lipolysis in massively burned children during treatment with recombinant human growth hormone (rhGH), and to ascertain whether decreased free fatty acid availability for re-esterification would alter the hepatic rate of secretion of triglycerides (TGs) bound to very low density lipoproteins (VLDLs). BACKGROUND: Fatty liver occurs in severely burned patients, often resulting in a twofold increase in liver size. This could be the result of an imbalance between increased provision of free fatty acids from peripheral lipolysis, coupled with no increase in fat oxidation, and insufficient rate of secretion of TGs from the liver. METHODS: In a cross-over study, six burned children were treated with either rhGH or rhGH plus propranolol. On the sixth day of treatment, isotopic tracer infusions were conducted to determine the rate of release of free fatty acid (Ra FFA) from peripheral tissue and the rate of secretion of VLDL-bound TGs by the liver. RESULTS: Exogenous rhGH increased Ra FFA in children with large third-degree burns. Propranolol decreased Ra FFA, but the rate of secretion of fatty acids in the form of VLDL-TG from the liver was maintained. Plasma FFA, as opposed to fatty acids newly synthesized in the liver, were the primary precursors for hepatic triglyceride synthesis. CONCLUSIONS: The administration of propranolol to burned children receiving rhGH is safe, has salutary cardiovascular effects, decreases the release of FFA from adipose tissue and increases the efficiency of the liver in secreting fatty acids as VLDL TGs.

Adolescent↗

PubMed1996

Comparison of mass isotopomer dilution methods used to compute VLDL production in vivo.

The recent development of mass isotopomer distribution methods represents an important new tool for quantifying synthetic rates. These methods allow precursor enrichment to be determined indirectly from the enrichment of the product, thus sidestepping the often difficult problem of measuring the precursor enrichment. Two different methods have been described to compute synthetic rates by this general approach in the laboratories of M. K. Hellerstein and J. K. Kelleher, and variations of these basic approaches have also been presented by W. N. Lee and by ourselves. A comparison between the different methods has never been reported. In this paper, we take a specific application, calculation of the fractional rate of incorporation of acetyl-CoA into very low density lipoprotein-bound palmitate, and compare the results obtained from all of the mass isotopomer methods using the same data set obtained in vivo in human subjects. We found that it is critical that the measured background isotopomer distribution of palmitate is used rather than the theoretical background isotopomer distribution. We also found that the different methods give comparable precursor enrichments and comparable fractional synthesis rates, provided that the enrichments in Kelleher's method are properly weighted. Thus the choice of method to use is a matter of personal preference.

Humans↗

PubMed1995

Stimulation of muscle protein synthesis by long-term insulin infusion in severely burned patients.

OBJECTIVE: To determine if long-term (7 days) infusion of insulin can ameliorate altered protein kinetics in skeletal muscle of severely burned patients and to investigate the hypothesis that changes in protein kinetics during insulin infusion are associated with an increased rate of transmembrane amino acid transport from plasma into the intracellular free amino acid pool. SUMMARY BACKGROUND DATA: In critically ill patients, vigorous nutritional support alone may often fail to entirely curtail muscle catabolism; insulin stimulates muscle protein synthesis in normal volunteers. METHODS: Nine patients with severe burns were studied once during enteral feeding alone (control period), and once after 7 days of high-dose insulin. The order of treatment with insulin was randomized. Data were derived from a model based on a primed-continuous infusion of L-[15N]phenylalanine, sampling of blood from the femoral artery and vein, and biopsies of the vastus lateralis muscle. RESULTS: Net leg muscle protein balance was significantly (p < 0.05) negative during the control period. Exogenous insulin eliminated this negative balance by stimulating protein synthesis approximately 350% (p < 0.01). This was made possible in part by a sixfold increase in the inward transport of amino acids from blood (p < 0.01). There was also a significant increase in leg muscle protein breakdown. The new rates of synthesis, breakdown, and inward transport during insulin were in balance, such that there was no difference in the intracellular phenylalanine concentration from the control period. The fractional synthetic rate of protein in the wound was also stimulated by insulin by approximately 50%, but the response was variable and did not reach significance. CONCLUSIONS: Exogenous insulin may be useful in promoting muscle protein synthesis in severely catabolic patients.

Adolescent↗

PubMed1993

Redox status and protein binding of plasma homocysteine and other aminothiols in patients with homocystinuria.

Elevations of homocyst(e)ine levels in the blood of patients with homocystinuria may explain the high cardiovascular morbidity. We determined levels of reduced, oxidized, and protein-bound homocyst(e)ine, cyst(e)ine, and cyst(e)inylglycine in plasma from eight patients with homocystinuria. The technique used involved trapping of reduced thiols by collecting blood directly into tubes containing sulfhydryl-reactive reagents. All patients had high levels of homocysteine (range, 1.9 to 91.2 mumol/L), and among the aminothiols investigated, this species showed the most drastic elevation compared with trace levels (< 0.4 mumol/L) found in healthy subjects. The ratio between free homocysteine and total homocyst(e)ine (reduced to total ratio) was above normal and positively correlated to the reduced to total ratio for cyst(e)ine, suggesting that an equilibrium exists between these species through sulfhydryl disulfide exchange. The other homocyst(e)ine species (oxidized and protein-bound) were also markedly increased in patients with homocystinuria. Plasma cysteine and cysteinylglycine levels were moderately increased, whereas plasma concentrations of protein-bound cyst(e)ine, protein-bound cyst(e)inylglycine, and free cystine were below normal. Homocysteine in particular and other homocyst(e)ine species are markedly increased in plasma of homocystinurics, and these changes are associated with pronounced alterations in the level and the redox status of other aminothiols. This should be taken into account when considering homocyst(e)ine as an atherogenic agent, and the role of various homocyst(e)ine species in the pathogenesis of homocystinuria.

Adolescent↗

PubMed1991

Peroxisome proliferating sulphur- and oxy-substituted fatty acid analogues are activated to acyl coenzyme A thioesters.

In liver homogenates from untreated rats the sulphur-substituted fatty acid analogues tetradecylthioacetic acid (CMTTD) was activated to its acyl-coenzyme A thioester. The activation was found to take place in the mitochondrial, microsomal and peroxisomal fractions. The activity of CMTTD-CoA synthetase was 50% compared to palmitoyl-CoA synthetase in all cellular fractions. When rats were treated with the peroxisome proliferating sulphur-substituted fatty acid analogues CMTTD and 3-dithiahexadecanedioic acid (BCMTD), the CMTTD-CoA synthetase activity was induced in mitochondrial, peroxisomal and microsomal fractions. Palmitoyl-CoA synthetase was induced proportionally. In rats treated with tetradecylthiopropionic acid (CETTD) of low peroxisome proliferating potency, the activities of CMTTD-CoA synthetase and palmitoyl-CoA synthetase were inhibited in mitochondrial and microsomal fractions. In contrast, all three sulphur-substituted acids induced the activity of palmitoyl-CoA synthetase and CMTTD-CoA synthetase in peroxisomes. Both the CMTTD-CoA and palmitoyl-CoA synthetase activities were induced by CMTTD and BCMTD, in close correlation to the induction of peroxisomal beta-oxidation. During the three treatment regimes, CMTTD-CoA synthetase activity ran parallel to the palmitoyl-CoA synthetase activity at a rate of 50% in all cellular fractions. Thus, CMTTD is assumed to be activated by the long-chain acyl-CoA synthetase enzyme. Rats were treated for 5 days with sulphur- and oxy-substituted fatty acid analogues, clofibric acid and fenofibric acid. All compounds which induced peroxisomal beta-oxidation activity in vivo could be activated to their respective CoA thioesters in liver homogenate. CETTD which induced peroxisomal beta-oxidation only two-fold, was activated at a rate of 50% compared to palmitate. Fenofibric acid induced peroxisomal beta-oxidation 9.6-fold, while it was activated at a rate of only 10% compared to palmitate. Thus, no correlation was found between rate of activation in vitro and induction of peroxisomal activity in vivo. On the other hand, tetradecylsulfoxyacetic acid (TSOA) and tetradecylsulfonacetic acid (TSA) (sulphuroxygenated metabolites of CMTTD) with no inductive effects, were not activated to their respective CoA derivatives. Altogether the data suggest that the enzymatic activation of the peroxisome proliferating compounds is essential for their proliferating activity, but the rate of activation does not determine the potency of the proliferators. The role of the xenobiotic-CoA pool in relation to the whole coenzyme A profile during peroxisome proliferation is discussed.

Animals↗

PubMed1990

Effects of thia-substituted fatty acids on mitochondrial and peroxisomal beta-oxidation. Studies in vivo and in vitro.

1. The effects of 3-, 4- and 5-thia-substituted fatty acids on mitochondrial and peroxisomal beta-oxidation have been investigated. When the sulphur atom is in the 4-position, the resulting thia-substituted fatty acid becomes a powerful inhibitor of beta-oxidation. 2. This inhibition cannot be explained in terms of simple competitive inhibition, a phenomenon which characterizes the inhibitory effects of 3- and 5-thia-substituted fatty acids. The inhibitory sites for 4-thia-substituted fatty acids are most likely to be the acyl-CoA dehydrogenase in mitochondria and the acyl-CoA oxidase in peroxisomes. 3. The inhibitory effect of 4-thia-substituted fatty acids is expressed both in vitro and in vivo. The effect in vitro is instantaneous, with up to 95% inhibition of palmitoylcarnitine oxidation. The effect in vivo, in contrast, is dose-dependent and increases with duration of treatment. 4. Pretreatment of rats with a 3-thia-substituted fatty acid rendered mitochondrial beta-oxidation less sensitive to inhibition by 4-thia-substituted fatty acids.

Animals↗

PubMed1990

Fatty acid metabolism in liver of rats treated with hypolipidemic sulphur-substituted fatty acid analogues.

The purpose of this study was to investigate early biochemical changes and possible mechanisms via which alkyl(C12)thioacetic acid (CMTTD, blocked for beta-oxidation), alkyl(C12)thiopropionic acid (CETTD, undergo one cycle of beta-oxidation) and a 3-thiadicarboxylic acid (BCMTD, blocked for both omega- (and beta-oxidation) influence the peroxisomal beta-oxidation in liver of rats. Treatment of rats with CMTTD caused a stimulation of the palmitoyl-CoA synthetase activity accompanied with increased concentration of hepatic acid-insoluble CoA. This effect was already established during 12-24 h of feeding. From 2 days of feeding, the cellular level of acid-insoluble CoA began to decrease, whereas free CoASH content increased. Stimulation of [1-14C]palmitoyl-CoA oxidation in the presence of KCN, palmitoyl-CoA-dependent dehydrogenase (termed peroxisomal beta-oxidation) and palmitoyl-CoA hydrolase activities were revealed after 36-48 h of CMTTD-feeding. Administration of BCMTD affected the enzymatic activities and altered the distribution of CoA between acid-insoluble and free forms comparable to what was observed in CMTTD-treated rats. It is evident that treatment of peroxisome proliferators (BCMTD and CMTTD), the level of acyl-CoA esters and the enzyme activity involved in their formation precede the increase in peroxisomal and palmitoyl-CoA hydrolase activities. In CMTTD-fed animals the activity of cyanide-insensitive fatty acid oxidation remained unchanged when the mitochondrial beta-oxidation and carnitine palmitoyltransferase operated at maximum rates. The sequence and redistribution of CoA and enzyme changes were interpreted as support for the hypothesis that substrate supply is an important factor in the regulation of peroxisomal fatty acid metabolism, i.e., the fatty acyl-CoA species appear to be catabolized by peroxisomes at high rates only when uptake into mitochondria is saturated. Administration of CETTD led to an inhibition of mitochondrial fatty acid oxidation accompanied with a rise in the concentration of acyl-CoA esters in the liver. Consequently, fatty liver developed. The peroxisomal beta-oxidation was marginally affected. Whether inhibition of mitochondrial beta-oxidation may be involved in regulation of peroxisomal fatty acid metabolism and in development of fatty liver should be considered.

Animals↗

PubMed1990

The hypolipidemic peroxisome-proliferating drug, bis(carboxymethylthio)-1.10 decane, a dicarboxylic metabolite of tiadenol, is activated to an acylcoenzyme A thioester.

Bis(carboxymethylthio)-1.10 decane (BCMTD), a thiodicarboxylic acid, was shown to be a hypolipidemic peroxisome-proliferating drug as it: (a) decreased the total serum triacylglycerols and cholesterol; (b) induced hepatomegaly; (c) increased the peroxisomal beta-oxidation and catalase activity and the activities of the multiorganelle localized enzymes: palmitoyl-CoA synthetase, palmitoyl-CoA hydrolase, glycerophosphate acyltransferase; (d) decreased the carnitine palmitoyltransferase and urate oxidase activities; and (e) induced the bifunctional eonyl-CoA hydratase in peroxisomes. The present study has confirmed the effect of tiadenol administration on the activities of key enzymes involved in hepatic fatty acid metabolism in male rats. However, the hepatic pleiotropic response was more marked with the dicarboxylic acid than with its alcohol. In a separate dose-response study BCMTD was found to be a more potent inducer of peroxisomal beta-oxidation compared to tiadenol. BCMTD can be activated in vitro to its coenzyme A thioester by a dicarboxyl-CoA synthetase. In control and BCMTD-treated animals, the synthetase activity was found in all cellular fractions except the cytosolic. Whether the acyl-CoA thioesters of peroxisome-proliferating drugs may be mediators of peroxisomal proliferation should be considered.

Acyl Coenzyme A↗

PubMed1990

Effects of the tumor promoter 12-O-tetradecanoylphorbol 13-acetate on peroxisomal activities and enzyme activities involved in lipid metabolism in rat liver.

The effects of 12-O-tetradecanoylphorbol 13-acetate (TPA) on hepatic lipids and key enzymes involved in esterification, hydrolysis and oxidation of long-chain fatty acids at increasing doses were investigated in rats. TPA administration tended to decrease the mitochondrial activities of palmitoyl-CoA synthetase and carnitine palmitoyltransferase. The microsomal palmitoyl-CoA synthetase activity was increased. TPA administration was also associated with a dose-dependent increase of glycerophosphate acyltransferase activity both in the mitochondrial and microsomal fractions in particular. The data are consistent with a decreased catabolism of long-chain fatty acids at the mitochondrial level, and an increased capacity for esterification of fatty acids in the microsomal fraction. Peroxisomal beta-oxidation was increased about 2-fold in the peroxisome-enriched fraction of TPA-treated rats while the catalase and urate oxidase activities were only marginally affected. TPA administration revealed elevated capacity for hydrolysis of palmitoyl-CoA and palmitoyl-L-carnitine in the microsomal fraction. Neither increased cytosolic palmitoyl-CoA hydrolase activity nor increased hydroxylation of lauric acid nor changes of the hepatic content of cytochrome P-450 isoenzymic forms were observed in the TPA-treated animals. There was no induction of the protein content of the bifunctional enoyl-CoA hydratase. Thus, TPA behaves more like choline-deficient diet and ethionine treatment than well-known peroxisome proliferators. It seems possible that TPA selectively stimulated the peroxisomal activities, i.e., peroxisomal beta-oxidation rather than evoking a peroxisome proliferation capacity.

Animals↗

PubMed1990

On the effect of peroxisomal beta-oxidation and carnitine palmitoyltransferase activity by eicosapentaenoic acid in liver and heart from rats.

Repeated administration of highly purified eicosapentaenoic acid (as ethyl ester) resulted in a decrease in plasma triglycerides and high density lipoprotein (HDL) cholesterol. This was accompanied by a stimulation in the activities of carnitine palmitoyltransferase, fatty acyl-CoA oxidase and peroxisomal beta-oxidation in the liver. The results suggest that the triglyceride-lowering effect observed with eicosapentaenoic acid may be due to a reduced supply of fatty acids for hepatic triglyceride synthesis because of increased fatty acid oxidation. Eicosapentaenoic acid feeding marginally affected the triglyceride content of heart and mitochondrial and peroxisomal enzyme activities.

Animals↗

PubMed1990

Morphologic effects of sulfur-substituted fatty acids on rat hepatocytes with special reference to proliferation of peroxisomes and mitochondria.

The morphologic effects of different sulfur-substituted mono- and dicarboxylic fatty acids on rat hepatocytes have been examined. The substance 1,10-biscarboxymethylthiodecane (BCMTD) is blocked for both beta- and omega-oxidation, whereas 1-monocarboxymethylthiodecane (CMTTD) is only non-beta-oxidizable. At equimolar doses BCMTD was considerably more potent than CMTTD in hypertrophic liver enlargement. At the ultrastructural level, BCMTD increased the volume fraction of the peroxisomes by a factor of 8, and their size and number by factors of 2.1 and 6.4, respectively. Furthermore, the frequency of dense cores in the peroxisomes decreased from 60 to 8%. CMTTD resulted in an increased volume fraction of peroxisomes (4.5-fold), in the mean volume (1.9-fold), and in the number of peroxisomes (3.7-fold). At the mitochondrial level, a gradual development toward megamitochondria was observed after CMTTD administration. BCMTD, however, increased the number of mitochondria but they tended to be smaller. Administration of both acids increased peroxisomal beta-oxidation and mitochondrial carnitine palmitoyltransferase activity, whereas the lipid content of hepatocytes was reduced with increasing doses of CMTTD and especially BCMTD. The acid 1-mono(carboxyethylthio)tetradecane (CETTD), which is able to undergo one cycle of beta-oxidation, caused no change in liver weight, and only marginal effects on peroxisomes and mitochondria were observed. In contrast to the BCMTD and CMTTD feeding, the animals developed a tremendous accumulation of fat in the livers: the volume fraction of lipid droplets increased 23-fold after CETTD feeding.

Animals↗

PubMed1989

Alkylthio acetic acids (3-thia fatty acids)--a new group of non-beta-oxidizable peroxisome-inducing fatty acid analogues--II. Dose-response studies on hepatic peroxisomal- and mitochondrial changes and long-chain fatty acid metabolizing enzymes in rats.

The activity of key enzymes involved in oxidation and esterification of long-chain fatty acids was investigated after male Wistar rats were treated with different doses of sulfur substituted fatty acid analogues, 1,10-bis(carboxymethylthiodecane) (BCMTD, non-beta-oxidizable and non-omega-oxidizable), 1-mono(carboxymethylthiotetradecane) (CMTTD, trivial name, alkylthio acetic acid, non-beta-oxidizable) and 1-mono(carboxyethylthiotetradecane) (CETTD trivial name, alkylthio propionic acid, beta-oxidizable). The sulfur substituted dicarboxylic acid and the alkylthio acetic acid induced in a dose-dependent manner the mitochondrial, microsomal and especially the peroxisomal palmitoyl-CoA synthetase activity, the mitochondrial and cytosolic palmitoyl-CoA hydrolase activity, the mitochondrial and especially the microsomal glycerophosphate acyltransferase activity and the peroxisomal beta-oxidation, especially revealed in the microsomal fraction. Morphometric analysis of randomly selected hepatocytes revealed that BCMTD and CMTTD treatment increased the number, size and volume fraction of peroxisomes and mitochondria. Thus, the observed changes in the specific activity of fatty acid metabolizing enzymes with multiple subcellular localization can partly be explained as an effect of changes in the s-values of the organelles as proliferation of mitochondria and peroxisomes occurred. The most striking effect of the alkylthio propionic acid was the formation of numerous fat droplets in the liver cells and enhancement of the hepatic triglyceride level. This was in contrast to BCMTD treatment which decreased the hepatic triglyceride content. In conclusion, the results provide evidence that administration of non-beta-oxidizable fatty acid analogues had much higher in vivo potency in inducing hepatomegaly and key enzymes involved in fatty acid metabolism, including proliferation of peroxisomes and mitochondria than is exhibited in the beta-oxidizable, alkylthio propionic acid. Moreover, the dicarboxylic acid was apparently three to six times more potent than the alkylthio acetic acid in inducing peroxisomal beta-oxidation and peroxisome proliferation when considered on a mumol/day basis. As palmitic acid and hexadecanedioic acid only marginally affected these hepatic responses, it is conceivable that the potency of the selected compounds as proliferators of peroxisomes and inducers of the associated enzymes depends on their accessibility for beta-oxidation.

Acetates↗

PubMed1989

Alkylthioacetic acid (3-thia fatty acids)--a new group of non-beta-oxidizable, peroxisome-inducing fatty acid analogues. I. A study on the structural requirements for proliferation of peroxisomes and mitochondria in rat liver.

The induction of peroxisome proliferation was examined in rat liver after administration of equal concentrations (1 mmol/kg body weight) of 1,10-bis(carboxymethylthiodecane) (BCMTD), 1-mono(carboxymethylthiotetradecane) (CMTTD), 1-mono(carboxymethylthiooctane) (CMTO), 1-mono(carboxyethylthiotetradecane) (CETTD), palmitic acid and hexadecanedioic acid (HDDA). BCMTD, a non-beta-oxidizable and non-omega-oxidizable sulphur-substituted fatty acid analogue was considerably more potent than CMTTD (only non-beta-oxidizable) in inducing enlargement of the liver and increasing peroxisomal activities (monitored by peroxisomal beta-oxidation, palmitoyl-CoA hydrolase and catalase activities). Morphometric analysis of randomly selected hepatocytes revealed that BCMTD and CMTTD treatment increased the number and size of peroxisomes and the relative volume fraction of the peroxisomes. All these cellular responses were more marked with BCMTD than compared with CMTTD. CMTO, a non-beta-oxidizable fatty acid analogue containing a lower hydrophobic alkyl-end than CMTTD and CETTD (a beta-oxidizable fatty acid analogue), showed a slight increase (1.4-1.8-fold) of peroxisomal beta-oxidation and caused marginally morphological changes of peroxisomes compared with CMTTD and BCMTD. The most striking effect of the alkylthiopropionic acid (CETTD) was an enhancement of the hepatic triacylglycerol level. Palmitic acid and hexadecanedioic acid only marginally affected the peroxisomal activities, but no morphological changes of peroxisomes and fat droplets were observed. The presented data strongly suggest that a minimal structural requirement for a peroxisome proliferator may be (1) a carboxylic acid group linked to (2) a hydrophobic backbone which (3) cannot be beta-oxidized i.e., the fatty acid analogues have a sulphur atom in the beta-position. It is also conceivable that blockage for omega-oxidation may potentiate the peroxisome-proliferating activities in as much as BCMTD was more potent than CMTTD. Two mitochondrial marker enzymes, carnitine palmitoyltransferase and succinate phenazine methosulphate oxidoreductase were differently affected after administration of the investigated compounds. Furthermore, BCMTD and CMTTD as well as HDDA treatments increased the number of mitochondria, but the mitochondria tended to be smaller. The overall results presented here indicate that the structural requirements for proliferation of mitochondria are not identical to those for proliferation of peroxisomes.

Animals↗