Administration of the fatty acid analogue tetradecylthioacetic acid (TTA) to rodents up-regulates... more Administration of the fatty acid analogue tetradecylthioacetic acid (TTA) to rodents up-regulates peroxisomal and mitochondrial lipid-metabolizing enzymes and induces a proliferation of these organelles in hepatocytes. We show here that male NMRI mice fed a diet containing 0.3% (w/w) TTA revealed a transient two-fold increase in the incorporation of [ 3 H]thymidine into the liver mtDNA followed by a 1.6-fold increase in the content of mtDNA. In addition, a transient three-fold increase in the mitochondrial thymidine kinase (TK2) activity and a slight increase in the DNA polymerase°a ctivity was observed, indicating that the TTA induced mitochondrial proliferation is linked to an up-regulation of the mitochondrial thymidine kinase activity. IUBMB Life, 51: 99 -104, 2001
The present study has confirmed previous findings of long-chain acyl-CoA hydrolase activities in ... more The present study has confirmed previous findings of long-chain acyl-CoA hydrolase activities in the mitochondrial and microsomal fractions of the normal rat liver.
The mechanisms behind the hypolipidemic effect of two sulfur-substituted fatty acid analogues, 3-... more The mechanisms behind the hypolipidemic effect of two sulfur-substituted fatty acid analogues, 3-thiadicarboxylic acid and tetradecylthioacetic acid, have been investigated in cultured hepatocytes. There was a dose-dependent reduction in incorporation of [3H] water into triacylglycerol and diacylglycerol when tetradecylthioacetic acid was added to rat hepatocytes cultured in the presence of 200 muM oleic acid. Tetradecylthioacetic acid also increased the oxidation of [14C]palmitic acid compared to oleic acid, inhibited the incorporation of radiolabeled precursors into diacylglycerol to a greater extent than into triacylglycerol, and reduced the secretion of triacylglycerol more than its synthesis. A stimulation, rather than a reduction, in glycerolipid synthesis and secretion by oxidation of fatty acids and reduces the synthesis and secretion of glycerolipids. 3-Thiadicarboxylic acid reduces the synthesis and secretion of both glycerolipids and cholesterol to approximately the same extent without a concomitant increase in the oxidation of fatty acids.
Recent work brings evidence about changes of the cell-mediated immumty (CMI) in tumorous diseases... more Recent work brings evidence about changes of the cell-mediated immumty (CMI) in tumorous diseases. It is supposed that ability of leucocytes adherence is one feature of tile CMI. For over 10 years we have been momtormg m vitro tile abahty of adherence of T lymphocytes (Ly)-acquired from blood of patients with ENT cancer -to a glass surface m dependence on presence or non-presence of antigen (Leukocyte Adherence Inhibition test -LAI assay). Both non-specific antigens and specafic antigens taken from a tumorous cells (oral and pharyngeal cancer) are used as antagens. In recent years we follow changes of tile ability of Ly adherence under tile influence of electromagnetic silmsoldal field (ESF). Materials and Methods: Ly were acquired by separation from blood of the patients wath oral and pharyngeal carcinoma. Specific antagen was prepared from a tumorous cell of ENT cancer. We momtored the abalaty of Ly adherence of sack people to tile glass surface m dependence on presence of antigen. At the same tilne, identical momtormg was carried out m Ly acquired from blood donors (check group). We repeated the traal m the presence of ESE Between 2002 and 2003, we checked m the same way the samples taken from 76 pataents wath ENT cancer. The pataents were checked before the therapy was introduced. Another 76 blood samples were acquired from the check group. The results we got were assessed by t-test for 2 dependent selectaons. Results: Nmnber of non-adherent Ly (NAT) as significantly lower without the exposataon to the ESF Ila colnparason wath the exposition to the ESF (level of sagnaficance p 0.0001). The NAT Ill a check group are slgmficantly lower m comparison Wltil the treated group, both without tile exposition and after the exposition. Even ill Ly acquired from healtily donors, tile NAT after the exposition to the ESF are lower. Conelusion: ESF lowers the NAT both m Ly of the patients with ENT cmacer, mad m Ly taken from volmatary blood donors. The difference of NAT Ill tile group of sick patients before exposition and following tile exposition is statistically important at tile chosen level of p=0.0001. If tile ablhty of Ly adherence is a demonstration of a CMI, then we may say that ESF influences the CMI both m patients with oral mad pharyngeal cancer, and healthy people.
In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (CI3-Sacetic aci... more In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (CI3-Sacetic acid) and tetradecylthioacetic acid (C,,-Sacetic acid), increase the mRNA levels of Agdesaturase both in a time-and dose-dependent manner. The increased A'-desaturase mRNA levels were accompanied by increased A'-desaturase activity and increased amounts of oleic acid (18: 1 n-9) and A'desaturated C14-Sacetic acid, A'-Desaturated C14-Sacetic acid was only detected in phospholipid and cholesterolester species after C,,-Sacetic acid treatment. In contrast, C,,-Sacetic acid was detected in all the different hepatic lipid fractions, but mainly in the phospholipids. Moreover, CIS-Sacetic acid and ClrSacetic acid were detected in both liver and very low density lipoprotein (VLDL). No A'desaturated 3-thia fatty acid products, however, were found in VLDL. Administration of mono-and dicarboxylic 3thia fatty acids to rats induced liver expression of the fatty acylCoA oxidase gene. After 1 week of C14-Sacetic acid treatment, the levels of fatty acyl-CoA oxidase mRNA increased !%fold, whereas the A'-desaturase mRNA was increased about 1.8-fold. Both fatty acyl-CoA oxidase and A9-desaturase mRNA increased about 8-fold after 12 weeks of treatment with C14-Sacetic a c i d . l In conclusion, this study demonstrates that C,,-Sacetic acid increases rat A'-desaturase gene expression and activity and that changes in hepatic lipids, e.g., 18:l n-9, are re-
We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations ... more We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations and monocytes in patients with human immunodeficiency virus type 1 (HIV-1) infection and in healthy controls. CD4+ lymphocytes from HIV-l-infected patients were primarily characterized by a substantial increase in oxidized glutathione levels and a considerable decrease in the ratio of reduced to total glutathione, in most cases below 0.5 in patients with symptomatic HIV-1 infection, rather than decreased levels of reduced glutathione. The increase in oxidized glutathione was strongly correlated with low numbers of CD4' lymphocytes in peripheral blood and impaired stimulated interieukin-2 production and proliferation in peripheral blood mononuclear cells, which is compatible with an immunopathogenic role for these redox disturbances. The HIV-1 -infected patients with I
To find out whether oxygen free radical liberated by activation of xanthine oxidase change the ti... more To find out whether oxygen free radical liberated by activation of xanthine oxidase change the tissue concentration of glutathione. Controlled study. 42 male Wistar rats. Laparotomy, induction of ischemia, and reperfusion. 27 rats were treated with allopurinol (to inhibit xanthine oxidase) and the remaining 15 acted as controls. Concentrations of reduced glutathione, oxidized glutathione, and total glutathione in hepatocytes, blood, and bile. Concentration of reduced and total glutathione in hepatocytes decreased significantly during reperfusion and oxidized glutathione was unchanged in all groups. Total glutathione in peripheral venous blood was reduced by half during the period of ischemia and increased gradually during reperfusion whereas the concentration of total glutathione in bile decreased appreciable during reperfusion. Production of bile improved significantly during reperfusion in the group treated with allopurinol compared with the control group. Xanthine oxidase may not be the main source of production of oxygen free radicals as allopurinol did not affect the hepatic concentration of glutathione during reperfusion.
Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lower... more Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC's content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis.
Marine food is an important source of omega-3 fatty acids with beneficial health effects. Oils fr... more Marine food is an important source of omega-3 fatty acids with beneficial health effects. Oils from marine organisms have different fatty acid composition and differ in their molecular composition. Fish oil (FO) has a high content of eicosapentaenoic and docosahexaenoic acids mainly esterified to triacylglycerols, while in krill oil (KO) these fatty acids are mainly esterified to phospholipids. The aim was to study the effects of these oils on the lipid content and fatty acid distribution in the various lipid classes in liver and brain of mice. Mice were fed either a high-fat diet (HF), a HF diet supplemented with FO or with KO (n = 6). After six weeks of feeding, liver and brain lipid extracts were analysed using a shotgun and TAG lipidomics approach. Student t-test was performed after log-transformation to compare differences between study groups. Six weeks of feeding resulted in significant changes in the relative abundance of many lipid classes compared to control mice. In both FO and KO fed mice, the triacylglycerol content in the liver was more than doubled. The fatty acid distribution was affected by the oils in both liver and brain with a decrease in the abundance of 18:2 and 20:4, and an increase in 20:5 and 22:6 in both study groups. 18:2 decreased in all lipid classes in the FO group but with only minor changes in the KO group. Differences between the feeding groups were particularly evident in some of the minor lipid classes that are associated with inflammation and insulin resistance. Ceramides and diacylglycerols were decreased and cholesteryl esters increased in the liver of the KO group, while plasmalogens were decreased in the FO group. In the brain, diacylglycerols were decreased, more by KO than FO, while ceramides and lactosylceramides were increased, more by FO than KO. The changes in the hepatic sphingolipids and 20:4 fatty acid levels were greater in the KO compared to the FO fed mice, and are consistent with a hypothesis that krill oil will have a stronger anti-inflammatory action and enhances insulin sensitivity more potently than fish oil.
The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), ... more The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S-methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP.
Administration of the fatty acid analogue tetradecylthioacetic acid (TTA) to rodents up-regulates... more Administration of the fatty acid analogue tetradecylthioacetic acid (TTA) to rodents up-regulates peroxisomal and mitochondrial lipid-metabolizing enzymes and induces a proliferation of these organelles in hepatocytes. We show here that male NMRI mice fed a diet containing 0.3% (w/w) TTA revealed a transient two-fold increase in the incorporation of [ 3 H]thymidine into the liver mtDNA followed by a 1.6-fold increase in the content of mtDNA. In addition, a transient three-fold increase in the mitochondrial thymidine kinase (TK2) activity and a slight increase in the DNA polymerase°a ctivity was observed, indicating that the TTA induced mitochondrial proliferation is linked to an up-regulation of the mitochondrial thymidine kinase activity. IUBMB Life, 51: 99 -104, 2001
The present study has confirmed previous findings of long-chain acyl-CoA hydrolase activities in ... more The present study has confirmed previous findings of long-chain acyl-CoA hydrolase activities in the mitochondrial and microsomal fractions of the normal rat liver.
The mechanisms behind the hypolipidemic effect of two sulfur-substituted fatty acid analogues, 3-... more The mechanisms behind the hypolipidemic effect of two sulfur-substituted fatty acid analogues, 3-thiadicarboxylic acid and tetradecylthioacetic acid, have been investigated in cultured hepatocytes. There was a dose-dependent reduction in incorporation of [3H] water into triacylglycerol and diacylglycerol when tetradecylthioacetic acid was added to rat hepatocytes cultured in the presence of 200 muM oleic acid. Tetradecylthioacetic acid also increased the oxidation of [14C]palmitic acid compared to oleic acid, inhibited the incorporation of radiolabeled precursors into diacylglycerol to a greater extent than into triacylglycerol, and reduced the secretion of triacylglycerol more than its synthesis. A stimulation, rather than a reduction, in glycerolipid synthesis and secretion by oxidation of fatty acids and reduces the synthesis and secretion of glycerolipids. 3-Thiadicarboxylic acid reduces the synthesis and secretion of both glycerolipids and cholesterol to approximately the same extent without a concomitant increase in the oxidation of fatty acids.
Recent work brings evidence about changes of the cell-mediated immumty (CMI) in tumorous diseases... more Recent work brings evidence about changes of the cell-mediated immumty (CMI) in tumorous diseases. It is supposed that ability of leucocytes adherence is one feature of tile CMI. For over 10 years we have been momtormg m vitro tile abahty of adherence of T lymphocytes (Ly)-acquired from blood of patients with ENT cancer -to a glass surface m dependence on presence or non-presence of antigen (Leukocyte Adherence Inhibition test -LAI assay). Both non-specific antigens and specafic antigens taken from a tumorous cells (oral and pharyngeal cancer) are used as antagens. In recent years we follow changes of tile ability of Ly adherence under tile influence of electromagnetic silmsoldal field (ESF). Materials and Methods: Ly were acquired by separation from blood of the patients wath oral and pharyngeal carcinoma. Specific antagen was prepared from a tumorous cell of ENT cancer. We momtored the abalaty of Ly adherence of sack people to tile glass surface m dependence on presence of antigen. At the same tilne, identical momtormg was carried out m Ly acquired from blood donors (check group). We repeated the traal m the presence of ESE Between 2002 and 2003, we checked m the same way the samples taken from 76 pataents wath ENT cancer. The pataents were checked before the therapy was introduced. Another 76 blood samples were acquired from the check group. The results we got were assessed by t-test for 2 dependent selectaons. Results: Nmnber of non-adherent Ly (NAT) as significantly lower without the exposataon to the ESF Ila colnparason wath the exposition to the ESF (level of sagnaficance p 0.0001). The NAT Ill a check group are slgmficantly lower m comparison Wltil the treated group, both without tile exposition and after the exposition. Even ill Ly acquired from healtily donors, tile NAT after the exposition to the ESF are lower. Conelusion: ESF lowers the NAT both m Ly of the patients with ENT cmacer, mad m Ly taken from volmatary blood donors. The difference of NAT Ill tile group of sick patients before exposition and following tile exposition is statistically important at tile chosen level of p=0.0001. If tile ablhty of Ly adherence is a demonstration of a CMI, then we may say that ESF influences the CMI both m patients with oral mad pharyngeal cancer, and healthy people.
In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (CI3-Sacetic aci... more In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (CI3-Sacetic acid) and tetradecylthioacetic acid (C,,-Sacetic acid), increase the mRNA levels of Agdesaturase both in a time-and dose-dependent manner. The increased A'-desaturase mRNA levels were accompanied by increased A'-desaturase activity and increased amounts of oleic acid (18: 1 n-9) and A'desaturated C14-Sacetic acid, A'-Desaturated C14-Sacetic acid was only detected in phospholipid and cholesterolester species after C,,-Sacetic acid treatment. In contrast, C,,-Sacetic acid was detected in all the different hepatic lipid fractions, but mainly in the phospholipids. Moreover, CIS-Sacetic acid and ClrSacetic acid were detected in both liver and very low density lipoprotein (VLDL). No A'desaturated 3-thia fatty acid products, however, were found in VLDL. Administration of mono-and dicarboxylic 3thia fatty acids to rats induced liver expression of the fatty acylCoA oxidase gene. After 1 week of C14-Sacetic acid treatment, the levels of fatty acyl-CoA oxidase mRNA increased !%fold, whereas the A'-desaturase mRNA was increased about 1.8-fold. Both fatty acyl-CoA oxidase and A9-desaturase mRNA increased about 8-fold after 12 weeks of treatment with C14-Sacetic a c i d . l In conclusion, this study demonstrates that C,,-Sacetic acid increases rat A'-desaturase gene expression and activity and that changes in hepatic lipids, e.g., 18:l n-9, are re-
We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations ... more We investigated the intracellular glutathione redox status in isolated lymphocyte subpopulations and monocytes in patients with human immunodeficiency virus type 1 (HIV-1) infection and in healthy controls. CD4+ lymphocytes from HIV-l-infected patients were primarily characterized by a substantial increase in oxidized glutathione levels and a considerable decrease in the ratio of reduced to total glutathione, in most cases below 0.5 in patients with symptomatic HIV-1 infection, rather than decreased levels of reduced glutathione. The increase in oxidized glutathione was strongly correlated with low numbers of CD4' lymphocytes in peripheral blood and impaired stimulated interieukin-2 production and proliferation in peripheral blood mononuclear cells, which is compatible with an immunopathogenic role for these redox disturbances. The HIV-1 -infected patients with I
To find out whether oxygen free radical liberated by activation of xanthine oxidase change the ti... more To find out whether oxygen free radical liberated by activation of xanthine oxidase change the tissue concentration of glutathione. Controlled study. 42 male Wistar rats. Laparotomy, induction of ischemia, and reperfusion. 27 rats were treated with allopurinol (to inhibit xanthine oxidase) and the remaining 15 acted as controls. Concentrations of reduced glutathione, oxidized glutathione, and total glutathione in hepatocytes, blood, and bile. Concentration of reduced and total glutathione in hepatocytes decreased significantly during reperfusion and oxidized glutathione was unchanged in all groups. Total glutathione in peripheral venous blood was reduced by half during the period of ischemia and increased gradually during reperfusion whereas the concentration of total glutathione in bile decreased appreciable during reperfusion. Production of bile improved significantly during reperfusion in the group treated with allopurinol compared with the control group. Xanthine oxidase may not be the main source of production of oxygen free radicals as allopurinol did not affect the hepatic concentration of glutathione during reperfusion.
Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lower... more Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks. Rats fed PPC had reduced total homocysteine plasma level and increased levels of choline, dimethylglycine and cysteine, whereas the plasma level of methionine was unchanged compared to control. PPC feeding increased the plasma level of TMAO, carnitine, its precursors trimethyllysine and γ-butyrobetaine. There was a close correlation between plasma TMAO and carnitine, trimethyllysine, and γ-butyrobetaine, but not between TMAO and choline. The present data suggest that PPC has a homocysteine lowering effect and is associated with altered plasma concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. Moreover, the present study reveals a non-obligatory role of gut microbiota in the increased plasma TMAO level as it can be explained by the PPC's content of TMAO. The increased level of carnitine and carnitine precursors is interpreted to reflect increased carnitine biosynthesis.
Marine food is an important source of omega-3 fatty acids with beneficial health effects. Oils fr... more Marine food is an important source of omega-3 fatty acids with beneficial health effects. Oils from marine organisms have different fatty acid composition and differ in their molecular composition. Fish oil (FO) has a high content of eicosapentaenoic and docosahexaenoic acids mainly esterified to triacylglycerols, while in krill oil (KO) these fatty acids are mainly esterified to phospholipids. The aim was to study the effects of these oils on the lipid content and fatty acid distribution in the various lipid classes in liver and brain of mice. Mice were fed either a high-fat diet (HF), a HF diet supplemented with FO or with KO (n = 6). After six weeks of feeding, liver and brain lipid extracts were analysed using a shotgun and TAG lipidomics approach. Student t-test was performed after log-transformation to compare differences between study groups. Six weeks of feeding resulted in significant changes in the relative abundance of many lipid classes compared to control mice. In both FO and KO fed mice, the triacylglycerol content in the liver was more than doubled. The fatty acid distribution was affected by the oils in both liver and brain with a decrease in the abundance of 18:2 and 20:4, and an increase in 20:5 and 22:6 in both study groups. 18:2 decreased in all lipid classes in the FO group but with only minor changes in the KO group. Differences between the feeding groups were particularly evident in some of the minor lipid classes that are associated with inflammation and insulin resistance. Ceramides and diacylglycerols were decreased and cholesteryl esters increased in the liver of the KO group, while plasmalogens were decreased in the FO group. In the brain, diacylglycerols were decreased, more by KO than FO, while ceramides and lactosylceramides were increased, more by FO than KO. The changes in the hepatic sphingolipids and 20:4 fatty acid levels were greater in the KO compared to the FO fed mice, and are consistent with a hypothesis that krill oil will have a stronger anti-inflammatory action and enhances insulin sensitivity more potently than fish oil.
The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), ... more The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S-methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP.
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Papers by Rolf Berge