Oddrun Anita Gudbrandsen

Metabolic effects of thia fatty acids.

Thia substituted fatty acids are saturated fatty acids which are modified by insertion of a sulfur atom at specific positions in the carbon backbone. During the last few years pleiotropic effects of the 3-thia fatty acid tetradecylthioacetic acid have been revealed. The biological responses to tetradecylthioacetic acid include mitochondrial proliferation, increased catabolism of fatty acids, antiadiposity, improvement in insulin sensitivity, antioxidant properties, reduced proliferation and induction of apoptosis in rapidly proliferating cells, cell differentiation and antiinflammatory action. These biological responses indicate that tetradecylthioacetic acid changes the plasma profile from atherogenic to cardioprotective. As a pan-peroxisome proliferator-activated receptor ligand, tetradecylthioacetic acid regulates the adipose tissue mass and the expression of lipid metabolizing enzymes, particularly those involved in catabolic pathways. In contrast, circumstantial evidences suggest that peroxisome proliferator-activated receptor-independent metabolic pathways may be of importance for the antioxidant, antiproliferative and antiinflammatory action of tetradecylthioacetic acid.

Dietary proteins with high isoflavone content or low methionine-glycine and lysine-arginine ratios are hypocholesterolaemic and lower the plasma homocysteine level in male Zucker fa/fa rats.

It has previously been demonstrated that soya protein, which contains isoflavones and low methionine-glycine and lysine-arginine ratios, has a hypocholesterolaemic effect. In the present study, the hypocholesterolaemic effects of an isoflavone-enriched casein diet (HDI) and a single-cell protein-based diet (SCP) devoid of isoflavones but with low methionine-glycine and lysine-arginine ratios were investigated in obese Zucker rats after 6 weeks of feeding. The control diet contained casein, which has high ratios of methionine-glycine and lysine-arginine. HDI and SCP feeding reduced the concentrations of total cholesterol and cholesteryl esters in plasma and liver, and changed the fatty acid composition of the hepatic cholesteryl esters. Faecal cholesterol and bile acid levels were markedly higher in SCP-fed rats than in controls, whereas HDI feeding had only minor effects. However, both HDI and SCP feeding increased the hepatic gene expression of cholesterol 7alpha hydroxylase. In contrast, the hepatic acyl-CoA synthetase and acyl-CoA:cholesterol acyltransferase activities and the gene expression of the LDL receptor were increased by HDI, but not by SCP feeding. The present results suggested that the cholesterol-lowering effect of SCP was related to the enterohepatic circulation, whereas HDI seemed to lower the plasma cholesterol via the circulation. Plasma homocysteine level was reduced in rats fed HDI and SCP compared to rats fed casein. In summary, diets enriched in isoflavones or containing proteins with low methionine-glycine and lysine-arginine ratios lowered the plasma cholesterol and homocysteine levels, changing the plasma profile from atherogenic to cardioprotective.

Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver

Tamoxifen can induce hepatic steatosis in women. In this study, we wanted to elucidate the mechanism behind the tamoxifen-induced accumulation of triacylglycerol in liver in female rats, and we hoped to prevent this development by combination treatment with the modified fatty acid tetradecylthioacetic acid (TTA). The increased hepatic triacylglycerol level after tamoxifen treatment was accompanied by decreased acetyl-coenzyme A carboxylase (ACC) and FAS activities, increased glycerol-3-phosphate acyltransferase (GPAT) activity, and a tendency to increased diacylglycerol acyltransferase (DGAT) activity. The activities and mRNA levels of enzymes involved in β-oxidation, ketogenesis, and uptake of lipids from liver were unaffected by tamoxifen, whereas the uptake of lipoproteins was unchanged and the uptake of fatty acids was decreased. Combination treatment with tamoxifen and TTA (Tam+TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT, and DGAT compared with tamoxifen-treated rats. The activities and mRNA levels of enzymes involved in β-oxidation, ketogenesis, and uptake of lipids were increased after Tam+TTA treatment. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged β-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal β-oxidation.

Low‐dose oral ferrous fumarate aggravated intestinal inflammation in rats with dss‐induced colitis

Background: Oral ferrous iron therapy may reinforce intestinal inflammation. One possible mechanism is by catalyzing the production of reactive oxygen species. We studied the effects of low‐dose oral ferrous fumarate on intestinal inflammation and plasma redox status in dextran sulfate sodium (DSS)‐induced colitis in rats. Methods: Forty male Wistar rats were divided into 5 groups: no intervention, sham gavage (distilled water), ferrous fumarate, DSS, and ferrous fumarate + DSS. Ferrous fumarate was dissolved in distilled water (0.60 mg Fe2+/kg per day) and administered by gavage on days 1 to 14. All rats were fed a standard diet. Colitis was induced by 5% DSS in drinking water on days 8 to 14. Rats were killed on day 16. Histologic colitis scores, fecal granulocyte marker protein, plasma malondialdehyde, plasma antioxidant vitamins, and plasma aminothiols were measured. Results: DSS significantly increased histologic colitis scores (P < 0.001) and fecal granulocyte marker protein (P < 0.01). Ferrous fumarate further increased histologic colitis scores (P < 0.01) in DSS‐induced colitis. DSS + ferrous fumarate decreased plasma vitamin A compared with controls (P < 0.01). Otherwise, no changes were seen in plasma malondialdehyde, plasma antioxidant vitamins, or plasma aminothiols. Conclusion: Low‐dose oral ferrous iron enhanced intestinal inflammation in DSS‐induced colitis in rats.

Dietary soya protein concentrate enriched with isoflavones reduced fatty liver, increased hepatic fatty acid oxidation and decreased the hepatic mRNA level of VLDL receptor in obese Zucker rats.

Casein-based diets containing a low (LDI) or high (HDI) dose of soya protein concentrate enriched with isoflavones were fed to obese Zucker rats for 6 weeks. HDI feeding, but not LDI feeding, reduced the fatty liver and decreased the plasma levels of alanine transaminase and aspartate transaminase. This was accompanied by increased activities of mitochondrial and peroxisomal beta-oxidation, acetyl-CoA carboxylase, fatty acid synthase and glycerol-3-phosphate acyltransferase in liver and increased triacylglycerol level in plasma. The decreased fatty liver and the increased plasma triacylglycerol level appeared not to be caused by an increased secretion of VLDL, as HDI decreased the hepatic mRNA levels of apo B and arylacetamide deacetylase. However, the gene expression of VLDL receptor was markedly decreased in liver, but unchanged in epididymal white adipose tissue and skeletal muscle of rats fed HDI, indicating that the liver may be the key organ for the reduced clearance of triacylglycerol-rich lipoproteins from plasma after HDI feeding. The n-3/n-6, 20:4n-6/18:2n-6 and (20:5n-3+22:6n-3)/18:3n-3 ratios were increased in liver triacylglycerol by HDI. The phospholipids in liver of rats fed HDI contained a low level of 20:4n-6 and a high level of 20:5n-3, favouring the production of anti-inflammatory eicosanoids. When obese Zucker rats were fed soya protein, this also resulted in reduced fatty liver, possibly through reduced clearance of VLDL by the liver. We conclude that the isoflavone-enriched soya concentrate as well as soya protein may be promising dietary supplements for treatment of non-alcoholic fatty liver.

Combination of fish oil and fish protein hydrolysate reduces the plasma cholesterol level with a concurrent increase in hepatic cholesterol level in high-fat-fed Wistar rats.

OBJECTIVE This study investigated the potential additive or synergistic effect of fish oil (FO) and fish protein hydrolysate (FPH) on cholesterol concentration in plasma and the liver. METHODS Male Wistar rats were fed high-fat diets (30% fat, 20% protein, wt/wt) containing FO (5%), FPH (10%), a combination of FO and FPH, or a high-fat control diet. After 7 wk of feeding, the rats were fasted for 12 h before lipid levels in plasma and the liver and hepatic activities of acyl-coenzyme A:cholesterol acyltransferase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and fatty acid synthase were measured. RESULTS The combination of FO and FPH in the diet profoundly reduced the plasma cholesterol level, mainly due to lowering of high-density lipoprotein cholesterol, whereas the hepatic total cholesterol concentration was elevated compared with control rats and rats fed diets containing FPH or FO alone. The elevated cholesterol concentration in the liver was caused by an increased amount of cholesteryl esters and was in correlation to an increased activity of acyl-coenzyme A:cholesterol acyltransferase. There was a reduced fatty acid synthase activity that could lead to a reduced lipogenesis in the rats fed a combination of FO and FPH. CONCLUSION A dietary combination of FO and FPH resulted in lower levels of plasma cholesterol and higher levels of hepatic cholesterol compared with dietary FO or FPH alone. Further studies are warranted to confirm whether the hypocholesterolemic effect was due to a reduced secretion of very low-density lipoprotein from the liver.

Tetradecylthioacetic acid attenuates dyslipidaemia in male patients with type 2 diabetes mellitus, possibly by dual PPAR‐α/δ activation and increased mitochondrial fatty acid oxidation

Aim:  We previously demonstrated that a modified fatty acid, tetradecylthioacetic acid (TTA), improves transport and utilization of lipids and increases mitochondrial fatty acid oxidation in animal and cell studies. We conducted an exploratory study of safety and effects of this novel drug in patients with type 2 diabetes mellitus and investigated the mechanism of action in human cell lines.

Inhibition of rat lipoprotein oxidation after tetradecylthioacetic acid feeding

We have previously shown that tetradecylthioacetic acid (TTA), a sulfur containing saturated fatty acid analogue, inhibits the oxidative modification of human low-density lipoprotein (LDL) in vitro. The oxidative modification of LDL is believed to be a crucial step in the progression of atherosclerosis. In the present study, we investigated the effect of TTA oral administration on the susceptibility of rat lipoprotein to undergo oxidative modification ex vivo. Lipoprotein resistance to copper-induced oxidation was highly improved after TTA administration to rats. Conjugated dienes produced after 150 min of lipoprotein oxidation were dramatically lowered in the TTA treated rats compared to controls. Malondialdehyde and lipid peroxides production by oxidation was highly limited. These effects were independent of any Vitamin E effects. More than 50% relative reduction in polyunsaturated fatty acids of the n-3 family, and more than 30% relative increase in 18:1n-9 fatty acid in the triacylglycerol (TAG)-rich lipoprotein were observed. TAG-rich lipoprotein lipids of TTA fed rats were decreased with more than 50% reduction in TAG. The data reported in this paper indicate a potent in vivo antioxidant capability of TTA that beside its hypolipidemic effect might be of importance in relation to the development of atherosclerosis.

Efficacy of fish intake on vitamin D status: a meta-analysis of randomized controlled trials

BACKGROUND It is well known that fish is the major natural source of vitamin D in the diet; therefore, this meta-analysis investigated the influence of fish consumption in randomized controlled trials (RCTs) on serum 25-hydroxyvitamin D [25(OH)D] concentrations. OBJECTIVE A literature search was carried out in Medline, Embase, Web of Science, and the Cochrane Library (up to February 2014) for RCTs that investigated the effect of fish consumption on 25(OH)D concentrations in comparison to other dietary interventions. RESULTS Seven articles and 2 unpublished study data sets with 640 subjects and 14 study groups met the inclusion criteria and were included in this meta-analysis. Compared with controls, the consumption of fish increased 25(OH)D concentrations, on average, by 4.4 nmol/L (95% CI: 1.7, 7.1 nmol/L; P < 0.0001, I(2) = 25%; 9 studies).The type of the fish also played a key role: the consumption of fatty fish resulted in a mean difference of 6.8 nmol/L (95% CI: 3.7, 9.9 nmol/L; P < 0.0001, I(2) = 0%; 7 study groups), whereas for lean fish the mean difference was 1.9 nmol/L (95% CI: -2.3, 6.0 nmol/L; P < 0.38, I(2) = 37%; 7 study groups). Short-term studies (4-8 wk) showed a mean difference of 3.8 nmol/L (95% CI: 0.6, 6.9 nmol/L; P < 0.02, I(2) = 38%; 10 study groups), whereas in long-term studies (∼6 mo) the mean difference was 8.3 nmol/L (95% CI: 2.1, 14.5 nmol/L; P < 0.009, I(2) = 0%; 4 study groups). CONCLUSION As the major food source of vitamin D, fish consumption increases concentrations of 25(OH)D, although recommended fish intakes cannot optimize vitamin D status.

Trans-10, cis-12-conjugated linoleic acid reduces the hepatic triacylglycerol content and the leptin mRNA level in adipose tissue in obese Zucker fa/fa rats

Conjugated linoleic acid (CLA) isomers have been reported to reduce body weight and beneficially affect glucose metabolism in animals, but the results are inconsistent and seem to depend on animal model and type of CLA isomer. In the present study, feeding male Zucker fa/fa rats diets supplemented with 1% trans-10, cis-12-CLA for 10 d reduced the liver TAG content without improving the overall adiposity, and enhanced hepatic mitochondrial and peroxisomal beta-oxidation. The increased carnitine palmitoyltransferase (CPT)-I activity and mRNA level as well as the increased n-3:n-6 PUFA ratio in liver suggest that trans-10, cis-12-CLA increased the hepatic beta-oxidation by stimulation of PPARalpha. The reduced hepatic TAG content may be partly due to lower activity of stearoyl-CoA desaturase, as the ratios of 18 : 1n-9:18 : 0 and 16 : 1n-7:16 : 0 were reduced in liver. Trans-10, cis-12-CLA increased the CPT-I mRNA in retroperitoneal white adipose tissue (WAT), and increased uncoupling protein-2 mRNA in epididymal and inguinal WAT depots. Leptin mRNA level was decreased in all examined WAT depots, implying reduced insulin sensitivity. The resistin mRNA level was increased in all WAT depots, whereas adiponectin mRNA was reduced in inguinal and retroperitoneal WAT. The present results suggest that dietary supplementation with trans-10, cis-12-CLA may increase the catabolism of lipids in liver and adipose tissue. Moreover, we provide new data suggesting that trans-10, cis-12-CLA modulates the expression of resistin and adiponectin inversely in adipose tissue. Hence, the present results suggest that trans-10, cis-12-CLA may have some beneficial effects on lipid metabolism and adiposity but possibly reduces insulin sensitivity.