Levels of omega 3 fatty acids, vitamin D, dioxins and dioxin-like PCBs in oily fish; a new perspective on the reporting of nutrient and contaminant data for risk-benefit assessments of oily seafood.

Oily seafood is an important food source which contains several key nutrients beneficial for human health. On the other hand, oily seafood also contains persistent organic pollutants (POPs), including the dioxin-like compounds (DLCs) polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDD/Fs) and dioxin-like-polychlorinated biphenyls (dl-PCBs), potentially detrimental to human health. For a comprehensive comparison of the beneficial and potentially adverse health effects of seafood consumption, risk-benefit analyses are necessary. Risk-benefit analyses require reliable quantitative data and sound knowledge of uncertainties and potential biases. Our dataset comprised more than 4000 analyses of DLCs and more than 1000 analyses each of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and vitamin D in the three most important Norwegian commercial oily seafood species: Atlantic herring (Clupea harengus), Atlantic mackerel (Scomber scombrus) and farmed Atlantic salmon (Salmo salar). The levels of several DLC congeners were below the limit of quantification (LOQ), making estimation of true levels challenging. We demonstrate that the use of upper bound substitution of censored data will overestimate, while lower bound substitution will underestimate the actual levels of DLCs. Therefore, we implement an alternative robust statistical method by combining Maximum Likelihood Estimation, Regression on Order Statistics and Kaplan-Meier analyses, which is better suited for providing estimations of levels of these contaminants in seafood. Moreover, we illustrate the impact of the toxic equivalency factor (TEF) system on estimation of the sums of DLCs by comparing the TEF system to an alternative system of relative effect potency (REP) factors (Consensus Toxicity Factors). The levels of nutrients and contaminants were related to adequate intake (AI) and tolerable weekly intake (TWI), respectively. We used AI and the TWI values established by the European Food Safety Authority (EFSA). The benefit and the risk were further viewed in the context of the Norwegian average intake of oily fish, and the Norwegian governmental official dietary recommendations of oily fish. Our results showed that both benefit and risk are met at the levels found of nutrients and DLCs in oily seafood. The comprehensive quantitative data presented here will be a key for future risk-benefit assessment of oily fish consumption. Together, our results underline that a refined formalized integrative risk-benefit assessment of oily fish in the diet is warranted, and that the data and methodology presented in this study are highly relevant for future integrated and multidisciplinary assessment of both risks and benefits of seafood consumption for human health.

Dietary intake of differently fed salmon: a preliminary study on contaminants.

BACKGROUND: In a previous study, a group of coronary heart disease (CHD) patients exhibited positive cardioprotective effects of fatty acids derived from a diet of farmed Atlantic salmon fed fish oil (Seierstad et al. 2005). This follow-up study examines these patients for plasma exposure to selected organic and inorganic contaminants found in seafood that may detract from the benefits of eating oily fish. METHODS: The study design was from Seierstad et al. (2005), where 58 patients were allocated into three groups consuming 700 g week(-1) of differently fed Atlantic salmon (Salmo salar) fillets for 6 weeks: 100% fish oil (FO), 100% rapeseed oil (RO), or 50% of each (FO/RO). RESULTS: Different fillets showed graded levels (FO > FO/RO > RO) of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), dioxin-like polychlorinated biphenyls (DLPCBs), indicator PCBs, polybrominated diphenyl ethers (PBDEs), and arsenic (As). Mercury (Hg) and lead (Pb) levels were similar across the three types of fillets. After 6 weeks of consumption, patient levels of PCDDs, DLPCBs, and PCBs in plasma decreased as the dietary intake of these contaminants increased. Plasma PBDEs only showed increases for the FO patients. Levels of inorganic contaminants in plasma showed only slight changes over the study period. CONCLUSIONS: These results show a reduction in the use of marine oils in fish feed reduces organic contaminant levels in farmed salmon while still providing a good dietary source of marine fatty acids.

Influence of dietary lipid composition on cardiac pathology in farmed Atlantic salmon, Salmo salar L.

The present study investigated the short-term (5 months) effect of replacing dietary marine oils with vegetable oils on the development of arteriosclerotic changes in the heart of Atlantic salmon, Salmo salar. The experiment was performed as a randomized observer-blinded and controlled trial. Farmed Atlantic salmon were randomly sampled from a study population containing 900 individuals. The salmon were divided into three groups and given diets with either 100% fish oil (Diet 1), a 50/50% mixture of fish oil and rapeseed oil (Diet 2) or 100% rapeseed oil (Diet 3). Ten sexually immature salmon from each dietary group were sampled in March and August 2002. Additionally, 47 sexually mature wild salmon were randomly collected in mid-September 2001. Serial histological sections were taken from the bulbus arteriosus and ventricle wall for histopathological evaluation of the coronary arteries and myocardium. No significant differences in mean coronary changes recorded by the main variable 'mean range lesion' (MRL) were detected between the groups in March or August. MRL increased significantly between March and August with Diet 2 (P < 0.01), was nearly significant with Diet 3 (P = 0.06) and was unchanged with Diet 1. This pattern coincided with the Diet 2 group having the highest increase in heart weight. MHC class II immunoreactive cells in the coronary changes were detected in sections from one individual in each group. Heart weight was the most dominant variable in the data set and explained linearly 15.5% of the variation in MRL. Body weight, fish length and heart weight were all significantly, positively and linearly correlated to MRL. The Diet 2 group had the highest growth rate and also exhibited a significant increase in MRL. The possible influence of diet composition on weight gain and MRL needs to be further elucidated. Increase in heart weight seems to be the dominating predictor of the appearance of MRL in Atlantic salmon. However, the present results cannot exclude the possibility that differences in fatty acid composition of fish feed can influence the development of arteriosclerotic changes in Atlantic salmon.

Dietary intake of differently fed salmon; the influence on markers of human atherosclerosis.

BACKGROUND: Cardioprotective effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) of marine origin are well recognized. Because of the shortness of marine resources vegetable oils are increasingly used in fish farming. The effects on human health of fish fed on vegetable oils are largely unknown. METHODS: In a double-blinded intervention study, 60 patients with coronary heart disease (CHD) were randomly allocated to three groups consuming approximately 700 g per week for 6 weeks of differently fed Atlantic salmon: 100% fish oil (FO), 100% rapeseed oil (RO) or 50% of each (FO/RO), resulting in fillets with high, intermediate and low levels of marine n-3 PUFAs. Patient analyses before and after the intervention period included serum fatty acid profile, serum lipoproteins, and markers of vascular inflammation. RESULTS: The serum fatty acid profiles of the patients after the intervention mirrored those of the corresponding salmon fillets and the respective salmon feeds. Significant differences between the groups were obtained, especially for the levels of total n-3 PUFAs and the n-3/n-6 FA ratio, which were markedly increased in the FO group in contrast to the two other groups (P < 0.02 for all). Additionally, significant reductions of serum triglycerides and of vascular cell adhesion molecule-1 and interleukin-6 were obtained in patients receiving the FO diet when compared with the two other groups (P < 0.05 for all). CONCLUSIONS: Tailor-made Atlantic salmon fillets very high in n-3 PUFAs of marine origin seem to impose favourable biochemical changes in patients with CHD when compared with ingestion of fillets with intermediate and low levels of marine n-3 PUFAs, when replaced by rapeseed oil.

Reduced joint pain after short-term duodenal administration of seal oil in patients with inflammatory bowel disease: comparison with soy oil.

BACKGROUND: Rheumatic joint pain is a common extra-intestinal complication of inflammatory bowel disease (IBD). Because the high ratio of n-6 to n-3 fatty acids (FAs) of the Western diet might promote rheumatic disorders, we sought to compare the effects of short-term duodenal administration of n-3-rich seal oil and n-6-rich soy oil on IBD-related joint pain. METHODS: Nineteen patients with IBD-related joint pain were included in the study; 9 had Crohn disease and 10 had ulcerative colitis. Ten millilitres seal oil (n = 10) or soy oil (n = 9) was self-administered through a nasoduodenal feeding tube 3 times daily for 10 days. RESULTS: Compared with soy oil treatment, seal oil significantly reduced the duration of morning stiffness (P = 0.024), number of tender joints (P = 0.035), intensity of pain (P = 0.025) and the doctor's scoring of rheumatic disease activity (P = 0.025) at the end of the 10-day treatment period. Analysis of the effects as area under the curve (area between the curve and baseline, zero) for the entire period from start of treatment until 6 months' post-treatment suggested a long-lasting beneficial effect of seal oil administration on joint pain, whereas soy oil tended (not significantly) to aggravate the condition. Consistently, the serum ratios of n-6 to n-3 FAs (P < 0.01) and arachidonic acid to eicosapentaenoic acid (P < 0.01) were reduced after treatment with seal oil. CONCLUSION: The results suggest distinctive, differential prolonged effects on IBD-related joint pain of short-term duodenal administration of n-3-rich seal oil (significant improvement) and n-6-rich soy oil (tendency to exacerbation).

Long-term retention of a novel antioxidant sulphur-substituted fatty acid analogue after local delivery in porcine coronary arteries.

OBJECTIVE: Antioxidants have been suggested to reduce restenosis after balloon angioplasty. A novel sulphur-containing fatty acid, tetradecylthioacetic acid (TTA), with antioxidant properties, is efficiently incorporated into cellular phospholipids. We have determined the uptake and retention of TTA after local coronary artery delivery in 20 pigs. DESIGN: Radiolabelled TTA was delivered to 40 main coronary arteries via a multiporous coronary angioplasty balloon catheter inflated before, after, or without overstretch vessel injury. The animals were killed at intervals of up to 6 weeks post-procedure. The radioactivity of the tissue sections was determined as nmol TTA/g tissue. RESULTS: Concentrations of TTA in the coronary arteries were 1.84 +/- 0.45 nmol/g up to 24 h, 1.50 +/- 0.96 nmol/g at 2 weeks, 0.22 +/- 0.11 nmol/g at 4 weeks and a trace was present at 6 weeks (p-value for trend <0.01). The arterial wall uptake at the delivery site was higher than distal to delivery (1.84 +/- 0.37 vs 0.55 +/- 0.13 nmol/g, p = 0.006) and perivascular fat (p < 0.01) but not higher than in the myocardium. Infusion before, after or without vessel injury was not important for tissue concentration. CONCLUSIONS: After local coronary artery delivery, the antioxidant TTA is taken up by the arterial wall in which it is retained for at least 4 weeks.

Proliferation of mitochondria and gene expression of carnitine palmitoyltransferase and fatty acyl-CoA oxidase in rat skeletal muscle, heart and liver by hypolipidemic fatty acids.

Morphological and biochemical effects were induced at the subcellular level in the skeletal muscle, heart and liver of male rats as a result of feeding with EPA, DHA, and 3-thia fatty acids. The 3-thia fatty acid, tetradecylthioacetic acid (TTA) and EPA induced mitochondrial growth in type I muscle fibers in both the diaphragm and soleus muscle, and the size distribution of mitochondrial areas followed a similar pattern. Only the 3-thia fatty acid induced mitochondrial growth in type II muscle fibers. The mean area occupied by the mitochondria and the size distribution of mitochondrial areas in both fiber types were highly similar in DHA-treated and control animals. Only the 3-thia fatty acid increased the gene-expression of carnitine palmitoyltransferase (CPT)-II in the diaphragm. In the heart, however, the gene expression decreased. In hepatocytes an increase in the mean size of mitochondria was observed after EPA treatment, concomitant with an increase in mitochondrial CPT-II gene expression. Administration of 2-methyl-substituted EPA (methyl-EPA) induced a higher rate of growth of mitochondria than EPA. At the peroxisomal level in the hepatocytes a 3-thia fatty acid, EPA, and DHA increased the areal fraction concomitant with the induction of gene expression of peroxisomal fatty acyl-CoA oxidase (FAO). In the diaphragm, mRNA levels of FAO were not affected by EPA or DHA treatment, whereas gene expression was significantly increased after 3-thia fatty acid treatment. In the heart, both 3-thia fatty acid, EPA and DHA tended to decrease the levels of FAO mRNA. The areal fraction of fat droplets in all three tissue types was significantly lower in the groups treated with 3-thia fatty acid. In the group treated with EPA a lower areal fraction of fat droplets was observed, while the DHA group was similar to the control. This indicates that EPA and DHA have different effects on mitochondrial biogenesis.

Lipid metabolism and tissue composition in Atlantic salmon (Salmo salar L.)--effects of capelin oil, palm oil, and oleic acid-enriched sunflower oil as dietary lipid sources.

Triplicate groups of Atlantic salmon (Salmo salar L.) were fed four diets containing different oils as the sole lipid source, i.e., capelin oil, oleic acid-enriched sunflower oil, a 1:1 (w/w) mixture of capelin oil and oleic acid-enriched sunflower oil, and palm oil (PO). The beta-oxidation capacity, protein utilization, digestibility of dietary fatty acids and fatty acid composition of lipoproteins, plasma, liver, belly flap, red and white muscle were measured. Further, the lipid class and protein levels in the lipoproteins were analyzed. The different dietary fatty acid compositions did not significantly affect protein utilization or beta-oxidation capacity in red muscle. The levels of total cholesterol, triacylglycerols, and protein in very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL), and plasma were not significantly affected by the dietary fatty acids. VLDL, LDL, and HDL fatty acid compositions were decreasingly affected by dietary fatty acid composition. Dietary fatty acid composition significantly affected both the relative fatty acid composition and the amount of fatty acids (mg fatty acid per g tissue, wet weight) in belly flap, liver, red and white muscle. Apparent digestibility of the fatty acids, measured by adding yttrium oxide as inert marker, was significantly lower in fish fed the PO diet compared to the other three diets.

Methylated eicosapentaenoic acid and tetradecylthioacetic acid: effects on fatty acid metabolism.

We introduced methyl or ethyl groups to the 2- or 3-position of the eicosapentaenoic acid (EPA) molecule to investigate whether the branching of EPA could influence its hypolipidemic effect in rats. The most effective branching involved two methyl groups in the 2-position and one methyl group in the 3-position. These EPA derivatives increased hepatic mitochondrial and peroxisomal beta-oxidation and decreased plasma lipids concomitant with suppressed acetyl-coenzyme A (CoA) carboxylase (EC 6.4.1.2) and fatty acid synthase (EC 2.3.1.85) activities. This was followed by elevated activities of camitine O-palmitoyltransferase (EC 2.3.1.21) and possibly 2,4-dienoyl-CoA reductase (EC 1.3.1.34), as well as induced mRNA levels of these enzymes and fatty acyl-CoA oxidase. The fatty acid composition in liver changed, with an increased 18:1 n-9 content, whereas the expression of delta9-desaturase remained unchanged. We investigated the flux of fatty acids in cultured hepatocytes, and found that oxidation of [1-14C]-labeled palmitic acid increased but the secretion of palmitic acid-labeled triglycerides decreased after addition of 2-methyl-EPA. The fatty acyl-CoA oxidase (EC 1.3.3.6) activity in these cells remained unchanged. A significant negative correlation was obtained between palmitic acid oxidation and palmitic acid-labeled synthesized triglycerides. To investigate whether the hypolipidemic effect occurred independently of induced peroxisomal beta-oxidation, we fed rats 2-methyl-tetradecylthioacetic acid. This compound increased the peroxisomal but not the mitochondrial beta-oxidation, and the plasma lipid levels were unchanged. In conclusion, EPA methylated in the 2- or 3-position renders it more potent as a hypolipidemic agent. Furthermore, this study supports the hypothesis that the mitochondrion is the primary site for the hypolipidemic effect.

Carnitine palmitoyltransferase I, carnitine palmitoyltransferase II, and acyl-CoA oxidase activities in Atlantic salmon (Salmo salar).

Salmon farmers are currently using high-energy feeds containing up to 35% fat; the fish's capability of fully utilizing these high-energy feeds has received little attention. Carnitine is an essential component in the process of mitochondrial fatty acid oxidation and, with the cooperation of two carnitine palmitoyltransferases (CPT-I and CPT-II) and a carnitine acylcarnitine transporter across the inner mitochondrial membrane, acts as a carrier for acyl groups into the mitochondrial matrix where beta-oxidation occurs. However, no reports are available differentiating between CPT-I and CPT-II activities in fish. In order to investigate the potential for fatty acid catabolism, the activities of key enzymes involved in fatty acid oxidation were determined in different tissues from farmed Atlantic salmon (Salmo salar), i.e., acyl-CoA oxidase (ACO) and CPT-I and CPT-II. Malonyl-CoA was a potent inhibitor of CPT-I activity not only in red muscle but also in liver, white muscle, and heart. By expressing the enzyme activities per wet tissue, the CPT-I activity of white muscle equaled that of the red muscle, both being >> liver. CPT-II dominated in red muscle whereas the liver and white muscle activities were comparable. ACO activity was high in the liver regardless of how the data were calculated. Based on the CPT-II activity and total palmitoyl-L-carnitine oxidation in white muscle, the white muscle might have a profound role in the overall fatty acid oxidation capacity in fish.

Docosahexaenoic and eicosapentaenoic acids are differently metabolized in rat liver during mitochondria and peroxisome proliferation.

The 3-thia fatty acids, tetradecylthioacetic acid and 3,10-dithiadicarboxylic acid are mitochondrion and peroxisome proliferators. Administration of these promotes an increased transport of endogenous fatty acids to these organelles and a higher capacity of beta-oxidation. Administration of 3-thia fatty acids to rats resulted in a significant decrease of the hepatic level of docosahexaenoic acid (DHA) (17-24%) and especially eicosapentaenoic acid (EPA) (40-80%) accompanied by increased gene expression of mitochondrial 2,4-dienoyl-CoA reductase and enoyl-CoA isomerase. The mitochondrial oxidation of EPA was increased more than 4-fold after administration of 3-thia fatty acids. EPA-CoA was a good substrate for mitochondrial carnitine acyltransferase-I and treatment with 3-thia fatty acids increased the activity 1.7-fold. DHA was a poor substrate for both mitochondrial and peroxisomal beta-oxidation. DHA-CoA was a very poor substrate for mitochondrial carnitine acyltransferase-I and -II, and the activity did not increase after treatment. However, the peroxisomal DHA-CoA oxidase increased 10-fold after 3-thia fatty acid treatment, whereas the peroxisomal EPA-CoA oxidase increased only 5-fold. In isolated hepatocytes, 16% of total metabolized EPA was oxidized and 76% was incorporated into glycerolipids, whereas DHA was oxidized very little. We conclude that under conditions of increased mitochondrial and peroxisomal proliferation by 3-thia fatty acids, a relatively higher oxidation rate of polyunsaturated n-3 fatty acids might result in a decreased hepatic level of EPA and DHA. Under these conditions DHA seems to be oxidized by the peroxisomes, whereas EPA, which can be oxidized in both organelles, is mainly oxidized by mitochondria.

Eicosapentaenoic acid and sulphur substituted fatty acid analogues inhibit the proliferation of human breast cancer cells in culture.

Numerous studies have shown dietary fatty acids to influence the progression of several types of cancers. The purpose of the present investigation was to examine the influence of various types of fatty acids, including omega-3 fatty acids and a new class of hypolipidemic peroxisome proliferating fatty acid analogues, namely the 3-thia fatty acids, on MCF-7 human breast cancer cell growth. 3-thia fatty acids represent non-beta-oxidizable fatty acid analogues in which a sulphur atom substitutes for the beta-methylene group (3-position) in the saturated and unsaturated fatty acids. The effects of increasing concentrations of palmitic acid, tetradecylthioacetic acid (a 3-thia fatty acid), eicosapentaenoic acid, docosahexaenoic acid, and two 3-thia polyunsaturated fatty acids on the proliferation of MCF-7 cells, maintained in serum-free culture, were studied. At the highest concentration of fatty acid used (64 microM) tetradecylthioacetic acid was found to be the most effective of all fatty acids tested in inhibiting cell growth, whilst palmitic acid and docosahexaenoic acid had no significant effect on cell growth. Thus, of the two dietary polyunsaturated omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, only eicosapentaenoic acid possesses an inhibitory effect on the proliferation of MCF-7 cells. In all cases the inhibitory effect of the fatty acid was found to be reversible. Tetradecylthioacetic acid has been shown to be a potent peroxisome proliferator. It was, therefore, hypothesized that tetradecylthioacetic acid may inhibit the human MCF-7 cell growth by increasing the level of oxidative stress within the cell. However, use of agents which modify the cell's protective apparatus against oxidative stress had no influence on the inhibitory effect of tetradecylthioacetic acid. These experiments indicate that tetradecylthioacetic acid inhibits cell growth by mechanisms which may be independent of oxidative status.

Mitochondrion is the principal target for nutritional and pharmacological control of triglyceride metabolism.

Fish oil polyunsaturated fatty acids and fibrate hypolipidemic drugs are potent hypotriglyceridemic agents that act by increasing fatty acid catabolism and decreasing triglyceride synthesis and secretion by the liver. A major unresolved issue is whether this hypotriglyceridemic effect can occur independent of induction of peroxisomal beta-oxidation, a predisposing factor for hepatocarcinogenesis. The present study was undertaken to determine which component of fish oil, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is responsible for its triglyceride-lowering effect. We demonstrate that EPA and not DHA is the hypotriglyceridemic component of fish oil and that mitochondria and not peroxisomes are the principal target. Results obtained by fenofibrate feeding support the hypothesis that the mitochondrion is the primary site for the hypotriglyceridemic effect. In contrast to fibrates, EPA did not affect hepatic apolipoprotein C-III gene expression. Therefore, increased mitochondrial beta-oxidation with a concomitant decrease in triglyceride synthesis and secretion seems to be the primary mechanism underlying the hypotriglyceridemic effect of EPA and fibrates in rats, rabbits and possibly also in humans. In addition, these data show that lowering of plasma triglycerides can occur independently of any deleterious peroxisome proliferation.

On the effects of thia fatty acid analogues on hydrolases involved in the degradation of metabolisable and non-metabolisable acyl-CoA esters.

1. We investigated the nature and roles of various xenobiotic acyl-CoA hydrolases in liver subcellular fractions from rat treated with sulphur-substituted (thia) fatty acids. To contribute to our understanding of factors influencing enzymes involved in the degradation of activated fatty acids, the effects on these activities of the oppositely acting thia fatty acid analogues, the peroxisome proliferating 3-thia fatty acids (tetradecylthioacetic acid and 3-dithiacarboxylic acid), which are blocked for beta-oxidation, and a non-peroxisome-proliferating 4-thia fatty acid (tetradecylthiopropionic acid), which undergoes one cycle of beta-oxidation, were studied. 2. The hepatic subcellular distributions of palmitoyl-CoA, tetradecylthioacetyl-CoA and tetradecylthiopropionyl-CoA hydrolase activities were similar to each other in the control and 3-thia fatty acid-treated rat. In control animals, most of these hydrolases were located in the microsomal fraction, but after treatment with the 3-thia fatty acids, the specific activities of the mitochondrial, peroxisomal, and cytosolic palmitoyl-CoA, tetradecylthioacetyl-CoA, and tetradecylthiopropionyl-CoA hydrolase activities were significantly increased. This increase in activity was seen mostly for the enzymes using tetradecylthiopropionyl-CoA and tetradecylthioacetyl-CoA as substrates. The increased mitochondrial activities for these two substrates were seen already after 1 day of treatment, whereas the peroxisomal activities increased after 3 days. No stimulation was seen after treatment with the 4-thia fatty acid analogue, tetradecylthiopropionic acid, but a decrease in peroxisomal hydrolase activities for all three substrates was observed. 3. The cellular distributions of clofibroyl-CoA, POCA-CoA, and sebacoyl-CoA hydrolase activities were different from those of the 'long-chain acyl-CoA' hydrolases mentioned above both in the normal and 3-thia fatty acid treated rat. This group of hydrolases was found in the mitochondrial, peroxisomal, and cytosolic fractions. 3-Thia fatty acid treatment increased the activities of clofibroyl-CoA and sebacoyl-CoA hydrolases in all three fractions. Clofibroyl-CoA and sebacoyl-CoA hydrolase activities were increased after 1 day of treatment. Only the cytosolic POCA-CoA hydrolase was stimulated after 3-thia fatty acid treatment after only 1 day of treatment, whereas treatment with the 4-thia fatty acid led to an increase of enzyme activity in the mitochondrial and peroxisomal fractions. 4. Based on the subcellular distributions and specific activities, we suggest that several enzymes exist which may act as regulators of intracellular acyl-CoA levels.

Effect of 3-thia fatty acids on the lipid composition of rat liver, lipoproteins, and heart.

To investigate the importance of factors influencing the fatty acid composition, lipid and lipoprotein metabolism in the rat, the effect of 3-thia fatty acids of chain-length ranging from octyl- to hexadecylthioacetic acid were studied. In liver, very low density lipoprotein (VLDL), and low density lipoprotein (LDL), the hypolipidemic 3-thia fatty acids, namely C12-S-acetic acid to C14-S-acetic acid increased the amount of monoenes, especially oleic acid (18:ln-9). In contrast, the content of polyunsaturated fatty acids in liver, VLDL, and LDL decreased, mostly attributed to a reduction of eicosapentaenoic acid (EPA, 20:5n-3). Noteworthy, the hypolipidemic 3-thia fatty acids reduced the amount of arachidonic acid (AA, 20:4n-6) in LDL and HDL. 3-Thia fatty acids accumulated in the liver. In heart, as in liver, 3-thia fatty acids replaced fatty acids of chain-length homologues. In contrast to liver, we were unable to detect any changes in 18:ln-9. However, the n-3 polyunsaturated fatty acid content increased, particularly 20:5n-3 and docosahexaenoic acid (DHA, 22:6n-3) leading to an increased n-3/n-6 ratio. In conclusion, this study demonstrates that hypolipidemic 3-thia fatty acids change the fatty acid composition of organs and lipoproteins. These changes are linked to the expression and activity of hepatic delta9-desaturase, fatty acid oxidation, and displacement of normal fatty acids by 3-thia fatty acids. The fatty acid composition is regulated differently in liver and heart after administration of hypolipidemic 3-thia fatty acids.

Up-regulated delta 9-desaturase gene expression by hypolipidemic peroxisome-proliferating fatty acids results in increased oleic acid content in liver and VLDL: accumulation of a delta 9-desaturated metabolite of tetradecylthioacetic acid.

In the liver of rats, monocarboxylic 3-thia fatty acids, tridecylthioacetic acid (C13-S-acetic acid) and tetradecylthioacetic acid (C14-S-acetic acid), increase the mRNA levels of delta 9-desaturase both in a time- and dose-dependent manner. The increased delta 9-desaturase mRNA levels were accompanied by increased delta 9-desaturase activity and increased amounts of oleic acid (18:1 n-9) and delta 9-desaturated C14-S-acetic acid. delta 9-Desaturated C14-S-acetic acid was only detected in phospholipid and cholesterolester species after C14-S-acetic acid treatment. In contrast, C14-S-acetic acid was detected in all the different hepatic lipid fractions, but mainly in the phospholipids. Moreover, C13-S-acetic acid and C14-S-acetic acid were detected in both liver and very low density lipoprotein (VLDL). No delta 9-desaturated 3-thia fatty acid products, however, were found in VLDL. Administration of mono- and dicarboxylic 3-thia fatty acids to rats induced liver expression of the fatty acyl-CoA oxidase gene. After 1 week of C14-S-acetic acid treatment, the levels of fatty acyl-CoA oxidase mRNA increased 5-fold, whereas the delta 9-desaturase mRNA was increased about 1.8-fold. Both fatty acyl-CoA oxidase and delta 9-desaturase mRNA increased about 8-fold after 12 weeks of treatment with C14-S-acetic acid. In conclusion, this study demonstrates that C14-S-acetic acid increases rat delta 9-desaturase gene expression and activity and that changes in hepatic lipids, e.g., 18:1 n-9, are reflected in the VLDL. The peroxisome-proliferating monocarboxylic thia fatty acids are good substrates for desaturases, as delta 9-desaturated metabolites of monocarboxylated thia acids were formed in the liver. Modification of delta 9-desaturation, however, appears not to be related to peroxisome proliferation.