While strong evidence from clinical studies suggests beneficial effects of carnitine supplementation on metabolic health, serious safety concerns associated with carnitine supplementation have been raised from studies in mice. Considering that the carnitine doses in these mice studies were up to 100 times higher than those used in clinical studies, the present study aimed to address possible safety concerns associated with long-term supplementation of a carnitine dose used in clinical trials. Two groups of NMRI mice were fed either a control or a carnitine-supplemented diet (1 g/kg diet) from weaning to 19 months of age, and parameters of hepatic lipid metabolism and stress signalling and skeletal muscle gene expression were analysed in the mice at 19 months of age. Concentrations of free carnitine and acetylcarnitine in plasma and tissues were higher in the carnitine than in the control group (P<0·05). Plasma concentrations of free carnitine and acetylcarnitine were higher in mice at adult age (10 and 15 months) than at advanced age (19 months) (P<0·05). Hepatic mRNA and protein levels of genes involved in lipid metabolism and stress signalling and hepatic and plasma lipid concentrations did not differ between the carnitine and the control group. Skeletal muscle transcriptome analysis in 19-month-old mice revealed only a moderate regulation between carnitine and control group. Lifelong carnitine supplementation prevents an age-dependent impairment of plasma carnitine status, but safety concerns associated with long-term supplementation of carnitine at doses used in clinical trials can be considered as unfounded.

Activators of PPARα have been demonstrated to inhibit atherosclerosis development due to lipid lowering in plasma and direct protective effects on the vasculature. Because dietary oxidised fats (OF) have strong PPARα-activating and lipid-lowering properties, we hypothesised that dietary OF has also an inhibitory influence on atherosclerosis development. To verify our hypothesis, we investigated the effect of feeding diets containing an OF (a 92 : 8 mixture of heated (170°C, 48 h) hydrogenated palm fat and fresh sunflower oil) compared with a fresh fat (fresh hydrogenated palm fat) on the development of atherosclerotic lesions in LDL receptor-deficient (LDLR− / − ) mice. We observed that a dietary OF caused a strong up-regulation of PPARα-regulated genes in the liver and a marked reduction in plasma concentrations of cholesterol and TAG (P < 0·05). Cross-sectional lesion area and the lipids and collagen levels in the aortic root were approximately 40–50 % lower in mice fed diets containing OF than in those fed diets containing fresh fat (P < 0·05). Immunohistochemical analysis of aortic root sections revealed an about 8-fold increased expression of PPARα and a markedly reduced expression of the proinflammatory vascular cell adhesion molecule-1 and smooth muscle cell (SMC)-specific marker α-actin in LDLR− / −  mice fed OF (P < 0·05). We postulate that OF exert anti-atherogenic effects by activation of PPARα both in the liver, which contributes to lipid lowering in plasma, and in the vasculature, which inhibits pro-atherogenic events such as monocyte recruitment and SMC proliferation and migration.

In recent years, l-carnitine has been used increasingly as a supplement in livestock animals. The present review gives an overview of the effects of dietary l-carnitine supplementation on the reproductive performance of sows. Results concerning the effect of l-carnitine supplementation during pregnancy on litter sizes are controversial. There are some studies reporting an increased number of piglets born alive per litter, while others could not find such an effect. In contrast, most studies performed show consistently that l-carnitine supplementation to a sow diet low in native carnitine during gestation increases piglet and litter weights at birth and enhances growth of litters during the suckling period. Biochemical mechanisms underlying the favourable effect of carnitine on intra-uterine growth have not been fully elucidated. There is, however, some evidence that carnitine influences the insulin-like growth factor-axis in sows and leads to greater placentae, which in turn improves intra-uterine nutrition, and stimulates oxidation of glucose in the fetuses. These effects may, at least in part, be responsible for higher birth weights of piglets. The stimulating effect of carnitine on growth of the litters might be due to an improved suckling behaviour of piglets born to l-carnitine-supplemented sows, causing the sows' milk production to rise. In conclusion, recent studies have clearly shown that dietary l-carnitine supplementation increases the reproductive performance of sows. These findings suggest that endogenous de novo synthesis of carnitine is insufficient to meet the metabolic requirement of sows during gestation.

Protein from lupin is supposed to have anti-atherogenic effects due to its lipid-lowering properties in laboratory animals. It is further suggested that the amino acid cysteine plays a crucial role in this aspect. The objective of the present study was to compare the effects of lupin protein and cysteine-supplemented casein with those of casein on atherosclerotic lesion development in apoE-deficient mice. For that purpose, thirty mice were fed an egg albumin-based Western-type diet containing test protein (100 g/kg) for 4 months. ApoE-deficient mice fed the lupin protein or the cysteine-supplemented casein had more than 50 % less aortic calcification than mice fed casein (P < 0·05). The quantified lesion area as a percentage of the total surface area, as well as the collagen and fat content of the lesions were not different between the three groups of mice. The concentration of VLDL TAG was higher in mice fed the lupin protein and the cysteine-supplemented casein than in mice fed casein (P < 0·05). The cholesterol concentrations of VLDL, LDL and HDL from mice fed the lupin protein and cysteine-supplemented casein were not different compared with the mice fed casein. Also, the plasma concentrations of homocysteine, Ca, inorganic phosphate, and the activity of glutathione peroxidase in plasma and liver did not differ between the three groups of mice. The present study shows that lupin protein and cysteine-supplemented casein compared with casein reduce the calcification of atherosclerotic lesions in apoE-deficient mice. This effect seems not to be mediated by effects on plasma lipoproteins, homocysteine and circulating minerals.

Conjugated linoleic acids (CLA) are biologically highly active lipid compounds that inhibit the development of atherosclerotic plaques in experimental animals. The underlying mechanisms of action, however, are only poorly understood. Since cell-culture experiments are appropriate to provide a detailed view into the mechanisms of action of a compound, the present review summarises results from in vitro studies dealing with the effects of CLA isomers and CLA mixtures on functional properties of cells of the vascular wall, such as endothelial cells, smooth muscle cells and monocyte-derived macrophages, which are amongst the major cells contributing to atherosclerotic lesion development. Based on these studies, it can be concluded that CLA exert several beneficial actions in cells of the vascular wall through the activation of nuclear PPAR. These actions of CLA, which may, at least partially, explain the inhibition of atherogenesis by dietary CLA, include modulation of vasoactive mediator release from endothelial cells, inhibition of inflammatory and fibrotic processes in activated smooth muscle cells, abrogation of inflammatory responses in activated macrophages, and reduction of cholesterol accumulation in macrophage-derived foam cells.

In mammals, (n-3) PUFA and conjugated linoleic acids (CLA) act as activators of PPARα and alter nuclear concentrations of sterol regulatory element-binding proteins (SREBP) in the liver, and thereby influence hepatic lipid catabolism and synthesis. In this study, we investigated the hypothesis that (n-3) PUFA and CLA exert similar effects in the liver of laying hens. Thirty hens (64 weeks old) were fed diets containing 30 g/kg of sunflower oil (control), fish oil (salmon oil) or CLA in TAG form (containing predominantly cis-9, trans-11 CLA and trans-10, cis-12 CLA) for 5 weeks. Hens fed fish oil had a higher expression of some PPARα target genes and a lower nuclear concentration of SREBP-2 in the liver and lower concentrations of cholesterol and TAG in plasma than control hens. Nuclear concentration of SREBP-1 and its target genes involved in lipogenesis were not altered in hens fed fish oil. Hens fed CLA had increased concentrations of TAG and cholesterol in the liver. However, their mRNA levels of PPARα target genes and nuclear concentrations of SREBP-1 and SREBP-2 as well as mRNA levels of their target genes in the liver were largely unchanged compared to control hens. The results of this study suggest that (n-3) PUFA cause a moderate activation of PPARα and lower cholesterol synthesis but do not impair fatty acid synthesis in the liver of laying hens. CLA lead to an accumulation of TAG and cholesterol in the liver of hens by mechanisms to be elucidated in further studies.

This study was performed to investigate whether dietary lysine concentration influences the carnitine status of pigs. Therefore, an experiment with twenty young pigs with an average body weight of 21 kg was performed which were fed either a control diet (9·7 g lysine/kg) or a diet with a moderate excess of lysine (16·8 g lysine/kg). Concentrations of all the other amino acids did not differ between the diets. Pigs fed the high-lysine diet had lower concentrations of free and total carnitine in plasma, liver, kidney and skeletal muscle than control pigs (P < 0·05). Pigs fed the high-lysine diet moreover had an increased concentration of trimethyllysine (TML), a reduced mRNA abundance of TML dioxygenase and reduced concentrations of γ-butyrobetaine (BB) in muscle, indicating that the conversion of TML into BB in muscle was impaired. Concentrations of BB, the metabolic precursor of carnitine, in plasma, liver and kidney were also reduced in pigs fed the high-lysine diet while the activity of BB dioxygenase in kidney was not different and that in liver was even increased compared to control pigs (P < 0·05). In conclusion, this study shows that a moderate dietary excess of lysine lowers plasma and tissue carnitine concentrations in pigs. Reduced concentrations of BB in liver and kidney suggest that the depressed carnitine status was likely caused by a decreased rate of carnitine synthesis due to a diminished availability of carnitine precursor, probably mainly as a result of an impaired BB formation in muscle.

To assess the effect of lupin protein on concentrations of lipids in plasma lipoproteins and liver and hepatic mRNA concentrations of genes involved in lipid metabolism, adult rats were fed egg albumin-based diets containing either lupin protein from Lupinus albus or casein (50 g/kg) supplemented (hypercholesterolaemic) or not (normolipaemic) with a cholesterol–cholate mixture for 20 d. Lupin protein compared with casein lowered the concentrations of TAG in liver (P < 0·01) and circulating VLDL + chylomicrons (P < 0·05) of hypercholesterolaemic rats, but not of normolipaemic rats. Hepatic mRNA concentrations of genes involved in fatty acid synthesis such as sterol regulatory element-binding protein-1c, glucose-6-phosphate dehydrogenase, fatty acid synthase, stearoyl-CoA desaturase-1 and acyl-CoA:glycerol-3-phosphate acyltransferase were lower and mRNA concentrations of lipoprotein lipase, hepatic lipase and apoA5 involved in TAG hydrolysis were higher in rats fed lupin protein than in rats fed casein. These effects were stronger in hypercholesterolaemic rats than in normolipaemic rats. Hypercholesterolaemic rats fed the lupin protein had higher liver cholesterol concentrations (P < 0·01) and lower levels of LDL-cholesterol (P < 0·05) than rats fed casein. No effect of lupin protein was observed on cholesterol concentration in VLDL + chylomicrons and HDL and hepatic mRNA concentrations of genes involved in cholesterol and bile acid metabolism. In conclusion, the present study shows that lupin protein has hypotriacylglycerolaemic action possibly via down regulation of fatty acid synthesis genes and up regulation of genes involved in TAG hydrolysis. Alterations in cholesterol metabolism could not be explained on the basis of mRNA data.

It has been shown that treatment of rats with clofibrate, a synthetic agonist of PPARα, increases mRNA concentration of organic cation transporters (OCTN)-1 and -2 and concentration of carnitine in the liver. Since oxidised fats have been demonstrated in rats to activate hepatic PPARα, we tested the hypothesis that they also up regulate OCTN. Eighteen rats were orally administered either sunflower-seed oil (control group) or an oxidised fat prepared by heating sunflower-seed oil, for 6 d. Rats administered the oxidised fat had higher mRNA concentrations of typical PPARα target genes such as acyl-CoA oxidase, cytochrome P450 4A1 and carnitine palmitoyltransferases-1A and -2 in liver and small intestine than control rats (P < 0·05). Furthermore, rats treated with oxidised fat had higher hepatic mRNA concentrations of OCTN1 (1·5-fold) and OCTN2 (3·1-fold), a higher carnitine concentration in the liver and lower carnitine concentrations in plasma, gastrocnemius and heart muscle than control rats (P < 0·05). Moreover, rats administered oxidised fat had a higher mRNA concentration of OCTN2 in small intestine (2·4-fold; P < 0·05) than control rats. In conclusion, the present study shows that an oxidised fat causes an up regulation of OCTN in the liver and small intestine. An increased hepatic carnitine concentration in rats treated with the oxidised fat is probably at least in part due to an increased uptake of carnitine into the liver which in turn leads to reduced plasma and muscle carnitine concentrations. The present study supports the hypothesis that nutrients acting as PPARα agonists influence whole-body carnitine homeostasis.

Trans-fatty acid intake is associated with an increased risk of CHD and diabetes. The effects of single trans-fatty acid isomers are largely unexplored. The present study examined the effects of a 6-week supplementation with two trans-18 : 1 isomers (trans-11 and trans-12) in human subjects on immune cells, several inflammatory and immunological biomarkers (for example, IL, TNFα, C-reactive protein, adiponectin, intercellular adhesion molecule-1, prostacyclin, phagocytic process). Following a 2-week adaptation period without supplements, the test group (n 12) received vaccenic acid (trans-11-18:1) and trans-12-18 : 1 in equal amounts (6·0 g/d) for 6 weeks. The control group (n 12) consumed an oil without trans-fatty acids and conjugated linoleic acids (CLA). Samples were collected at the end of both periods. Trans-11- and trans-12-18 : 1 were significantly increased in cellular lipids. The endogenous synthesis of cis-9, trans-11-CLA from trans-11-18 : 1 was demonstrated via increased CLA in cellular lipids of the test group. Generally, trans-isomer supplementation did not affect either inflammatory biomarkers (for example, IL-6, IL-8, TNFα) or immune function (for example, phagocytosis) during the present study. The dietary supplementation of trans-11- and trans-12-18 : 1 (6 g/d) and their accumulation in leucocytes had no effects on biomarkers of inflammation and immune function. However, because of the limited data on the safety of trans-fatty acid intake and effects of individual trans isomers on human health (for example, trans-9-18 : 1, trans-10-18 : 1) at present, it is prudent to reduce trans-fat intake in general.

Recent studies have shown that dietary oxidised fats influence the lipid metabolism in rats by activation of PPARα. In this study, we investigated whether a mildly oxidised fat causes activation of PPARα in pigs which are non-proliferators like man. Eighteen pigs were assigned to two groups and received either a diet containing 90 g/kg of a fresh fat or the same diet with 90 g/kg of an oxidised fat prepared by heating for 24 h at 180°C in a deep fryer. Pigs fed the oxidised fat had a higher peroxisome count, a higher activity of catalase and a higher mRNA concentration of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in the liver and a higher concentration of 3-hydroxybutyrate in plasma than pigs fed the fresh fat (P < 0·05). Hepatic mRNA concentrations of acyl-CoA oxidase and carnitine palmitoyltransferase-1 tended to be increased in pigs fed the oxidised fat compared to pigs fed the fresh fat (P < 0·10). Pigs fed the oxidised fat, moreover, had higher mRNA concentrations of sterol regulatory element-binding protein (SREBP)-1 and its target genes acetyl-CoA carboxylase and stearoyl-CoA desaturase in the liver and higher mRNA concentrations of SREBP-2 and its target genes 3-hydroxy-3-methylglutary-CoA reductase and LDL receptor in liver and small intestine. In conclusion, this study shows that even a mildly oxidised fat causes activation of PPARα in the liver of pigs. Up-regulation of SREBP and its target genes in liver and small intestine suggests that the oxidised fat could stimulate synthesis of cholesterol and TAG in these tissues.

It is known that various dietary plant proteins are capable of influencing the lipid metabolism of human subjects and animals when compared with casein. Less, however, is known about the effects of fish protein on the cholesterol and triacylglycerol metabolism. Therefore, two experiments were conducted in which rats were fed diets containing 200 g of either fish protein, prepared from Alaska pollack fillets, or casein, which served as control, per kilogram, over 20 and 22 d, respectively. As parameters of lipid metabolism, the concentrations of cholesterol and triacylglycerols in the plasma and liver, the faecal excretion of bile acids and the hepatic expression of genes encoding proteins involved in lipid homeostasis were determined. In both experiments, rats fed fish protein had higher concentrations of cholesteryl esters in the liver, a lower concentration of cholesterol in the HDL fraction (ρ>1·063 kg/l) and lower plasma triacylglycerol concentrations than rats fed casein (P<0.05). The gene expression analysis performed in experiment 2 showed that rats fed fish protein had higher relative mRNA concentrations of sterol regulatory element-binding protein (SREBP)-2, 3-hydroxy-3-methylglutaryl coenzyme A reductase, LDL receptor, apo AI, scavenger receptor B1 and lecithin-cholesterol-acyltransferase in their liver than did rats fed casein (P<0·05). The faecal excretion of bile acids and the mRNA concentrations of cholesterol 7α-hydroxylase, SREBP-1c and corresponding target genes were not altered. These findings show that fish protein had multiple effects on plasma and liver lipids that were at least in part caused by an altered expression of the hepatic genes involved in lipid homeostasis.

It has been shown that l-carnitine supplementation of sows increases their milk production and the postnatal growth of the suckling piglets. To test the hypothesis that this effect is due to an improved suckling behaviour of the piglets, two experiments with sows were performed. Two groups of thirteen or ten sows each (in experiments 1 and 2, respectively) were fed diets with or without supplemental l-carnitine during pregnancy (125mg/d) and lactation (250mg/d). After birth, the litters of all sows were standardised to equal sizes of eleven and nine piglets per litter in experiments 1 and 2, respectively. In experiment 1, the piglets of l-carnitine-supplemented sows had a higher total suckling time per day on days 3, 6 and 9, and greater weight gains during the suckling period, than the piglets of control sows (P<0·05). In experiment 2, all litters were taken away from their mothers and switched to other sows. Half of the control sows and half of the l-carnitine-supplemented sows were given litters born to control sows, the other half of each group being given litters born to l-carnitine-supplemented sows. Piglets born to l-carnitine-supplemented sows had a higher total suckling time per day on day 3 and greater body weight gains during the first 14d compared with piglets born to control sows (P<0·05). This study shows that piglets born to sows supplemented with l-carnitine are able to suckle for longer, which enables them to obtain more milk and grow faster than piglets born to control sows.

The present study was performed to investigate the effect of dietary fat and vitamin E on concentrations of cholesterol oxidation products (COP) in broiler muscle. A total of 144 1-d-old broiler chicks were fed diets with either palm oil, soyabean oil or linseed oil and vitamin E concentrations of 20, 40 or 200 mg/kg for 35 d. COP concentrations were analysed in raw, heat-processed (180°C, 20 min) and frozen-stored (−20°C, 6 months) breast and thigh muscles. COP concentrations were influenced by dietary vitamin E concentration, dietary fat, treatment and type of muscle (P<0·001). Increasing the dietary vitamin E concentration generally reduced the concentration of COP. This effect was strongest in broilers fed linseed oil and weakest in broilers fed palm oil; the effect of vitamin E was also stronger in heated muscles than in raw or frozen-stored muscles. Moreover, the concentration of COP in thigh muscle was more strongly influenced by dietary vitamin E than that in breast muscle. COP concentrations in muscles were on average highest in broilers fed linseed oil and lowest in broilers fed palm oil, but the effect of the dietary fat also depended on the vitamin E concentration, the treatment and the type of muscle. In conclusion, our study shows that dietary fat and vitamin E influence the concentrations of total COP in broiler muscle. However, the effects of these factors were not only influenced by interactions between each other, but also depended on the treatment of the muscle and the type of muscle.

The present study was performed to investigate whether lipid peroxidation products in thermoxidised dietary oil fed during rearing, pregnancy and lactation influences the reproductive performance of female rats and the antioxidant status of their offspring. Twenty-four female rats were divided into two groups at 4 weeks of age. They were fed diets containing fresh or oxidised oil (the latter prepared by heating at a temperature of 50°C for 16 d) for 14 weeks. At the age of 12 weeks female rats were mated. The number of total pups and pups born alive was not different between both groups. However, individual pups and litters of dams fed oxidised oil were lighter at birth and gained less weight during the suckling period than those of dams fed fresh oil (P>0·05). Pups of dams fed oxidised oil contained less protein and more fat in their carcasses than those of dams fed fresh oil (P>0·05). The milk of dams fed oxidised oil had a lower concentration of triacylglycerols and a lower energy content than that of dams fed the fresh oil (P>0·05). The pups of dams fed oxidised oil had higher concentrations of lipid peroxidation products in the liver at birth and day 19 of lactation than those of dams fed fresh oil (P>0·05). In conclusion, the present study shows that feeding oxidised oil with a high concentration of lipid peroxidation products to female rats during rearing, pregnancy and lactation influences the development and antioxidant status of fetus and suckling pups.

In his discussion of modern society, Habermas begins with Weber's thesis of a universal rationalization process within which the rationalization of law plays a central part. Thus his starting point is the classical thesis of the formal rationalization of law as advanced by Weber (1960; Schluchter, 1979). Habermas tries to show that Weber's theorizing is deficient because he underestimates the specific historical role of the materialization of law (1981, Vol. 1: 332). Additionally, such theorizing does not allow us an adequate grasp of some recent developments that proceduralize law (Teubner, 1983, 1984; Eder, 1986). From the perspective of Weber's theory of formal rationalization, the processes that materialize and proceduralize law appear to be aberrations from the normal path of modern legal development. Habermas suggests that, far from being deficient, these processes are necessary forms of law in the process of modernization. The appearance of deficiency proceeds from Weber's attempt to separate morality from law and to conceptualize a moral-free law, a corollary of Weber's plea for a value-free science. Habermas concludes that formal rationalization is an inadequate model of law operating in the modern welfare state. Thus a new model is in order.