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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 19 recordsLinked to original sources
PubMed1992

Effect of n-3 and n-6 fatty acids on hepatic microsomal lipid metabolism: a time course study.

The present study examines the time dependent effects of n-6 and n-3 polyunsaturated fatty acids on liver microsomal lipid metabolism in FVB mice fed a diet supplemented with a mixture of free fatty acids (mainly 18:3n-6 and 20:5n-3) at 25 mg/g diet. Significant changes in the fatty acid composition of total liver and microsomal lipids were observed after 7 days on the diets. Thereafter, some animals remained on the same diet while others were fed a diet supplemented with hydrogenated coconut oil (HCO). With the exception of 20:5n-3 which showed a slower recovery, establishment of the HCO pattern was rapid indicating that the diet-induced changes could be easily reversed. The unsaturation index, the cholesterol/phospholipid ratio and the microviscosity of the microsomal membranes were not affected by these dietary manipulations. Unsaturated fatty acid supplementation reduced the activity of delta 9 desaturase by 50%. Feeding the HCO diet to mice previously fed the EPA/GLA diet led to a progressive increase in delta 9 desaturase activity, reaching 80% of the day zero values after 14 days. The monoene content of hepatic total lipids reflected, in most cases, the changes in enzyme activity. This study shows that a low dose of a n-3 and n-6 free fatty acid mixture increases the quantities of members of the n-3 family, without loss of n-6 fatty acids in microsomal membranes and modifies the activity of delta 9 desaturase without altering the microsome physicochemical parameters.

Animals↗
PubMed1992

The use of gamma-linolenic acid in diabetic neuropathy.

EF4 is an entirely new approach to the management of diabetic neuropathy. EF4 (providing gamma-linolenic acid or gamolenic acid, GLA) has been shown to reverse existing diabetic neuropathy in trials in seven centres. Diabetic animals and humans have a reduced ability to convert dietary linoleic acid to GLA. GLA and its metabolites are required for normal neuronal structure and function and a normal microcirculation. The lack of GLA and its metabolites may play a major role in the development of the neuropathy. EF4 helps to correct the biochemical defects, restores levels of GLA metabolites towards normal and produces highly significant clinical and neurophysiological improvements in diabetic neuropathy.

Animals↗
PubMed1992

Effect of maternal dietary fats with variable n-3/n-6 ratios on tissue fatty acid composition in suckling mice.

This report examines the distribution of n-3 and n-6 fatty acids in heart, kidney and liver phosphatidylcholine and phosphatidylethanolamine of suckling mice from dams fed a fat-supplemented diet with variable n-3/n-6 ratios. After conception and throughout the pregnancy and lactation period, dams were fed a fat-free liquid diet supplemented with 20% by energy of oil mixtures (fish oil concentrate, rich in 20:5n-3 and 22:6n-3, and safflower oil concentrate, rich in 18:2n-6). The diets contained similar amounts of combined n-3 and n-6 fatty acids but variable ratios of n-3 to n-6 fatty acids (0, 0.25, 0.5, 1, 2 and 4). In 12-day-old suckling mice, as the n-3/n-6 ratio in the maternal diet increased (up to approx. 0.5), the tissue levels of 20:5n-3, 22:5n-3 and 22:6n-3 increased, whereas those of 18:2n-6 and 20:4n-6 decreased. The responses were similar in both phospholipid subclasses, but varied between different tissues. Generally, the n-3/n-6 ratios were significantly greater in pup tissues than in milk fat, indicating preferential incorporation of n-3 over n-6 fatty acids into phospholipids during growth. However, the incorporation of n-3 fatty acids in pups was significantly suppressed whereas that of n-6 fatty acids was increased when 18:2n-6 was replaced by its delta 6-desaturation product, 18:3n-6 (concentrated from evening primrose oil), as the source of n-6 fatty acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Effect of dietary linoleic acid content on the distribution of triacylglycerol molecular species in rat adipose tissue.

The present study examined the effect of varying dietary linoleate intake (0.01, 0.24, 2.4, 24, 80 or 160 g/kg diet) for 24 weeks on the distribution of triacylglycerol (TG) molecular species in rat epididymal adipose tissue. Adipose TG fractions were purified by thin-layer chromatography and separated into different molecular species by reverse-phase high-performance liquid chromatography. The identification of TG species was based on fatty acid composition, retention time and the theoretical carbon number. When the dietary 18:2n-6 content was equal to or less than 24 g/kg, no significant amounts of n-6 fatty acids (mainly 18:2n-6) were observed in adipose tissue TG despite the fact that the levels of 20:4n-6 in liver phospholipids increased significantly. There were 12 major molecular species in adipose tissue when the dietary 18:2n-6 content was less than 2.4 g/kg. When the dietary 18:2n-6 content reached 24 g/kg, an additional six TG species containing one, two or three molecules of 18:2n-6 were observed. The levels of TG molecules containing two or three 18:2n-6 residues were further increased when the diet contained very large amounts of linoleic acid (160 g/kg). Conversely, those TG species containing only one 18:2n-6 residue became less abundant. It is suggested that the accumulation of these linoleate-rich TG molecular species in adipose tissue, particularly di- and trilinoleoyl containing TG, is the result of an adequate or an excessive intake of linoleic acid.

Adipose Tissue↗
PubMed1992

The relationship between schizophrenia and essential fatty acid and eicosanoid metabolism.

Essential fatty acids (EFAs) and their eicosanoid derivatives are important constituents of the brain and regulators of neuronal function. There is direct and indirect evidence of impaired metabolism of prostaglandin (PG)E1 in schizophrenia. There is also direct evidence of abnormal EFA biochemistry with plasma phospholipids from five populations and brain phospholipids from another all showing reduced levels of linoleic acid and elevated levels of 22-carbon EFAs of both n-6 and n-3 series. Clinical trials of PGE1 and of the PGE1 precursors, gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DGLA) have shown modest therapeutic effects. In view of lack of therapeutic process involving drugs based on the dopamine concept of schizophrenia, it is time for new approaches based on the EFA/PG concept to be evaluated thoroughly.

Alprostadil↗
PubMed1992

Effects of repeated gestation and lactation on milk n-6 fatty acid composition in rats fed on a diet rich in 18:2n-6 or 18:3n-6.

The present study examined the effect of repeated gestation and lactation on the levels of long-chain n-6 polyunsaturated fatty acids in rat milk fat, and examined whether such levels might be modulated by supplementing the diet of the lactating dams with either (g/kg) 50 safflower oil (SFO; containing 800 g 18:2n-6/kg), or 50 evening primrose oil (EPO; containing 720 g 18:2n-6 and 90 g 18:3n-6/kg). The milk was collected at three different times (days 1, 8 and 15) in each given lactation period from female Sprague-Dawley rats which were successively bred for four pregnancies and lactations. Results showed that dietary fat and breeding frequency had no significant effects on milk triacylglycerol content, but they modified the pattern of milk fatty acids in both triacylglycerol and phospholipid fractions. After three or four successive breedings rats fed on EPO produced milk containing less saturated but more monounsaturated and polyunsaturated fatty acids compared with those fed on SFO. During the course of lactation the levels of n-6 metabolites, e.g. 18:3n-6, 20:3n-6 and 20:4n-6, in milk fat declined progressively. However, they were consistently higher in the EPO group than in the SFO group. These findings suggest that the levels of long-chain n-6 metabolites in the milk fat may be increased through supplementing the maternal diet with 18:3n-6.

Animals↗
PubMed1992

Effects of cholesterol on viability and (n - 6) fatty acid metabolism in cultured human monocyte-like cells (U937).

Effects of supplementation of growth-promoting cholesterol on metabolism of the cytotoxic (n - 6) polyunsaturated fatty acids in cultured human monocyte-like cells (U937) have been examined. U937 cells were incubated in 5% delipidated fetal bovine serum containing 0 or 38.7 microM cholesterol. The rate of uptake and the distribution of metabolites of (n - 6) fatty acids (such as 18:2(n - 6), 18:3(n - 6), and 20:3(n - 6), and 20:4(n - 6)) were examined by adding radiolabelled fatty acid at a level of 1 microgram/mL (3.3 microM for 20-carbon fatty acids and 3.6 microM for 18-carbon-fatty acids). For assessing the cytotoxicity, (n - 6) fatty acids were added to medium at a concentration of 5 micrograms/mL (16.4 microM for 20-carbon fatty acids and 17.9 microM for 18-carbon fatty acids). Cholesterol supplementation suppressed the uptake of all (n - 6) fatty acids and reduced the cytotoxic effects of 18:2(n - 6), 20:3(n - 6), and 20:4(n - 6), but not 18:3(n - 6). In addition, cholesterol supplementation increased peroxide production and metabolism of (n - 6) fatty acids in U937 cells. Thus, the differential suppressive effect of cholesterol on the cytotoxicity of different fatty acids could not be attributed to an inhibitory effect on fatty acid delta 6- and delta 5-desaturation, or to an antioxidant effect on peroxide formation.

Cell Death↗
PubMed1992

The effect of chemical hepatocarcinogenesis on liver phospholipid composition in rats fed N-6 and N-3 fatty acid-supplemented diets.

The effect of dietary fats on essential fatty acid metabolism in rats subjected to chemically induced hepatocarcinogenesis was studied. Sixty male rats were fed a diet supplemented with one of the following three oil compositions: 10% hydrogenated coconut oil (HCO); 5% hydrogenated coconut oil and 5% gamma-linolenic acid (18:3n-6)-rich evening primrose oil (EPO); or 5% hydrogenated coconut oil and 5% marine oil (FO). Half of the animals in each dietary regimen were subjected to hepatocarcinogenesis induction using diethylnitrosamine and 2-acetylaminofluorene (2-AAF) followed by partial hepatectomy, whereas the other half underwent hepatectomy without receiving diethylnitrosamine and 2-acetylaminofluorene. Liver phospholipid composition was analyzed. In comparison to the HCO group, the EPO group showed raised levels of arachidonic acid (20:4n-6) and suppressed n-3 fatty acids. The FO group, on the other hand, showed suppressed levels of n-6 and increased n-3 fatty acids. Hepatocarcinogenesis suppressed the level of 20:4n-6 and this effect was greater in the FO rats. The levels of dihomo-gamma-linolenic acid (20:3n-6) were increased by the hepatocarcinogenic treatment, and this effect was further accentuated in the EPO rats. These results suggest that hepatocarcinogenesis may suppress the activity of delta-5-desaturase, which may be one of the reasons why tumor cell membranes have low levels of long chain fatty acids, especially 20:4n-6 cells, and have an impaired capacity to undergo lipid peroxidation.

Animals↗
PubMed1991

Fatty acid levels in the brains of schizophrenics and normal controls.

Essential fatty acids are important constituents of the brain. There is evidence that levels in blood of certain essential fatty acids and their eicosanoid derivatives may be abnormal. We now report that in the frontal cortex of schizophrenic patients there are significant differences from normal in the fatty acid composition of phosphatidylethanolamine. These differences from normal were not found in the cerebellar cortex.

Aged↗
PubMed1991

Essential and other fatty acids in plasma in schizophrenics and normal individuals from Japan.

Plasma phospholipid and cholesterol ester fatty acid levels were measured in samples from normal individuals, schizophrenics, and patients with affective and paranoid disorders in Japan. The schizophrenics were divided into groups with normal and reduced platelet sensitivity to the aggregation-inhibiting effects of prostaglandin (PG) E1. As in samples from schizophrenics in several other countries, linoleic acid levels were significantly below normal, as was the ratio of linoleic acid to its metabolites. Phospholipid fatty acid levels were normal in patients with paranoid or affective disorders. When the schizophrenics were divided into those with and without an abnormal response to PGE1, oleic acid was higher and eicosapentaenoic acid lower in those patients with an abnormal response. This study lends further support to the idea that schizophrenics may differ from controls in their essential fatty acid and eicosanoid metabolism.

Adult↗
PubMed1991

Gamma-linolenic acid dietary supplementation can reverse the aging influence on rat liver microsome delta 6-desaturase activity.

We have recently demonstrated that in rats the process of delta 6-desaturation of linoleic and alpha-linolenic acids slows with aging. One method of counteracting the effect of slowed desaturation of linoleic acid would be to provide the 6-desaturated metabolite, gamma-linolenic acid (18:3(n-6) GLA) directly. We have here investigated the 6-desaturation of both linoleic and alpha-linolenic acids in liver microsomes of young and old rats given GLA in the form of evening primrose oil (EPO) (B diet) in comparison to animals given soy bean oil alone (A diet), monitoring also the fatty acid composition of liver microsomes and relating this to the microviscosity of the membranes. In young rats the different experimental diets did not produce any difference in delta 6-desaturase (D6D) activity on either substrate suggesting that, when D6D activity is at or near its peak, the variations in diet tested are unable to influence it. In the old animals the rate of 6-desaturation of linoleic and particularly of alpha-linolenic acid was significantly greater in the B diet fed animals than in the A diet fed. The effects of the diets on the fatty acid composition of liver microsomes were consistent with the findings with regard to 6-desaturation. Administration of GLA partially corrected the abnormalities of n-6 essential fatty acid (EFA) metabolism by raising the concentration of 20:4(n-6) and other 6-desaturated EFAs. Furthermore, the GLA rich diet also increased the levels of dihomo-gamma-linolenic acid and of 6-desaturated n-3 EFAs in the liver microsomes. The microviscosity of microsomal membranes as indicated by DPH polarization was correlated with the unsaturation index of the same membranes. There was a very strong correlation between the two. In both young and old rats the B diet reduced the microviscosity and increased the unsaturation index. However, the effect was much greater in the old animals.

Aging↗
PubMed1991

Modification of liver fatty acid metabolism in mice by n-3 and n-6 delta 6-desaturase substrates and products.

The effects of dietary supplementation of either alpha-linolenic acid (18:3(n-3)) or stearidonic acid (18:4(n-3)) in combination with either linoleic acid (18:2(n-6)) or gamma-linolenic acid (18:3(n-6)) on liver fatty acid composition in mice were examined. Essential fatty acid deficient male C57BL/6 mice were separated into four groups of seven each and were fed a fat-free semi-purified diet supplemented with 1% (w/w) fatty acid methyl ester mixture (1:1), 18:2(n-6)/18:3(n-3), 18:2(n-6)/18:4(n-3), 18:3(n-6)/18:3(n-3), or 18:3(n-6)/18:4(n-3). After 7 days on the diets, fatty acid compositions in liver phosphatidylcholine and phosphatidylethanolamine fractions were analyzed. In groups fed 18:4(n-3) (18:2(n-6)/18:4(n-3) or 18:3(n-6)/18:4(n-3)) as compared to those fed 18:3(n-3) (18:2(n-6)/18:3(n-3) or 18:3(n-6)/18:3(n-3)), the levels of 20:4(n-3), 20:5(n-3) and 22:5(n-3) were increased, whereas those of 20:3(n-6) and 20:4(n-6) were decreased. When 18:3(n-6) replaced 18:2(n-6) as the source of n-6 acids, the levels of 18:3(n-6), 20:3(n-6), 20:4(n-6) and 22:5(n-6) were increased, whereas those of 20:4(n-3) and 20:5(n-3) were reduced. Replacing 18:3(n-3) by 18:4(n-3) reduced the (n-6)/(n-3) ratio by approx. 30%, whereas replacing 18:2(n-6) by 18:3(n-6) increased the (n-6)/(n-3) ratio by approx. 2-fold. These findings indicated that delta 6-desaturase products were metabolized more readily than their precursors. Both products also competed for the subsequent metabolic enzymes. However, the n-6 fatty acids derived from 18:3(n-6) were incorporated more favourably into liver phospholipids than n-3 fatty acids derived from 18:4(n-3).

Animals↗
PubMed1991

Is the main problem in free radical damage caused by radiation, oxygen and other toxins the loss of membrane essential fatty acids rather than the accumulation of toxic materials?

Ionising radiation, oxygen radicals, cytotoxic drugs, alcohol, inflammation, neuroleptics and many other agents are thought to damage cells in part by promoting the formation of free radicals. These radicals in turn lead to the peroxidation of essential fatty acids (EFAs) and the formation of a wide range of toxic metabolites. The production of toxic radicals and metabolites is thought to be the main cause of the damage. It is suggested that this view may be wrong, with the major component of the toxicity being attributable to loss of the highly unsaturated EFAs from membranes. If this view is correct, then antioxidant and anti-free radical therapy will be inadequate to prevent and reverse such damage. Treatment must include measures to replace the missing EFAs.

Animals↗
PubMed1991

Fatty acids in plasma phospholipids and cholesterol esters from identical twins concordant and discordant for schizophrenia.

The fatty acid compositions of plasma phospholipids and cholesterol esters were measured in 18 pairs of twins discordant for schizophrenia and 20 pairs concordant for schizophrenia. In the twins discordant for schizophrenia the only significant abnormalities were elevations of adrenic (22:4n-6) and docosapentaenoic (22:5n-6) acids in the schizophrenic twins. These fatty acids have also recently been reported to be elevated in brains from schizophrenics. The twins concordant for schizophrenia showed many differences from the normal discordant twins. 22:4n-6 and 22:5n-6 were even more abnormal than in the schizophrenic discordant twins. In addition, linoleic acid was significantly reduced, an abnormality which has been found consistently in other schizophrenic populations. These observations are consistent with the concept that unsaturated fat metabolism may be abnormal in schizophrenia.

Adult↗
PubMed1991

Tin and fatty acids in dementia.

Serum elements and fatty acids of red cell and plasma phospholipids, cholesterol esters and high density lipoproteins, were studied in patients with Alzheimer's disease (SDAT) and with multi-infarct dementia (MID). Increased 20:4n6 in MID was the finding most consistent in the different tissues. The red cell phospholipids were more unsaturated in MID than in SDAT but in SDAT the plasma phospholipids were more saturated. Serum Al, Sn and V concentrations were higher in SDAT than in MID while serum Mn concentrations were higher in MID. Sn and V correlated negatively with the unsaturation index of the red cell phospholipids and Sn showed a striking pattern of correlations with the red cell phospholipid fatty acids in SDAT: it was significantly positively correlated with 16:0 and 18:1n-9 and negatively correlated with 20 and 22 carbon n-3 and n-6 essential fatty acids. Since we have shown elevated tin levels in patients with Alzheimer's disease, and since organic tin compounds given to animals produce a syndrome with similarities to Alzheimer's disease, there is a need for investigation of the role of tin in lipid metabolism in dementia.

Aged↗