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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 109 records · Page 6Linked to original sources
PubMed1993

Effect of salt-loading and spontaneous hypertension on in vitro metabolism of [1-14C]linoleic and [2-14C]dihomo-gamma-linolenic acids.

The present study compared the effect of spontaneous hypertension and salt-loading on in vitro metabolism of 18:2n-6 (linoleic acid) and 20:3n-6 (dihomo-gamma-linolenic acid). Ten weanling spontaneously hypertensive rats (SHR) and 10 normotensive Wistar-Kyoto rats (WKY) maintained on a rodent lab chow were given tap water with (n = 5) or without (n = 5) addition of 1% NaCl for 4 weeks. Thereafter, animals were killed and liver microsomes were prepared. Aliquots of microsomes suspended in the phosphate-sucrose buffer containing MgCl2, ATP, CoA, and NADPH were incubated with 0.3 microCi of [1-14C]-18:2n-6 or [2-14C]-20:3n-6 at 37 degrees C for 15 min. The activity of delta 6- and delta 5-desaturases, and the distribution of radioactivity in different lipid fractions and in phospholipid fatty acids were determined. Results showed that both spontaneous hypertension and salt-loading suppressed the desaturation of radiolabeled 18:2n-6 and of 20:3n-6. Incubation of microsomes with [1-14C]-18:2n-6 resulted in 29% of radioactivity being associated with phospholipid fraction, of which 3% was associated with 18:3n-6. Incubation with radiolabeled 20:3n-6 resulted in 30% of the radioactivity being incorporated into phospholipids, of which 50% was associated with 20:4n-6 (arachidonic acid). Salt-loading suppressed the incorporation of radiolabeled fatty acids into phospholipids, more so in SHR than in WKY. Thus, salt-loading not only suppressed the desaturation of 18:2n-6 and 20:3n-6, but also interfered with the acylation of n-6 fatty acids into the phospholipid fraction.

Animals↗
PubMed1993

Relationship between mouse liver delta 9 desaturase activity and plasma lipids.

This study was undertaken to investigate the total plasma fatty acid composition and the relationship between plasma triacylglycerol (TG) levels and liver delta 9 desaturase activity in mice fed n-3 and/or n-6 fatty acid or hydrogenated coconut oil (HCO) (maximum 25 mg/g) supplemented diets. Generally, plasma TG levels and delta 9 desaturase activity were inversely correlated with the ratio of the sum of long chain n-6 fatty acids to 18:2n-6 and to the ratio of the sum of long chain n-3 fatty acids to 18:n-3, but they were positively correlated with the ratio of products and substrates (18:1/18:0) of the enzyme in plasma total lipids. The n-3 fatty acid (mainly 20:5n-3) enriched diet, when compared to the HCO diet at 21 d, caused a significant reduction in plasma TG levels but not in delta 9 desaturase activity. However, a marked reduction in plasma TG content (50-60%) and delta 9 desaturase activity (55-70%) was observed when both 20:5n-3 and 18:3n-6 were supplemented in the diet. The plasma TG levels and delta 9 desaturase activity rose again when the animals were fed the HCO diet or chow. The results suggest that low dose supplementation of a mixture of n-3 (mainly 20:5n-3) and n-6 (18:3n-6) fatty acids modified both plasma TG content and liver delta 9 desaturase activity, in parallel.

Animals↗
PubMed1993

Comparison of the metabolism of alpha-linolenic acid and its delta 6 desaturation product, stearidonic acid, in cultured NIH-3T3 cells.

The incorporation and metabolism of alpha-linolenic acid (18:3n-3) and its delta 6 desaturase product, stearidonic acid (18:4n-3), were compared by NIH-3T3 cells. In the presence of fetal calf serum, cells accumulated exogenously added 18:3n-3 and 18:4n-3 apparently at the expense of oleic acid (18:1n-9). Both 18:3n-3 and 18:4n-3 were elongated and desaturated to eicosatetraenoic acid (20:4n-3), eicosapentaenoic acid (20:5n-3) and docosapentaenoic acid (22:5n-3), but not to docosahexaenoic acid (22:6n-3), and were incorporated into phospholipids and triacylglycerols. Over a 4-d period, the growth of NIH-3T3 cells was slightly stimulated in the presence of 18:3n-3 (20 micrograms/mL) but was strongly inhibited in the presence of 18:4n-3 at the same concentration. This inhibition may be caused by enhanced lipid peroxidation as a result of the high levels of 18:4n-3 present.

3T3 Cells↗
PubMed1993

The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms.

Gamma-linolenic acid (GLA) has recently been found to be beneficial in the management of breast pain and of diabetic neuropathy. GLA is a precursor of unsaturated fatty acids which are important in membrane structures, as second messengers in their own right and as precursors of eicosanoids. While the mechanisms of GLA action are likely to be complex, non-eicosanoid effects are probably of substantial importance. These effects include modification of membrane fluidity and of the functions of lipid-associated receptors and changes in the inositol cycle.

Breast Diseases↗
PubMed1993

The modulation of radiation-induced damage to pig skin by essential fatty acids.

The ability of essential fatty acids (EFAs) to modulate radiation-induced normal tissue injury was assessed in pig skin. Female Large White pigs (approximately 25 Kg) received 3 ml/day orally of either an 'active' oil [So-1100, containing 9% gamma-linolenic acid (GLA)] or a 'placebo' oil (So-1129) for just 4 weeks before or for 4 weeks before and for 16 weeks after irradiation; localised irradiation of skin was with single doses of beta-rays from 22.5 mm diameter 90Sr/90Y plaques. The severity of the acute reaction, assessed in terms of erythema or moist desquamation, was significantly less in those pigs that received So-1100 both before and after irradiation, as compared with those receiving that oil only prior to irradiation and the 'placebo' groups. Dose modification factors (DMFs) of between 1.13-1.24 were obtained. A similar reduction in the severity of acute skin injury was seen in pigs receiving So-1100 for only 10 weeks after irradiation. Late skin damage, assessed in terms of late erythema or dermal necrosis, was also reduced with So-1100, with DMFs of 1.14-1.51. No such modification was observed if So-1100 was only administered for 4 weeks prior to irradiation. No adverse side-effects were apparent as a result of EFA administration. So-1100 may represent a safe and valuable method of increasing the therapeutic gain in radiotherapy.

Animals↗
PubMed1993

Fatty acid metabolism in health and disease: the role of delta-6-desaturase.

Linoleic acid is the main dietary essential fatty acid (EFA). To be fully utilized by the body, it must be metabolized to a range of other substances. The first step in this pathway is delta-6-desaturation to gamma-linolenic acid (GLA). This step is slow and rate-limiting, particularly in humans. If delta-6-desaturation is impaired for any reason, the supply of further metabolites may be inadequate for normal function. If the consumption of further metabolites is excessive, then a normal rate of delta-6-desaturation may be inadequate. In these circumstances the direct supply of GLA or further metabolites may be of value. This concept is illustrated by atopic eczema and diabetes, which may represent inherited and acquired examples of inadequate delta-6-desaturation.

Dermatitis, Atopic↗
PubMed1993

Abnormalities in dihomo-gamma-linolenic acid release in the pathogenesis of hypertension.

Spontaneously hypertensive rats (SHR) respond to angiotensin and norepinephrine with an exaggerated pressor response. We have investigated the possibility that increased vascular reactivity in SHR may be related to a reduced synthesis of prostaglandin E1 (PGE1) resulting from a defect in the release of its precursor, dihomo-gamma-linoleic acid (DGLA). Isolated perfused mesenteric vascular beds of SHR and age matched Wistar-Kyoto rats (WKY) were perfused with Kreb's bicarbonate buffer. The effluent was collected and the fatty acid composition determined by gas chromatography. In SHR the release of DGLA, arachidonic acid, eicosapentaenoic acid, and virtually all other fatty acids detected in the effluent were reduced when compared to their normotensive controls. This difference could not be explained by low tissue fatty acid levels because these were higher in SHR. Evening primrose oil (EPO) when added to the diet increased the release of DGLA but not of other prostanoid precursors. EPO also reduced vascular reactivity and reduced blood pressure in SHR. It is suggested that the defect in the release of DGLA may be involved in the pathogenesis of hypertension because it occurs early before hypertension has actually occurred.

8,11,14-Eicosatrienoic Acid↗
PubMed1993

Cholesterol metabolism and violence: a study of individuals convicted of violent crimes.

To examine the relationship between plasma lipoproteins and apolipoproteins in men with convictions for violent offences, blood was obtained from 15 men with a history of violence who were serving prison sentences for violent offences, and 25 age-matched male controls from the staff of the Argyll and Bute Psychiatric Hospital, who had no criminal records. The two groups did not differ in plasma total cholesterol concentrations, HDL-C, LDL-C, VLDL-C or in HDL subfractions. The most significant differences in the offenders were higher apoprotein AIV (3.62 vs 0.85: p = < 0.000001) and higher apoprotein E (7.70 vs 5.19: p = < 0.0002).

Adult↗
PubMed1993

Effects of maternal dietary n-3 and n-6 fatty acids (pre- and post-delta 6 desaturation) on tissue glycerophospholipid fatty acid compositions in dams and suckling mice.

The present study examined the effects of supplementation of either 18:3n-3 or a mixture of its post-delta 6-desaturation metabolites, 20:5n-3/22:6n-3, in combination with either 18:2n-6 or its immediate delta 6-desaturation product, 18:3n-6, in the maternal diet (n-3 to n-6 ratio at 0.25) on brain, liver, heart, and kidney glycerophospholipid fatty acid composition in dams (B6D2F1 mice) and their 12-day-old suckling pups. As expected, n-3 and n-6 fatty acids competed for incorporation into tissue glycerophospholipids in both dams and their suckling pups. Feeding a 20:5n-3/22:6n-3 as compared with an 18:3n-3 rich diet increased the tissue levels of 20:5n-3 and 22:5n-3, whereas it decreased those of 20:3n-6 and 20:4n-6. Replacing 18:2n-6 with 18:3n-6 in the maternal diet increased significantly the levels of 18:3n-6, 20:3n-6, and 20:4n-6, whereas it reduced those of 20:5n-3. However, the effects of maternal dietary fats on tissue fatty acid compositions in pups were qualitatively similar to but quantitatively smaller than those in dams. The discrepancy might be due to differences in the composition of fatty acids taken up and synthesized by the dams and that transferred to the pups.

Animals↗
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↗