Molecular modeling and experimental confirmation of selective mobilization of polyunsaturates from triacylglycerols.
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Animals↗
Biomedical subjects
S C Cunnane
Publications and source records attributed to S C Cunnane.
Combined effect of vegetable protein (soy) and soluble fiber added to a standard cholesterol-lowering diet.
Dietary treatment of hyperlipidemia focuses on reducing saturated fat and dietary cholesterol. Other aspects of diet are not emphasized at present, despite growing evidence that a number of plant components decrease serum cholesterol. We therefore determined whether a combination of two plant components, vegetable protein and soluble fiber, further reduce serum lipids when incorporated into the currently advocated low-saturated-fat diet. Thirty-one hyperlipidemic men and women ate two 1-month low-fat (<7% of total energy from saturated fat), low-cholesterol (<80 mg cholesterol/d) metabolic diets in a randomized crossover study. The major differences between test and control diets were an increased amount of vegetable protein (93% v 23% of total protein), of which 33 g/d was soy, and a doubling of soluble fiber. Fasting blood samples were obtained at the start and end of each phase. On the last 3 days of each phase, fecal collections were obtained. Compared with the low-fat control diet, the test diet decreased total cholesterol (6.2% +/- 1.2%, P < .001), low-density lipoprotein (LDL) cholesterol (6.7% +/- 1.7%, P < .001), apolipoprotein B (8.2% +/- 1.2%, P < .001), and the ratios of LDL to high-density lipoprotein (HDL) cholesterol (6.3% +/- 2.0%, P = .004) and apolipoprotein B to A-I (5.4% +/- 1.5%, P = .001). A combination of vegetable protein and soluble fiber significantly improved the lipid-lowering effect of a low-saturated-fat diet. The results support expanding the current dietary advice to include increased vegetable protein and soluble fiber intake so that the gap in effectiveness between a good diet and drug therapy is reduced.
Aged↗
Docosahexaenoate requirement and infant development.
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Child Development↗
Uptake of 13C-tracer arachidonate and gamma-linolenate by the brain and liver of the suckling rat observed using 13C-NMR.
Arachidonic acid (AA; 20:4n-6) is one of the principal components of the phosphoglycerides in neural cell membranes. During the critical period of postnatal development in mammals, AA is supplied preformed, directly from the milk or derived from precursor fatty acids such as gamma-linolenic acid (GLA; 18:3n-6). In this study, 13C-NMR spectroscopy was applied to investigate the incorporation of [1-(13)C]AA and [3-(13)C]GLA into liver and brain lipids of 7-15-day-old rats. The main objective was to establish the importance of dietary GLA for tissue AA accretion relative to the contribution from preformed dietary AA. [1-(13)C]AA and [3-(13)C]GLA were injected into the stomach of 7-day-old rats as a mixture. 13C-NMR spectroscopy of lipid extracts revealed incorporation of [1-(13)C]AA and [5-(13)C]AA (the latter derived from metabolism of the injected [3-(13)C]GLA) into phosphoglycerides and triacylglycerols. Preformed AA was 10 (liver)-17 (brain) times more efficient in contributing to tissue AA than AA derived from precursor GLA. In separate experiments, NMR spectroscopy was used to assess uptake of [1-(13)C]AA directly in living rats and intact organs. Results showed that intact liver and brain contain an appreciable amount of NMR-detectable lipids. The in vivo/in vitro information obtained from organs provided details on the mobility and turnover of tissue lipids.
Animals↗
Health aspects of partially defatted flaxseed, including effects on serum lipids, oxidative measures, and ex vivo androgen and progestin activity: a controlled crossover trial.
BACKGROUND: Currently there is considerable interest in the potential health benefits of oil seeds, such as soy and flaxseed, especially in relation to cardiovascular disease and cancer. OBJECTIVE: We therefore evaluated health aspects of partially defatted flaxseed in relation to serum lipids, indicators of oxidative stress, and ex vivo sex hormone activities. DESIGN: Twenty-nine hyperlipidemic subjects (22 men and 7 postmenopausal women) completed two 3-wk treatment periods in a randomized, crossover trial. Subjects were given muffins that contributed approximately 20 g fiber/d from either flaxseed (approximately 50 g partially defatted flaxseed/d) or wheat bran (control) while they consumed self-selected National Cholesterol Education Program Step II diets. Both muffins had similar macronutrient profiles. Treatment phases were separated by > or = 2 wk. RESULTS: Partially defatted flaxseed reduced total cholesterol (4.6+/-1.2%; P = 0.001), LDL cholesterol (7.6+/-1.8%; P < 0.001), apolipoprotein B (5.4+/-1.4%; P = 0.001), and apolipoprotein A-I (5.8+/-1.9%; P = 0.005), but had no effect on serum lipoprotein ratios at week 3 compared with the control. There were no significant effects on serum HDL cholesterol, serum protein carbonyl content, or ex vivo androgen or progestin activity after either treatment. Unexpectedly, serum protein thiol groups were significantly lower (10.8+/-3.6%; P = 0.007) at week 3 after the flaxseed treatment than after the control, suggesting increased oxidation. CONCLUSIONS: These data indicate that partially defatted flaxseed is effective in lowering LDL cholesterol. No effects on lipoprotein ratios, ex vivo serum androgen or progestin activity, or protein carbonyl content were observed. The significance of increased oxidation of protein thiol groups with flaxseed consumption requires further investigation.
Adult↗
The long history of essential fatty acids but belated knowledge about linoleate deficiency per se: a paradox.
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Fatty Acids, Essential↗
Fatty acid profiles of maternal adipose tissue in relation to infant development.
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Adipose Tissue↗
Critical assessment of in vivo 13C NMR spectroscopy and gas-liquid chromatography in the study of adipose tissue composition.
Routine measurement of adipose tissue composition by repeated biopsy invokes both ethical and practical difficulties, limiting long-term serial studies of adipose tissue composition. In vivo 13C nuclear magnetic resonance (NMR) spectroscopy has been applied as a non-invasive alternative, although it has not as yet been fully validated. In this study we critically assess in vivo 13C NMR spectroscopy and gas-liquid chromatography for the analysis of adipose tissue composition. The advantages and drawbacks of both methods are discussed, in particular to the study of adipose tissue during dietary manipulation and development. Our results show that the NMR measurements of adipose tissue composition are highly reproducible, but they can significantly differ froM those obtained by gas-liquid chromatography (GLC) from the same volunteer. We show that the discrepancy between these two techniques arises from inherent limitations of both 13C NMR spectroscopy and GLC. Finally, we show that 13C NMR spectroscopy remains a useful non-invasive tool for the study of adipose tissue, and will enable us to perform long-term serial studies to further our knowledge of lipid metabolism.
Adipose Tissue↗
Recycling of carbon into lipids synthesized de novo is a quantitatively important pathway of alpha-[U-13C]linolenate utilization in the developing rat brain.
Docosahexaenoate is important for normal neural development. It can be derived from alpha-linolenate, but carbon from alpha-linolenate is also recycled into de novo lipid synthesis. The objective of this study was to quantify the amount of alpha-linolenate used to produce docosahexaenoate versus lipids synthesized de novo that accumulate in the brain of the developing rat. A physiological dose of carbon-13-labeled alpha-linolenate was injected into the stomachs of mother-reared 6-day-old rat pups. Total lipids of brain, liver, and gut were extracted from rats killed 3 h to 30 days after dosing. Carbon-13 enrichment was determined by isotope ratio mass spectrometry. Carbon-13-enriched alpha-linolenate was not detected in the brain at any time point, and its levels in liver and gut exceeded detection limits at most time points, so tracer mass was quantified mainly for three end products--docosahexaenoate, palmitate, and cholesterol. Carbon-13-enriched cholesterol, palmitate, docosalphahexaenoate, and water-soluble metabolites were detected in brain, liver, and gut Enrichment (in micrograms of carbon-13 per organ) in brain cholesterol exceeded that in brain docosahexaenoate by four- to 16-fold over the duration of the study. Enrichment in brain palmitate exceeded that in brain docosahexaenoate by three- to 30-fold over the first 8 days of the study. These results indicate that carbon from alpha-linolenate is not exclusively conserved for synthesis of longer n-3 polyunsaturates but is a readily accessible carbon source for de novo lipogenesis during early brain development in the suckling rat. Owing to a high rate of beta-oxidation and carbon recycling, dependence on alpha-linolenate as the sole source of docosahexaenoate may incur a potential risk of providing insufficient docosahexaenoate for the developing brain.
Aging↗
Rift Valley lake fish and shellfish provided brain-specific nutrition for early Homo.
An abundant, balanced dietary intake of long-chain polyunsaturated fatty acids is an absolute requirement for sustaining the very rapid expansion of the hominid cerebral cortex during the last one to two million years. The brain contains 600 g lipid/kg, with a long-chain polyunsaturated fatty acid profile containing approximately equal proportions of arachidonic acid and docosahexaenoic acid. Long-chain polyunsaturated fatty acid deficiency at any stage of fetal and/or infant development can result in irreversible failure to accomplish specific components of brain growth. For the past fifteen million years, the East African Rift Valley has been a unique geological environment which contains many enormous freshwater lakes. Paleoanthropological evidence clearly indicates that hominids evolved in East Africa, and that early Homo inhabited the Rift Valley lake shores. Although earlier hominid species migrated to Eurasia, modern Homo sapiens is believed to have originated in Africa between 100 and 200 thousand years ago, and subsequently migrated throughout the world. A shift in the hominid resource base towards more high-quality foods occurred approximately two million years ago; this was accompanied by an increase in relative brain size and a shift towards modern patterns of fetal and infant development. There is evidence for both meat and fish scavenging, although sophisticated tool industries and organized hunting had not yet developed. The earliest occurrences of modern H. sapiens and sophisticated tool technology are associated with aquatic resource bases. Tropical freshwater fish and shellfish have long-chain polyunsaturated lipid ratios more similar to that of the human brain than any other food source known. Consistent consumption of lacustrine foods could have provided a means of initiating and sustaining cerebral cortex growth without an attendant increase in body mass. A modest intake of fish and shellfish (6-12% total dietary energy intake) can provide more arachidonic acid and especially more docosahexaenoic acid than most diets contain today. Hence, 'brain-specific' nutrition had and still has significant potential to affect hominid brain evolution.
Africa, Eastern↗
Substantial carbon recycling from linoleate into products of de novo lipogenesis occurs in rat liver even under conditions of extreme dietary linoleate deficiency.
A significant portion of the beta-oxidized carbon skeleton of some polyunsaturated fatty acids can be recycled into de novo lipogenesis, i.e., cholesterol, saturates and monounsaturates. The recycling of carbon from linoleate was quantified in liver lipids of severely linoleate-deficient rats to determine whether it is more likely to be a function of redundancy or could be obligatory. After 13 wk on a control (2 energy % linoleate) or severely linoleate-deficient (<0. 05 energy % linoleate) diet, 7 muCi [1-14C]linoleate was given by gavage and the rats were killed 48 h later. A second linoleate-deficient group received an oral bolus of 256 mg linoleate as a supplement with the radiotracer. In comparison to the controls, 14C recovery in liver total lipids of the linoleate deficient group was increased about 5-fold with increased dpm/g in linoleate (13.7-fold higher), arachidonate (2.7-fold higher) and products of de novo lipogenesis (3.5-fold higher). In livers of control rats, 14C distribution was: 41% arachidonate, 29% linoleate, 22% sterols, 3% oleate, 3% palmitate, and 2% stearate. In livers of linoleate-deficient rats, 14C distribution was: 63% linoleate, 19% arachidonate, 11% sterols, 4% oleate, 3% palmitate, and <1% stearate. Thus, in controls, equivalent amounts of 14C were in products of de novo lipogenesis as in linoleate (29-30%), and in livers of linoleate-deficient rats, a similar proportion of 14C was in products of de novo lipogenesis as was converted to arachidonate (18-19%). We conclude that carbon recycling into de novo lipogenesis accounts for a significant, obligatory component of linoleate metabolism even during extreme linoleate deficiency.
Animals↗
Changes in adipose tissue composition in malnourished patients before and after liver transplantation: a carbon-13 magnetic resonance spectroscopy and gas-liquid chromatography study.
We investigated adipose tissue fatty acid composition in 22 moderately to severely malnourished patients with cirrhosis and in 22 healthy volunteers by in vivo carbon-13 magnetic resonance spectroscopy (MRS). Gas-liquid chromatography (GLC) of adipose tissue samples was also performed in 11 of the patients and in 4 volunteers. In vivo 13C magnetic resonance spectra were obtained from the subcutaneous adipose tissue before and after eight weeks following orthotopic liver transplantation (OLT). Adipose tissue biopsy samples were obtained for GLC analysis at the time of transplantation in the patients and at inguinal hernia repair in the 4 volunteers. No significant differences were found in the subcutaneous adipose tissue total-saturated, -polyunsaturated or -monounsaturated fatty acid composition between patients and healthy volunteers by in vivo 13C MRS. GLC analysis of adipose tissue samples confirmed that total levels of saturated, poly-, and monounsaturated fatty acids remained the same but revealed significant differences in levels of individual fatty acids, particularly n-3 fatty acids (total n-3, cirrhotics: .84% +/- .07% vs. controls: 1.36% +/- .13%, P < .01). Eight weeks following transplantation, recipients showed a considerable increase in body mass (pretransplantation: 59.3 +/- 3.2 vs. posttransplantation: 63.2 +/- 3 kg, P < .01). 13C MRS revealed a significant increase in saturated fatty acids (pretransplantation: 21.6 +/- 2.8 vs. posttransplantation: 25.5% +/- 1.2%, P < .05) and a significant decrease in unsaturated fatty acids. The application of noninvasive MRS techniques may be important to identify the differential uptake of fats, examining both specific fatty acids and different body fat compartments. In the future, this may be useful in optimizing the dietary management of severely malnourished patients with chronic liver disease before liver transplantation.
Adipose Tissue↗
[3-13C] gamma-linolenic acid: a new probe for 13C nuclear magnetic resonance studies of arachidonic acid synthesis in the suckling rat.
Our objective was to develop a suitable probe to study metabolism of polyunsaturated fatty acids by 13C nuclear magnetic resonance (NMR) in the suckling rat pup. [3-13C] gamma-Linolenic acid was chemically synthesized, and a 20 mg (Experiment 1) or 5 mg (Experiment 2) dose was injected into the stomachs of 6-10-day-old suckling rat pups that were then killed over a 192 h (8 d) time course. 13C NMR showed that 13C in gamma-linolenate peaked in liver total lipids by 12-h post-dosing and that [5-13C]-arachidonic acid peaked in both brain and liver total lipids 48-96 h post-dosing. 13C enrichment in brain gamma-linolenic acid was not detected by NMR, but gas chromatography-combustion-isotope ratio mass spectrometry showed that its mass enrichment in brain phospholipids at 48-96 h post-dosing was 1-2% of that in brain arachidonic acid. 13C was present in liver and brain cholesterol and in perchloric acid-extractable water-soluble metabolites in the brain, liver and carcass. We conclude that low but measurable amounts of exogenous gamma-linolenic acid do access the suckling rat brain in vivo. The slow time course of [5-13C] arachidonic acid appearance in the brain suggests most of it was probably transported there after synthesis elsewhere, probably in the liver. Some carbon from gamma-linolenic acid is also incorporated into lipid products other than n-6 long-chain polyunsaturated fatty acids.
Animals↗
Metabolic effects of non-absorbable carbohydrates.
Food components which are incompletely absorbed in the small intestine or not absorbed at all but are delivered to the colon have been part of the diet throughout the course of human evolution. Our great ape cousins may derive 30% or more of their dietary calories from colonic uptake of short-chain fatty acids (SCFAs) generated in the colon. The metabolic effects of dietary carbohydrate entering the colon are many and include laxation, the growth of the fecal biomass, nitrogen entrapment and SCFA generation. These SCFAs in turn may nourish mucosal cells, spare glutamine utilization, enhance hepatic gluconeogenesis and lipogenesis and possibly influence renal handling of uric acid. The health implications are significant in terms of modifying risk factors for disease and disease prevention and justify interest in the metabolic effects of non-absorbable sugars such as lactulose.
Animals↗
Effect of psyllium in hypercholesterolemia at two monounsaturated fatty acid intakes.
We performed two studies to determine whether the lipid-lowering effect of viscous soluble fiber was modified by monounsaturated fatty acid (MUFA). First, psyllium (1.4 g/MJ) was compared with wheat bran (control) in 1-mo metabolic diets by using a randomized crossover design (n = 32 hyperlipidemic subjects). The background diet contained approximately 6% of energy as MUFA (20% of total fat). The second study (n = 27 hyperlipidemic subjects) was similar to the first but the background diet contained approximately 12% MUFA (29% of total fat) because of the addition of canola oil. At both fat intakes, psyllium resulted in significant reductions in total, low-density-lipoprotein (LDL), and high-density-lipoprotein (HDL) cholesterol compared with the wheat bran control. For the psyllium diet at 6% compared with 12% MUFA, the decreases in LDL cholesterol were 12.3 +/- 1.5% (P < 0.001) and 15.3 +/- 2.4% (P < 0.001), respectively. With the higher-MUFA diet triacylglycerol fell significantly over the control phase (16.6 +/- 5.5%, P = 0.006) and the ratio of LDL to HDL cholesterol fell significantly over the psyllium phase (7.3 +/- 2.8%, P = 0.015). Psyllium and MUFA intakes were negatively related to the percentage change in the ratio of LDL to HDL cholesterol (r = -0.34, P = 0.019 and r = -0.44, P = 0.002, respectively). Chenodeoxycholate synthesis rate increased (30 +/- 13%, P = 0.038) with the psyllium diet in the 12 subjects in whom this was assessed. We conclude that psyllium lowered LDL- and HDL-cholesterol concentrations similarly at both MUFA intakes. However, there may be some advantage in combining soluble fiber and MUFA to reduce the ratio of LDL to HDL cholesterol.
Apolipoproteins B↗
The majority of dietary linoleate in growing rats is beta-oxidized or stored in visceral fat.
On a quantitative, whole-body basis, little is known about the amount of linoleate that is converted to arachidonate or the partitioning of linoleate and its longer-chain derivatives among lean and fat tissues. The aim of the present study was to examine linoleate balance and organ partitioning in rats consuming a low but adequate level of linoleate. Weanling male Sprague-Dawley rats were given free access to a semipurified diet containing 2.3% of energy as linoleate. Food intake, fecal output and body weight gain were measured for 26 d. Whole-body fatty acid balance analysis showed that 75.5% of the linoleate consumed disappeared (apparently by beta-oxidation), 18.7% was accumulated as linoleate, 3.0% was converted to (n-6) longer-chain polyunsaturated fatty acids, and 1.2% was excreted in the feces Visceral fat contained 64% of the accumulated linoleate, and 23% was in lean tissues. Comparable values for alpha-linolenate were as follows: disappearance (84.9%), accumulation (10.9%), excretion in the feces (2.2%), and conversion to (n-3) longer-chain polyunsaturated fatty acids (1.4%). Visceral fat contained 67% of the accumulated alpha-linolenate, and 23% was in lean tissues. Visceral fat also accumulated 26% of newly synthesized (n-6) longer-chain polyunsaturated fatty acids and 31% of the (n-3) longer-chain polyunsaturated fatty acids. Thus, only 6.5% of dietary linoleate consumed at a low but adequate level for rats appeared in lean tissues as linoleate or its fatty acid metabolites; the rest was beta-oxidized or stored in fat, mostly in visceral fat. These results lead us to speculate whether losses through beta-oxidation contribute to the recommended intake for linoleate in growing rats.
Adipose Tissue↗
Pure linoleate deficiency in the rat: influence on growth, accumulation of n-6 polyunsaturates, and [1-14C]linoleate oxidation.
Essential fatty acid deficiency has been widely studied but the extent to which its effects are attributable specifically to deficiency of linoleate as opposed to deficiency of all unsaturated fatty acids is unknown. Our objective was to evaluate the effect of pure linoleate deficiency on growth as well as changes in the metabolism and oxidation of n-6 polyunsaturates. The diets contained 20 energy % fat blended from 3 energy % pure oleate, 2 energy % linoleate (0.01 energy % in the linoleate-deficient group), 0.3 energy % pure alpha-linolenate, and the balance as palmitate and stearate from fully hydrogenated soybean oil. Thirty-five-day-old rats consumed the two diets for 84 days, after which the linoleate-deficient rats weighed 15% less than the controls (P < 0.05), had mild scaling on the paws, and visible hair loss (in a few rats). Compared with the controls, the ratio of eicosatrienoate to arachidonate after 84 days was elevated in liver (170-fold) and serum (520-fold) phospholipids of the linoleate-deficient group. In total, linoleate-deficient rats consumed 122 mg of linoleate and had a net whole body loss of 479 mg n-6 polyunsaturates compared with an intake of 24,130 mg and a net whole body gain of 7206 mg n-6 polyunsaturates in the control group. Linoleate-deficient rats oxidized 1% of an oral bolus of [1-14C]linoleate over 8 h compared with 34% in the control rats (P < 0.05). We conclude that pure linoleate deficiency has marked effects on accumulation of n-6 polyunsaturates but induces milder gross symptoms, particularly growth retardation, than classical essential fatty acid deficiency. alpha-Linolenate and possibly oleate may have a sparing effect on linoleate oxidation from body stores during linoleate deficiency.
Adipose Tissue↗
In vivo 13C nuclear magnetic resonance: applications and current limitations for noninvasive assessment of fatty acid status.
As a noninvasive method, in vivo 13C nuclear magnetic resonance has potentially important applications in understanding the metabolism of long chain fatty acids in organs of living humans. At present, this methodology is most advanced for research on glucose utilization. However, the main 13C signals visible in vivo are from fatty acids in adipose tissue and the olefinic signals can be used to noninvasively estimate adipose tissue content and relative dietary intake of polyunsaturates and monounsaturates. The low natural abundance of 13C improves the utility of this isotope for fatty acid tracer studies. Due to excessive signal broadening, uniform 13C-labelling seems to have limited application in in vivo fatty acid studies. Tracer fatty acids with 13C enrichment at a specific carbon position, i.e., [13-13C] gamma-linolenate, appear to be the most useful for in vivo tracer studies. Development of methods permitting resolution of 13C enrichment in structural lipids of lean tissues will be an important breakthrough which may make human tracer studies feasible and worthwhile.
Adipose Tissue↗