Diet-Regulating Microbiota and Host Immune System in Liver Disease

The gut microbiota has been known to modulate the immune responses in chronic liver diseases. Recent evidence suggests that effects of dietary foods on health care and human diseases are related to both the immune reaction and the microbiome. The gut-microbiome and intestinal immune system play a central role in the control of bacterial translocation-induced liver disease. Dysbiosis, small intestinal bacterial overgrowth, translocation, endotoxemia, and the direct effects of metabolites are the main events in the gut-liver axis, and immune responses act on every pathways of chronic liver disease. Microbiome-derived metabolites or bacteria themselves regulate immune cell functions such as recognition or activation of receptors, the control of gene expression by epigenetic change, activation of immune cells, and the integration of cellular metabolism. Here, we reviewed recent reports about the immunologic role of gut microbiotas in liver disease, highlighting the role of diet in chronic liver disease.     

Influence of dietary partially hydrogenated vegetable and marine oils on membrane composition and function of liver microsomes and platelets in the rat

The aim of the present study was to investigate the influence of partially hydrogenated vegetable and marine oils on membrane composition and function of liver microsomes and platelets with particular reference to the metabolism of linoleic acid and the production of arachidonic acid metabolites. Four groups of male weanling rats were fed linoleic acid supplemented diets containing 20% (w/w) of partially hydrogenated low erucic acid rapeseed oil (HLRSO), partially hydrogenated herring oil (HHO), olive oil (OO) and trierucin + triolein (TE) for 10 weeks. An additional two groups were fed partially hydrogenated low erucic acid rapeseed oil and partially hydrogenated herring oil without linoleic acid supplementation (HLRSO- and HHO-, respectively). Substantial amounts oftrans fatty acids were incorporated into liver microsomes (12.6% in group HLRSO) and platelets (7.0% in group HLRSO-). This incorporation was not dependent on the dietary linoleic acid level. Hepatic microsomal Δ⁵-desaturase activity was significantly increased after HLRSO feeding compared to OO feeding. Δ⁶-Desaturase activity did not vary in the linoleic acid supplemented groups. Both Δ⁵- and Δ⁶-desaturase activities were significantly increased in groups without linoleic acid supplementation. Docosenoic acid was incorporated into platelet phospholipids in contrast to liver microsomes. In the platelet, docosenoic acid seemed to have a special preference for phosphatidylserine. Very small amounts were incorporated into platelet phosphatidylinositol. Feeding diets HLRSO, HHO and OO did not influence rat platelet cyclooxygenase or 12-lipoxygenase activity. Platelets from rats fed TE, however, produced significantly less 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) than platelets from rats fed OO. Feeding of HLRSO- and HHO- resulted in a significantly diminished production of the arachidonic acid metabolites 12-HETE, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 6-keto-prostaglandin F_1α in stimulated platelets and aorta. Thus, high dietary levels oftrans isomers of monoenoic acids do not interfere with platelet cyclooxygenase or lipoxygenase activity provided sufficient amounts of linoleic acid are available.     

Decrease in platelet reduced glutathione increases lipoxygenase activity and decreases vitamin E

Unstimulated normal human blood platelets were treated with azodicarboxylic acidbis(dimethylamide) (diamide), a thiol-oxidizing agent. Oxygenated arachidonic acid (AA) metabolites, malondialdehyde (MDA), and tocopherols were then quantified by high-performance liquid chromatography (HPLC). Diamide treatment partially decreased the amount of reduced glutathione (GSH) content and induced a subsequent decrease in peroxidase activity. However, formation of 12-hydroxy-eicosatetraenoic acid (12-HETE), the end-product of lipoxygenation of AA, increased. Formation of MDA, a marker of overall lipid peroxidation, was also enhanced. Furthermore, platelet α-tocopherol, but not γ-tocopherol, significantly decreased. These results indicate that enhanced “basal” lipoxygenase activity, as a marker of specific AA oxygenation, may be linked to decreased platelet antioxidant status.     

Platelet and aorta arachidonic and eicosapentaenoic acid levels andin vitro eicosanoid production in rats fed high-fat diets

There is a significant interest in the interrelationship between long-chain n-3, and n-6 fatty acids due to their ability to modulate eicosanoid production. In general, the intake of arachidonic acid (AA) results in enhanced eicosanoid production, whereas n-3 polyunsaturated fatty acids (PUFA) decrease the production of eicosanoids from AA. The purpose of this study was to investigate whether the effects of dietary AA on eicosanoid production in the rat were correlated with the AA and EPA levels in platelets and aorta (eicosanoid-producing tissues). Four groups of male Sprague-Dawley rats were fed a highfat diet enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (approximately 100 mg/day of EPA+DHA) for 24 d. During the last 10 d, the four groups were orally supplemented with 0,30,60, and 90 mg/day of ethyl arachidonate. A further group of rats was fed a control diet (without longchain n-3 PUFA) for 24 d.In vitro aorta prostacyclin (PGI₂) production, serum thromboxane A₂ (TxA₂) production and plasma, and platelet and aorta phospholipid (PL) fatty acids were measured. Enriching the diet with n-3 PUFA resulted in significant reductions in tissue AA levels and an increase in the n-3 PUFA, particularly EPA. On this diet, the AA to EPA ratio was 1:1 in platelet PL, and it was 2:1 in the aorta PL. There were significant decreases in thein vitro PGI₂ and TxA₂ production compared with the control animals. The inclusion of AA in the diet resulted in marked increases in AA levels in the platelet and aorta PL with corresponding decreases in EPA. The lowest dose of AA (30 mg/rat) reversed the effects of 100 mg/day of n-3 PUFA on AA levels in platelet and aortic PL and onin vitro aorta PGI₂ and serum TxA₂ production. The dietary AA caused a differential (twofold) increase in TxA₂ relative to PGI₂ for all three levels of AA supplementation. There were greater changes in the levels of AA and/or EPA in platelet PL compared with the aorta PL, which might have accounted for the differential effects of these PUFA on thromboxane production compared with PGI₂ production in this study.     

Tryptophan Metabolism and Gut-Brain Homeostasis

Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.     

The effect of dietary arachidonic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans

Arachidonic acid (AA) is the precursor of thromboxane and prostacyclin, two of the most active compounds related to platelet function. The effect of dietary AA on platelet function in humans is not understood although a previous study suggested dietary AA might have adverse physiological consequences on platelet function. Here normal healthy male volunteers (n=10) were fed diets containing 1.7 g/d of AA for 50 d. The control diet contained 210 mg/d of AA. Platelet aggregation in the platelet-rich plasma was determined using ADP, collagen, and AA. No statistical differences could be detected between the aggregation before and after consuming the high-AA diet. The prothrombin time, partial thromboplastin time, and the antithrombin III levels in the subjects were determined also. There were no statistically significant differences in these three parameters when the values were compared before and after they consumed the high-AA diet. The in vivo bleeding times also did not show a significant difference before and after the subjects consumed the high-AA diet. Platelets exhibited only small changes in their AA content during the AA feeding period. The results from this study on blood clotting parameters and in vitro platelet aggregation suggest that adding 1.5 g/d of dietary AA for 50 d to a typical Western diet containing about 200 mg of AA produces no observable physiological changes in blood coagulation and thrombotic tendencies in healthy, adult males compared to the unsupplemented diet. Thus, moderate intakes of foods high in AA have few effects on blood coagulation, platelet function, or platelet fatty acid composition.     

Polyunsaturated fatty acids, inflammation, and immunity

The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n−6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n−3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n−3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n−3 PUFA in fish oil are antiinflammatory and immunomodulatory.     

Are Alterations in DNA Methylation Related to CKD Development?

The modifications in genomic DNA methylation are involved in the regulation of normal and pathological cellular processes. The epigenetic regulation stimulates biological plasticity as an adaptive response to variations in environmental factors. The role of epigenetic changes is vital for the development of some diseases, including atherogenesis, cancers, and chronic kidney disease (CKD). The results of studies presented in this review have suggested that altered DNA methylation can modulate the expression of pro-inflammatory and pro-fibrotic genes, as well those essential for kidney development and function, thus stimulating renal disease progression. Abnormally increased homocysteine, hypoxia, and inflammation have been suggested to alter epigenetic regulation of gene expression in CKD. Studies of renal samples have demonstrated the relationship between variations in DNA methylation and fibrosis and variations in estimated glomerular filtration rate (eGFR) in human CKD. The unravelling of the genetic–epigenetic profile would enhance our understanding of processes underlying the development of CKD. The understanding of multifaceted relationship between DNA methylation, genes expression, and disease development and progression could improve the ability to identify individuals at risk of CKD and enable the choice of appropriate disease management.     

New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid

Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system’s role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.     

Fatty acids,the immune response,and autoimmunity: A question of n−6 essentiality and the balance between n−6 and n−3

The essentiality of n−6 polyunsaturated fatty acids (PUFA) is described in relation to a thymus/thymocyte accretion of arachidonic acid (20∶4n−6, AA) in early development, and the high requirement of lymphoid and other cells of the immune system for AA and linoleic acid (18∶2n−6, LA) for membrane phospholipids. Low n−6 PUFA intakes enhance whereas high intakes decrease certain immune functions. Evidence from in vitro and in vivo studies for a role of AA metabolites in immune cell development and functions shows that they can limit or regulate cellular immune reactions and can induce deviation toward a T helper (Th)2-like immune response. In contrast to the effects of the oxidative metabolites of AA, the longer-chain n−6 PUFA produced by γ-linolenic acid (18∶3n−6, GLA) feeding decreases the Th2 cytokine and immunoglobulin (Ig)G1 antibody response. The n−6 PUFA, GLA, dihomo-γ-linolenic acid (20∶3n−6, DHLA) and AA, and certain oxidative metabolites of AA can also induce T-regulatory cell activity, e.g., transforming growth factor (IGF)-β-producing T cells; GLA feeding studies also demonstrate reduced proinflammatory interleukin (IL)-1 and tumor necrosis factor (TNF)-α production. Low intakes of long-chain n−3 fatty acids (fish oils) enhance certain immune functions, whereas high intakes are inhibitory on a wide range of functions, e.g., antigen presentation, adhesion molecule expression, Th1 and th2 responses, proinflammatory cytokine and eicosanoid production, and they induce lymphocyte apoptosis. Vitamin E has a demonstrable critical role in long-chain n−3 PUFA interactions with immune functions, often reversing the effects of fish oil. The effect of dietary fatty acids on animal autoimmune disease models depends on both the autoimmune model and the amount and type of fatty acids fed. Diets low in fat, essential fatty acid deficient (EFAD), or high in long-chain n−3 PUFA from fish oils increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, whereas high-fat LA-rich diets increase disease severity. In experimentally induced T cell-mediated autoimmune disease, EFAD diets or diets supplemented with long-chain n−3 PUFA augment disease, whereas n−6 PUFA prevent or reduce the severity. In contrast, in both T cell- and antibody-mediated autoimmune disease, the desaturated/elongated metabolites of LA are protective. PUFA of both the n−6 and n−3 families are clinically useful in human autoimmune-inflammatory disorders, but the precise mechanisms by which these fatty acids exert their clinical effects are not well understood. Finally, the view that all n−6 PUFA are proinflammatory requires revision, in part, and their essential regulatory and developmental role in the immune system warrants appreciation.     

Differential effects of dietary fatty acids on the accumulation of arachidonic acid and its metabolic conversion through the cyclooxygenase and lipoxygenase in platelets and vascular tissue

Semisynthetic diets containing either corn oil (CO) or butter (B) (11 and 2.2 en % as linoleic acid, respectively) were fed to male rabbits for periods of 3 weeks and 3 months. The CO diet, in respect to the B diet, induced higher levels of linoleic acid (LA) and lower levels of arachidonic acid (AA) in platelet phospholipids, lower levels of AA in aortic phosphatidylinositol (PI) and accumulation of both LA and AA in liver lipids. The thresholds for aggregation with AA, but not with collagen, were higher in the CO group and the formation of thromboxane B₂ (TXB₂) from [¹⁴C] AA, but not from endogenous substrate after collagen stimulation, was lower in the same group. Formation of PGE₂-like material by incubated aortas was higher in the B group. In the CO group, platelet cyclooxygenase appeared to be selectively depressed. The correlations among diet-induced fatty acid changes in platelet and aortic lipids, platelet aggregation and thromboxane and prostacyclin formation are discussed.     

Enhancement of eicosaenoic acid lipoxygenation in human platelets by 12-hydroperoxy derivative of arachidonic acid

Human platelet lipoxygenase activity toward several eicosaenoic acids was measured in intact cells as well as in subcellular fractions (cytosol and membranes). In whole platelets, the lipoxygenation of eicosaenoic acids was enhanced greatly by high concentrations of aspirin, which partially inhibit the peroxidase activity associated with the pathway. The lipoxygenation also was increased by arachidonic acid (AA) or its lipoxygenase product, 12-hydroxyperoxy-eicosatetraenoic acid (12-HPETE). Similarly, prostanoid precursors, dihomogammalinolenic (DHLA) and eicosapentaenoic (EPA) acids also were better converted by cyclooxygenase in the presence of AA or 12-HPETE. Among the eicosaenoic acids tested, EPA oxygenation was affected most. Using cytosol or membranes as the lipoxygenase source instead of whole cells led to completely different results. AA exerted a competitive inhibition upon the other eicosaenoic acid oxygenation except that of EPA, for which a dual effect of AA was observed. This makes questionable the use of platelet subfractions for investigating lipoxygenase activity. We conclude that platelet lipoxygenation of eicosaenoic acids appears peroxide-dependent, especially for apparent poor substrates like EPA. This might be relevant in respect to 12-HPETE, which is the main hydroperoxy derivative to be produced during platelet activation.     

Implications of Sphingolipid Metabolites in Kidney Diseases

Sphingolipids, which act as a bioactive signaling molecules, are involved in several cellular processes such as cell survival, proliferation, migration and apoptosis. An imbalance in the levels of sphingolipids can be lethal to cells. Abnormalities in the levels of sphingolipids are associated with several human diseases including kidney diseases. Several studies demonstrate that sphingolipids play an important role in maintaining proper renal function. Sphingolipids can alter the glomerular filtration barrier by affecting the functioning of podocytes, which are key cellular components of the glomerular filtration barrier. This review summarizes the studies in our understanding of the regulation of sphingolipid signaling in kidney diseases, especially in glomerular and tubulointerstitial diseases, and the potential to target sphingolipid pathways in developing therapeutics for the treatment of renal diseases.     

The effects of dietary α-linolenic acid compared with docosahexaenoic acid on brain, retina, liver, and heart in the guinea pig

The aim of this study was to compare two different strategies to elevate brain, retina, liver, and heart docosahexaenoic acid (DHA) levels in guinea pigs. Fist, we used an increasing dose of α-linolenic acid (AIA) relative to a constant linoleic acid (LA) intake, and second, we used two levels of dietary DHA provided in conjunction with dietary arachidonic acid (AA). The percentage DHA and AA of total phospholipids in retina, liver, and heart, and in the brain phosphotidylethanolamine and phosphatidylcholine was studied in female pigmented guinea pigs (3 wk old) fed one of five semisynthetic diets containing 10% (w/w) lipid for 12 wk. The LA content in the diets was constant (17% of total fatty acids), with the ALA content varying from 0.05% (diet SFO), to 1% (diet Mix), and to 7% (diet CNO). Two other diets LCP) and LCP3) had a constant LA/ALA ratio (17.5∶1) but varied in the levels of dietary AA and DHA supplementation. Diet LCP1 was structured to closely replicate the principal long chain polyunsaturated fatty acids (PUFA) found in human breast milk and contained 0.9% AA and 0.6% DHA (% of total fatty acids) whereas diet LCP3 contained 2.7% AA and 1.8% DHA. At the end of the study, animals were sacrificed and tissues taken for fatty acid analyses. We found no significant effects of diets on the growth of guinea pigs. Diets containing ALA has profoundly different effects on tissue fatty acid compositions compared with diets which contained the long chain PUFA (DHA and AA). In the retina and brain phospholipids, high-ALA diets or dietary DHA supplementation produced moderate relative increases in DHA levels. There was no change in retinal or brain AA proportions following dietary AA supplementation, even at the highest level. This was in contrast to liver and heart where tissue DHA proportions were low and AA predominated. In these latter tissues, dietary ALA had little effect on tissue DHA proportions although the proportion of AA was slightly depressed at the highest dietary ALA intake, but dietary DHA and AA supplements led to large increases (up to 10-fold) in the proportions of these PUFA. Tissue uptake of dietary AA and DHA appeared maximal for the LCP1 diet (replicate of breast milk) in the heart. There were no significant changes in the plasma levels of 11-dehydrothromboxane B₂ (a thromboxane A₂ metabolite), for any diet. The data confirm that dietary ALA is less effective than dietary DHA supplementation (on a gram/gram basis) in increasing tissue DHA levels and that tissues vary greatly in their response to exogenous AA and DHA, with the levels of these long chain metabolites being most resistant to change in the retina and brain compared with liver and heart. Dietary DHA markedly increased tissue DHA proportions in both liver and heart, whereas the major effect of dietary AA was in the liver. Future studies of the effects of dietary DHA and AA supplementation should examine a variety of tissues rather than focusing only on neural tissue.     

Measurement of the incorporation of orally administered arachidonic acid into tissue lipids

The applicability of a stable isotope method to monitor the mixing of dietary arachidonic acid with endogenous arachidonic acid in tissue lipids was evaluated. Rats were fed octadeuterated arachidonic acid during a 20-day period, and the entry of the dietary acid into lipid esters of various tissues was examined by gas chromatographymass spectrometric (GC-MS) analysis of their fatty acids. The rats were maintained on a fat-free diet from weaning until 63 days old to enhance the ratio of the dietary acid to endogenous arachidonate. Three separate forms of eicosatetraenoic acid in the tissue lipids could be distinguished by GC-MS: octadeuterated arachidonic acid (recent dietary origin), unlabeled arachidonic acid (maternal origin) and unlabeled, 4,7,10,13-eicosatetraenoic acid (originating from palmitoleic acid). The total eicosatetraenoic acid in the tissue lipids contained about 90% arachidonate from recent dietary origin in lung, kidney, heart and fat, 70% in muscle and liver and 27% in brain. The n−7 isomer of eicosatetraenoic acid was estimated to make up 6% or less of the total eicosatetraenoic acid in lung, kidney, brain, muscle and heart tissue lipids, but it comprised around 15% of the total eicosatetraenoic acid in liver. The unlabeled arachidonic acid of maternal origin thus comprised only about 10% of the eicosatetraenoic acid in all tissues examined except muscle and brain, where it was 24% and 70% of the eicosatetraenoic acid, respectively. The relative amounts of the three forms of eicosatetraenoic acid are consistent with a limited access of dietary arachidonate to the brain tissue and with a competition between the dietary n−6 isomer and the endogenous n−7 isomer for esterification in the liver. Because most muscle mass would have formed after weaning, the high proportion of maternal arachidonate in the muscle lipids suggested that maternal arachidonate may have been displaced from other tissues to muscle, from which it equilibrated slowly with dietary arachidonate acid. The combination of deuterated arachidonic acid and GC-MS analysis thus furnished more detailed information about the composition and origin of eicosatetraenoic, acid in tissue lipid esters than that previously available from radiotracer studies or GC-MS analyses alone.     

n−3 Polyunsaturated fatty acids and inflammation: From molecular biology to the clinic

The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n−6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n−3 FA. However, n−3 FA have a number of other effects that might occur down-stream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n−3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.     

Severe fatty liver in rats fed a fat-free ethanol diet,and its prevention by small amounts of dietary arachidonate

Rats were fed ethanol and a fat-free diet for 30 days to determine whether dietary fat is needed for the development of fatty liver. The severity of fatty liver was similar to that of rats fed an isocaloric diet with 35% fat. Small amounts (29 mg/day) of dietary arachidonic acid prevented alcoholic fatty liver. Rats fed either the alcohol (AF) or control (CF) fat-free diets developed essential fatty acid deficiency (EFAD) as measured by the triene/tetraene ratio of liver and plasma lipids. Rats fed arachidonic acid (AA, alcohol and CA, control diets) did not develop EFAD. Although EFAD alone did not cause the development of fatty liver, the combination of dietary ethanol and EFAD did. The ratios of 16∶1/16∶0 and 18∶1/18∶0 in liver lipids indicated that desaturase enzymes were less active and lipogenesis was reduced in rats fed the AA diet compared to those fed the AF diet. In contrast, stimulated lipogenesis appears to have been the cause of fatty liver in rats fed the AF diet. Presented at the XII International Congress of Nutrition, San Diego, CA, August 1981. Abbreviations: Diets are indicated as fat-free with ethanol (AF), fat-free without ethanol (CF), or similar diets with 0.9% of the calories as arachidonic acid with (AA) or without (CA) ethanol. The composition of these diets is discribed in the text and Table 1.     

Dietary arachidonic and linoleic acids: Comparative effects on tissue lipids

The effects of preformed dietary arachidonic acid (AA, 20∶4n−6) on murine phospholipid fatty acid composition in tissues capable (liver) and incapable (peritoneal exudate cells, PEC) of desaturating and elongating linoleic acid (LA, 18∶2n−6) to AA were investigated. The results were compared with those obtained on matched animals on LA diets by either substituting or supplementing dietary LA with AA. Modest amounts of AA ethyl ester (0.5 wt%) included in the diet significantly increased tissue phospholipid AA levels by 39% and 57% in the liver and in PEC, respectively. The changes were further enhanced when dietary LA and AA intakes were equivalent,i.e., 57% and 68% in liver and PEC, respectively. This enrichment was observed in all phospholipid classes analyzed, with the greatest impact on phosphatidylcholine. In addition, the doubling of dietary LA had little effect on tissue phospholipid AA levels. The data suggest that while the level of n−6 PUFA may have an important effect on tissue fatty acid composition, the type of n−6 PUFA in the diet could be of greater significance.     

Dietary α-linolenate suppresses endotoxin-induced platelet-activating factor production in rat kidney

In comparison with dietary high-linoleate safflower oil, high α-linolenate perilla oil decreased alkylacyl-and alkenylacyl-glycerophosphocholine (GPC) content in rat kidney by roughly 30 and 25%, respectively. The fatty acid composition was also modified by high α-linolenate oil; arachidonic acid (AA) level in alkylacyl-GPC, a platelet-activating factor (PAF) precursor, decreased by 30% along with concomitant increases in the n-3 fatty acid levels. PAF contents under resting conditions were similarly low in the two dietary groups. Fifteen minutes after endotoxin administration, PAF and lyso-PAF contents increased significantly, and the PAF content in the high α-linolenate group was 60% lower than in the high linoleate group; the lyso-PAF contents also tended to be lower. Lyso-PAF acetyltransferase and CoA-independent transacylase activities in kidney microsomes increased significantly after endotoxin administration, while PAF acetylhydrolase activity in the cytosol was relatively unchanged. The lyso-PAF acetyltransferase and PAF acetylhydrolase activities did not differ between the two dietary groups, but the CoA-independent, transacylase activity was roughly 30% lower in the high α-linolenate group. In agreement with in vitro study, our present study demonstrates that dietary high α-linolenate suppresses PAF production in rat kidney during systemic endotoxemia, and which is mainly due to the decrease in alkylacyl-GPC content, altered fatty acid compositions of the precursor lipids and lower CoA-independent transacylase activity.