Liver Docosahexaenoic Acid Research Articles

Effects of short-term supplementation with DHA-enriched phosphatidylcholine and phosphatidylserine on lipid profiles in the brain and liver of n-3 PUFA-deficient mice in early life after weaning.

Lack of n-3 polyunsaturated fatty acids during the period of maternity drastically lowers the docosahexaenoic acid (DHA) level in the brain of offspring and studies have demonstrated that different molecular forms of DHA are beneficial to brain development. The aim of this study was to investigate the effect of short-term supplementation with DHA-enriched phosphatidylserine (PS) and phosphatidylcholine (PC) on DHA levels in the liver and brain of congenital n-3-deficient mice. Dietary supplementation with DHA significantly changed the fatty acid composition of various phospholipid molecules in the cerebral cortex and liver while DHA-enriched phospholipid was more effective than DHA triglyceride (TG) in increasing brain and liver DHA. Both DHA-PS and DHA-PC could effectively increase the DHA levels, but DHA in the PS form was superior to PC in the contribution of DHA content in the brain ether-linked PC (ePC) and liver lyso-phosphatidylcholine molecular species. DHA-PC showed more significant effects on the increase of DHA in liver TG, PC, ePC, phosphatidylethanolamine (PE) and PE plasmalogen (pPE) molecular species and decreasing the arachidonic acid level in liver PC plasmalogen, ePC, PE and pPE molecular species compared with DHA-PS. The effect of dietary interventions with different molecular forms of DHA for brain and liver lipid profiles is different, which may provide theoretical guidance for dietary supplementation of DHA for people. © 2024 Society of Chemical Industry.

Between family variation in EPA and DHA storage among Atlantic salmon (Salmo salar) fed a fish oil-free diet

Biosynthesis and storage of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is under dietary and genetic control in Atlantic salmon (Salmo salar). Enhanced EPA and DHA biosynthesis and storage may improve utilization, and thus reduce marine forage fish oil use in aquafeeds. To determine phenotypic variability in EPA and DHA tissue content and growth performance, 50 families (n = 30 salmon/family, 48 g/fish initial weight) of Atlantic salmon (Saint John River strain) were reared in freshwater and fed either a fish oil (FO) control diet or FO-free diet. After 16 weeks, body size was recorded. Salmon fed the FO-free diet overall showed significantly lower growth performance compared to salmon fed the FO control diet, regardless of family. To determine the relationship between growth and FA content, the five families with the highest and the five families with the lowest weight gain were sampled for tissue and liver FA analysis. There was a significant interaction between growth and diet. The family x diet interaction was significant for final weight, final length, weight gain, growth rate and feed conversion ratio. Among the five fastest growing families, there was a significant family effect for EPA and DHA storage in the liver but not for muscle. Among the five slowest growing families, by comparison salmon had similar liver DHA and EPA content, independent of diet treatment. Family and diet were interacting factors that determine EPA and DHA storage in liver. Certain fast-growing families also had significantly higher DHA content in liver and muscle. This study demonstrates the potential for selecting families that can better utilize a diet without marine forage fish oil.

Gestational Diabetes Mellitus Remodels the Fetal Brain Fatty Acid Profile Through Placenta-Brain Lipid Axis in C57BL/6J Mice

BackgroundPolyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are critical for proper fetal brain growth and development. Gestational diabetes mellitus (GDM) could affect maternal–fetal fatty acid metabolism. ObjectiveThis study aimed to explore the effect of GDM and high-fat (HF) diet on the DHA transport signaling pathway in the placenta-brain axis and fatty acid concentrations in the fetal brain. MethodsInsulin receptor antagonist (S961) and HF diet were used to establish an animal model of GDM. Eighty female C57BL/6J mice were randomly divided into control (CON), GDM, HF, and HF+GDM groups. The fatty acid profiles of the maternal liver and fetal brain were analyzed by gas chromatography. In addition, we analyzed the protein amounts of maternal liver fatty acid desaturase (FADS1/3), elongase (ELOVL2/5) and the regulatory factor sterol-regulatory element-binding protein (SREBP)-1c, and the DHA transport signaling pathway (Wnt3/β-catenin/MFSD2a) of the placenta and fetal brain using western blotting. ResultsGDM promoted the decrease of maternal liver ELOVL2, ELOVL5, and SREBP-1c. Accordingly, we observed a significant decrease in the amount of maternal liver arachidonic acid (AA), DHA, and total n–3 PUFA and n–6 PUFA induced by GDM. GDM also significantly decreased the amount of DHA and n–3 PUFA in the fetal brain. GDM downregulated the Wnt3/β-catenin/MFSD2a signaling pathway, which transfers n–3 PUFA in the placenta and fetal brain. The HF diet increased n–6 PUFA amounts in the maternal liver, correspondingly increasing linoleic acid, gamma-linolenic acid, AA, and total n–6 PUFA in the fetal brain, but decreased DHA amount in the fetal brain. However, HF diet only tended to decrease placental β-catenin and MFSD2a amounts (P = 0.074 and P = 0.098, respectively). ConclusionsMaternal GDM could affect the fatty acid profile of the fetal brain both by downregulating the Wnt3/β-catenin/MFSD2a pathway of the placental–fetal barrier and by affecting maternal fatty acid metabolism.

Investigating the plasma-liver-brain axis of omega-3 fatty acid metabolism in mouse knock-in for the human apolipoprotein E epsilon 4 allele

The metabolism of docosahexaenoic acid (DHA), an omega-3 fatty acid, is different in carriers of APOE4, the main genetic risk factor for late-onset Alzheimer's disease. The brain relies on the plasma DHA pool for its need, but the plasma-liver-brain axis in relation to cognition remains obscure. We hypothesized that this relationship is compromised in APOE4 mice considering the differences in fatty acid metabolism between APOE3 and APOE4 mice. Male and female APOE3 and APOE4 mice were fed either a diet enriched with DHA (0.7 g DHA/100 g diet) or a control diet for 8 months. There was a significant genotype × diet interaction for DHA concentration in the liver and adipose tissue. In the cortex, a genotype effect was found where APOE4 mice had a higher concentration of DHA than APOE3 mice fed the control diet. There was a significant genotype × diet interaction for the liver and hippocampal arachidonic acid (AA). APOE4 mice had 20–30% lower plasma DHA and AA concentrations than APOE3 mice, independent of diet. Plasma and liver DHA levels were significantly correlated in APOE3 and APOE4 mice. In APOE4 mice, there was a significant correlation between plasma, adipose tissues, cortex DHA and the Barnes maze and/or with a better recognition index. Moreover, higher AA levels in the liver and the hippocampus of APOE4 mice were correlated with lower cognitive performance. Our results suggest that there is a plasma-liver-brain axis of DHA that is modified in APOE4 mice. Moreover, our data support that APOE4 mice rely more on plasma DHA than APOE3 mice, especially in cognitive performance. Any disturbance in plasma DHA metabolism might have a greater impact on cognition in APOE4 carriers.

Effects of plant-based versus marine-based omega-3 fatty acids and sucrose on brain and liver fatty acids in a mouse model of chemotherapy

ABSTRACT Chemotherapy can result in toxic side effects in the brain. Intake of marine-based omega-3 polyunsaturated fatty acids (n-3 PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alter brain fatty acids, potentially improving brain function. However, it is unclear if alpha-linolenic acid (ALA), the plant-based n-3, affects brain PUFAs during chemotherapy. The objective of this study was to examine the effects of dietary ALA, EPA and DHA, with high or low sucrose, on brain PUFAs in a mouse model of chemotherapy. Secondarily, the use of liver PUFAs as surrogate measures of brain PUFAs was examined. Lipid peroxidation (4-HNE) and neurotrophic markers (BDNF) were assessed. Female C57Bl/6 mice (n = 90) were randomized to 1 of 5 diets (high EPA + DHA/high or low sucrose, high ALA/high or low sucrose, or control with no EPA + DHA/low ALA/low sucrose) and injected with doxorubicin-based chemotherapy or saline. Brain EPA and DHA were greater (p < 0.0001) with high EPA + DHA diets, regardless of sucrose; there were no significant differences in brain PUFAs between high ALA diets and control. Chemotherapy-treated mice had higher brain and liver DHA (p < 0.05) and lower brain and liver linoleic acid (p < 0.0001). Brain n-3 and n-6 PUFAs were strongly correlated with liver n-3 (r = 0.8214, p < 0.0001) and n-6 PUFAs (r = 0.7568, p < 0.0001). BDNF was correlated with brain total PUFAs (r = 0.36; p < 0.05). In conclusion, dietary ALA in proportions approximately two times greater than consumed by humans did not appreciably increase brain n-3 PUFAs compared to low ALA intake. Liver PUFAs may be a useful surrogate marker of brain PUFAs in this mouse model.

Schizochytrium sp. (T18) Oil as a Fish Oil Replacement in Diets for Juvenile Rainbow Trout (Oncorhynchus mykiss): Effects on Growth Performance, Tissue Fatty Acid Content, and Lipid-Related Transcript Expression.

Simple SummaryOne of the main concerns in aquaculture is the overreliance on wild-sourced fish oil as the main source of omega-3 fatty acids in diets for farmed fish. Microbes, such as Schizochytrium, naturally produce high levels of omega-3 fatty acids that could potentially replace fish oil in aquaculture feeds. In this study, we tested the oil from a new strain of Schizochytrium (T18) to replace fish oil in diets for farmed rainbow trout and looked at fish growth performance, muscle and liver fatty acid content, and the expression of transcripts involved in fat metabolism. Trout were raised for 8 weeks and fed diets with either: (1) fish oil control, (2) low inclusion of microbial oil, or (3) higher inclusion of microbial oil. Inclusion of Schizochytrium sp. (T18) oil at high or low levels in the diet resulted in a similar growth performance as seen in trout fed the control diet; however, muscle and liver fatty acid profiles were impacted by diet. Overall, our results showed that Schizochytrium (T18) is an effective source of omega-3 fatty acids in diets for rainbow trout.In this study, we evaluated whether oil extracted from the marine microbe, Schizochytrium sp. (strain T18), with high levels of docosahexaenoic acid (DHA), could replace fish oil (FO) in diets for rainbow trout (Oncorhynchus mykiss). Three experimental diets were tested: (1) a control diet with fish oil (FO diet), (2) a microbial oil (MO) diet with a blend of camelina oil (CO) referred to as MO/CO diet, and (3) a MO diet (at a higher inclusion level). Rainbow trout (18.8 ± 2.9 g fish−1 initial weight ± SD) were fed for 8 weeks and evaluated for growth performance, fatty acid content and transcript expression of lipid-related genes in liver and muscle. There were no differences in growth performance measurements among treatments. In liver and muscle, eicosapentaenoic acid (EPA) was highest in trout fed the FO diet compared to the MO/CO and MO diets. Liver DHA was highest in trout fed the MO/CO diet compared to the FO and MO diets. Muscle DHA was highest in trout fed the MO and MO/CO diets compared to the FO diet. In trout fed the MO/CO diet, compared to the MO diet, fadsd6b was higher in both liver and muscle. In trout fed the FO or MO/CO diets, compared to the MO diet, cox1a was higher in both liver and muscle, cpt1b1a was higher in liver and cpt1a1a, cpt1a1b and cpt1a2a were higher in muscle. Schizochytrium sp. (T18) oil was an effective source of DHA for rainbow trout.

Dietary inclusion of full-fat Hermetia illucens prepupae meal in practical diets for rainbow trout (Oncorhynchus mykiss): Lipid metabolism and fillet quality investigations

Insects are able to bio-convert organic by-products into a sustainable biomass for aquafeed formulation. Specifically, among several insect species, Hermetia illucens (H) is particularly interesting for its nutritious traits but, unfortunately, the lipidic fraction is poorly represented by polyunsaturated fatty acids n-3 and poses some limits in its application in aquafeed formulation.The present study undertook an interdisciplinary approach to explore the effects of three experimental diets containing increasing levels of full-fat H meal (H0 diet based on fishmeal and purified protein-rich vegetable ingredients; H25 and H50 diets containing 25% or 50% of full-fat H meal replacing fishmeal, respectively), on rainbow trout (Oncorhynchus mykiss) fed over a 98 days experimental period. The expression of genes related to lipid metabolism by RT-qPCR, liver histology, as well as the qualitative traits of fillets and fatty acid (FA) composition were investigated. Interestingly, fads2 gene expression in pyloric caeca increased in fish fed diets containing the highest full-fat H meal inclusion (H50 > H0; p < .05). Liver histological examinations showed normal morphological aspect even though hepatic FA profiles seemed to resemble those of the diets. However, liver docosahexaenoic acid did not significantly differ between the dietary groups and showed a mean value of 11.07 g FA methyl esters/100 g total FA methyl esters. Despite the FA profile of the three diets differed depending on the H meal inclusion level, biometrics, fillet physical traits, total lipids and the overall FA profile were not jeopardised, not even eicosapentaenoic and docosahexaenoic acids.The overall results showed that the dietary full-fat H meal inclusion under study did not impair fish fillet quality, guaranteeing its nutritional value. Some effects on lipid metabolism were observed, as suggested by liver, pyloric caeca and mid intestine gene expression and liver FA profile. Future studies on the biological mechanisms behind the macroscopic traits of fish fed unprocessed insects are warmly encouraged.

Influence of different oil sources on growth, disease resistance, immune response and immune-related gene expression on the hybrid grouper (♀ Epinephelus fuscoguttatus × ♂ E. lanceolatu), to Vibrio parahaemolyticus challenge

The aim of this study was to investigate the effects of feeding alternative dietary oils to hybrid grouper fish (♀Epinephelus fuscoguttatus × ♂E. lanceolatu) on their growth, histological morphology of hepatocytes, disease resistance, immune response, and expression of immune-related genes. Seven experimental fish meal-based isonitrogenous and isolipidic diets were formulated containing 5% fish oil (FO; acting as controls) and various vegetable oils (VOs): corn oil (CO), sunflower oil (SO), tea oil (TO), olive oil (OO), rice oil (RO), and mixed oil (MO); comprising equal amounts of these oils). Each diet was fed to triplicate groups of 40 fish (initial mean body weight ± standard error = 15.09 ± 0.01 g) for eight weeks. The results show that 1) alternative dietary oils had no significant effects on weight gain rate, specific growth rate, protein efficiency ratio, and survival rate compared with controls (P > 0.05). The weight gain rate (WGR) and specific growth rate (SGR) of the SO group were lower than in the CO and OO groups. 2) These were no differences in morphological indexes among groups; except for the CO group, in which the condition factor and hepatosomatic index were lower than those in other groups. 3) Compared with controls, the whole-body moisture and crude protein contents in the VO groups were higher, while their crude lipid contents were lower. 4) The fatty acid contents in liver and muscle were affected by lipid type, and the contents of eicosapentaenoic acid and docosahexaenoic acid in liver and muscle in the VO groups were markedly lower than in controls. 5) Compared with control group, VO groups damaged the histological morphology of hepatocytes. 6) After a challenge with the Vibrio parahaemolyticus bacterium, there were no differences in mortality among groups. However, VO enhanced the activity of non-specific immune enzymes while down-regulating the expression of Nrf2 and inducing the expression of pro-inflammatory factors (IL1β, TNFα, TLR22, and MyD88) in the kidney. It can be concluded that dietary VO substitution does not affect the growth of fish but damaged the histological morphology of hepatocytes and induced the expression of pro-inflammatory factors in tissues. Finally, OO and CO were recommended as the appropriate lipid replacement for FO.

High-Fat Diet Elevates Liver Docosahexaenoic Acid Possibly through Over-Expression of Very Long-Chain Fatty Acid Elongase 2 in C57BL/6J Mice.

The liver is the main site of lipid metabolism and vitamin A storage. Dietary factors are known to affect liver function, thereby leading to metabolic abnormalities. Here, we assessed the impact of long-term feeding of a high-fat diet on hepatic vitamin A status and lipid metabolism. For this purpose, 14 male and 14 female 35-day-old mice (strain C57BL/6J) were each divided into 2 groups of 7 animals and fed either a stock diet or a high-fat (HF) diet for 26 weeks. In addition to increased body weight/weight gain, the HF diet induced hypertriglyceridemia in both (p<0.01). However, liver triglyceride levels were comparable among groups, which could be partly explained by unaltered expression of various lipogenic pathway proteins such as sterol regulatory element binding protein 1 (SREBP1), fatty acid synthase (FAS), microsomal triglyceride transfer protein (MTTP), and glycerol 3-phosphate acyl transferase (GPAT). On the other hand, hepatic retinol stores increased significantly in both sexes, whereas males displayed elevated circulatory retinol levels. Notably, long-term feeding of a HF diet elevated n-3 polyunsaturated fatty acid (PUFA) and docosahexaenoic acid (DHA, C22:6) levels in the liver (p≤0.001), which is in line with the over-expression of very long-chain fatty acid elongase 2 (ELOVL2) protein in both sexes of mice (p<0.01). In conclusion, very long-term feeding of a HF diet increased hepatic retinol stores and induced hypertriglyceridemia. However, it had no effect on hepatic triglyceride accumulation, possibly due to increased DHA levels arising from the ELOVL2-mediated elongation pathway.

DHA Cycling Halves the DHA Supplementation Needed to Maintain Blood and Tissue Concentrations via Higher Synthesis from ALA in Long–Evans Rats

Eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) recommendations are frequently stated at 500 mg/d; however, adherence to these recommendations would result in a large global commercial EPA/DHA production deficit. Previously, our laboratory demonstrated that acute DHA intake in rats can increase the capacity for synthesis-secretion of n-3 (ω-3) polyunsaturated fatty acids (PUFAs). We aimed to investigate the utility of a dietary DHA cycling strategy that employs 2 wk of repeated DHA feeding for a total of 3 cycles over 12 wk. Male Long-Evans rats were fed a 10% fat diet by weight comprised of either 1) a 2-wk, 2% α-linolenic acid (ALA, DHA-ALA group 18:3n-3) diet followed by a 2-wk, 2% DHA+2% ALA diet over 3 consecutive 4-wk periods ("DHA cycling," DHA-ALA group); 2) a 2% DHA+2% ALA diet (DHA group) for 12 wk; or 3) a 2% ALA-only diet (ALA group) for 12 wk. At 15 wk old, blood and tissue fatty acid concentrations and liver mRNA expression and 13C-DHA natural abundances were determined. DHA concentrations in plasma, erythrocytes, and whole blood between the DHA-ALA group and the DHA groups were not different (P≥0.05), but were 72-110% higher (P<0.05) than in the ALA group. Similarly, DHA concentrations in liver, heart, adipose, and brain were not different (P≥0.05) between the DHA-fed groups, but were at least 62%, 72%, 320%, and 68% higher (P<0.05) than in the ALA group in liver, heart, adipose, and skeletal muscle, respectively. Compound-specific isotope analysis indicated that 310% more liver DHA in the DHA-ALA group compared with the DHA group is derived from dietary ALA, and this was accompanied by a 123% and 93% higher expression of elongation of very long-chain (Elovl)2 and Elovl5, respectively, in the DHA-ALA group compared with the ALA group. DHA cycling requires half the dietary DHA while achieving equal blood and tissue DHA concentrations in rats. Implementation of such dietary strategies in humans could reduce the gap between global dietary n-3 PUFA recommendations and commercial production.

Genomic, Transcriptomic, and Epigenomic Features Differentiate Genes That Are Relevant for Muscular Polyunsaturated Fatty Acids in the Common Carp.

Polyunsaturated fatty acids (PUFAs) are a set of important nutrients that mainly include arachidonic acid (ARA4), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and α-linolenic acid (ALA). Recently, fish-derived PUFAs have been associated with cardiovascular health, fetal development, and improvement of brain functions. Studies have shown that fish muscular tissues are rich in PUFAs, which are influenced by various factors, including genetic variations, regulatory profiles, and methylation status of desaturase genes during fatty acid desaturation and elongation processes. However, the genetic mechanism and the pathways involved in fatty acid metabolism in fishes remain unclear. The overall aim of this study was to assess differences in gene expression responses among fishes with different fatty acid levels. To achieve this goal, we conducted genome-wide association analysis (GWAS) using a 250K SNP array in a population of 203 samples of common carp (Cyprinus carpio) and identified nine SNPs and 15 genes associated with muscular PUFA content. Then, RNA-Seq and whole genome bisulfite sequencing (WGBS) of different groups with high and low EPA, DHA, ARA4, and ALA contents in muscle, liver and brain tissues were conducted, resulting in 6,750 differentially expressed genes and 5,631 genes with differentially methylated promoters. Gene ontology and KEGG pathway enrichment analyses of RNA-Seq and WGBS results identified enriched pathways for fatty acid metabolism, which included the adipocytokine signaling pathway, ARA4 and linoleic acid metabolism pathway, and insulin signaling pathway. Integrated analysis indicated significant correlations between gene expression and methylation status among groups with high and low PUFA contents in muscular tissues. Taken together, these multi-level results uncovered candidate genes and pathways that are associated with fatty acid metabolism and paved the way for further genomic selection and carp breeding for PUFA traits.

Egg quality, fatty-acid composition and gastrointestinal morphology of layer hens fed whole flaxseed with enzyme supplementation

ABSTRACT1. Flaxseed is a rich source of α-linolenic acid (ALA, 18:3 n–3). Feeding flaxseed to hens can increase n–3 fatty acids (FA) in eggs. However, non-starch polysaccharides (NSP) in flaxseed decrease nutrient digestibility and can have a negative impact on egg n–3 FA incorporation. Addition of carbohydrase enzymes to flaxseed-based diets can decrease the anti-nutritive effects of NSP.2. An experiment was conducted to investigate the effect of enzyme supplementation on FA composition and gastrointestinal morphology in hens fed flaxseed. A total of seventy-two, 51-week old brown layer hens were randomly assigned to one of the four dietary treatments (six replicates with three hens per replicate): corn-soybean based diet containing 0% flax (Control), 10% flax (Flax), Flax+0.05% enzyme (Flax+E1), or Flax+0.1% enzyme (Flax+E2) in a 120-day feeding trial.3. Egg weight was highest in hens fed Flax+E1 (P < 0.05). Yolk weight was higher in Flax+E1 compared with the control and Flax+E2 and was not different from Flax treatment. ALA and total n–3 FA was highest in eggs from Flax+E2 hens (P < 0.05). Addition of enzyme has no effect of on docosahexaenoic acid (DHA), total long chain (>20-C FA), or n–6:n–3 FA ratio in eggs from hens fed flaxseed-based diets (P > 0.05). Over nine-fold increase in hepatic ALA was observed in the liver of hens fed flaxseed-based diets when compared with the control diet (P < 0.0001). No effect of enzyme supplementation was observed on liver ALA, DHA or long chain n–3 FA (P > 0.05). Enzyme supplementation reduced arachidonic acid, total n–6 and LC n–6 FA in liver tissue from hens fed flaxseed-based diets (P > 0.05).4. Villi height and width was higher in the duodenum and jejunum of hens fed flax-based diets compared to the control (P < 0.05). Enzyme supplementation led to an increase in villi width in jejunum (P < 0.05) in hens fed Flax+E2 (P < 0.05). No effect of diet was observed in the crypt depth and villi height:crypt depth ratio in the jejunum (P > 0.05).5. It was concluded that enzyme supplementation enhanced total n–3 FA deposition in eggs and liver and influence gastrointestinal morphology in layer hens fed flaxseed.

Combined administration of docosahexaenoic acid and thyroid hormone synergistically enhances rat liver levels of resolvins RvD1 and RvD2

Supplementation with omega-3 fatty acids or thyroid hormone (T3) exhibit negative effects on inflammatory reactions in experimental animals. The aim of this work was to assess the hypothesis that docosahexaenoic acid (DHA) plus T3 co-administration enhances liver resolvin (Rv) levels as inflammation resolution mediators. Combined DHA (daily doses of 300 mg/kg for 3 consecutive days)-T3 (0.05 mg/kg at the fourth day) administration significantly increased the content of hepatic RvD1 and RvD2, without changes in that of RvE1 and RvE2, an effect that exhibits synergy when compared to the separate DHA and T3 treatments. Under these conditions, liver DHA levels increased by DHA administration were diminished when combined with T3 (p < 0.05), suggesting enhancement in resolvin D biosynthesis in extrahepatic tissues. It is concluded that co-administration of DHA and T3 rises the capacity of the liver for inflammation resolution by augmenting RvD1(2) availability, which represents an important protocol in hepatoprotection in the clinical setting.

Lessening hepatic injury in cholestatic liver by optimal dietary docosahexaenoic acid supplementation in rats

Background: Dietary adjuvant management for the cholestatic liver disease before/after surgery is an important clinical issue. This study investigated the possibility for the dietary supplementation of docosahexaenoic acid (DHA) to treat cholestasis liver through the bile duct ligation (BDL) rat model. Materials and Methods: Thirty-six male Wistar rats were divided into four groups (N: no BDL; BL, 1P, 5P: received BDL) and consumed either a regular diet (N, BL) or of DHA-enriched diet (1P: at 1% and 5P: at 5% weight percentage) for 4 weeks. The liver fatty acids (FAs) profiles, serum aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, interleukin-2 (IL-2), interferon γ (INF-γ), and pathological examination with H and E, Masson, CD56 (natural killer cell), CD68 (macrophage) were examined. Results: The DHA dietary supplement increased liver DHA after BDL. Liver DHA N 8.09 ± 0.60% and BL 8.41 ± 0.55% were the lowest than the supplemented groups 1P 12.57 ± 1.16%, 5P 18.36 ± 2.00% (P = 0.000). However, liver arachidonic acid (20:4n-6) 1P 23.13 ± 2.19% was the highest than N 18.86 ± 4.31%, BL 17.13 ± 3.07%, 5P 18.78 ± 1.76% (P = 0.001). The serum AST (U/L) in N 147.4 ± 28.2 and 1P 155.9 ± 35.1 were lower than B 317.1 ± 195.8, 5P 326.9 ± 141. 8 (P = 0.006). The serum alkaline phosphatase (U/L) showed the same trend N 49.8 ± 5.4, 1P 67.6 ± 21.1 were lower than the BL 172.2 ± 108.1, 5P 171.1 ± 149.1 (P = 0.017). Pathological examination with H and E, Masson revealed the fibrosis was prominent in BL, 5P. However, there were no significant differences in serum ALT, total bilirubin, IL-2, INF-γ, and immunohistochemical stain for the CD56, CD68. Conclusions: The results suggested that optimal dietary supplementing of DHA (1P) had less destruction and liver enzymes released after the BDL. However, higher enriched DHA (5P) could not benefit from this dietary treatment. The body weight did not increase even with this enriched high FAs diet after BDL for 4 weeks.

Broiler Tissue Enrichment with Docosahexaenoic Acid (DHA) through Dietary Supplementation with &amp;lt;i&amp;gt;Aurantiochytrium limacinum&amp;lt;/i&amp;gt; Algae

The omega-3 fatty acid (n-3 FA) content of broiler tissues can be increased through dietary supplementation of hens with n-3 FA-rich microalgae. The aim of this study was to evaluate the effect of three different dietary inclusion levels of a docosahexaenoic acid (DHA)-rich microalgae (AURA) on broiler performance and the enrichment of tissues with n-3 FA. The randomized study was conducted using 352 birds, housed in 32 pens with 11 birds per pen. Pens were randomly assigned to one of four treatments, with each treatment replicated 8 times. The treatments included one unsupplemented control (0%) and three wheat-soya based experimental diets supplemented with AURA at a level of 0.5%, 1.5% and 2.5% for the starter, grower and finisher periods. Birds were weighed on days 0, 10, 24, 35 and 41, and feed intake was recorded per pen. On day 41, five birds per treatment were euthanized and individually weighed. Thigh muscle, breast muscle, liver, kidney and skin samples were taken post-mortem, freeze dried and DHA content quantified, following fat extraction and methylation, by GC-FID (AOAC 996.06 method). Performance and tissue data were analyzed by ANOVA with Dunnett’s (2-sided) post-hoc test to determine the differences between the mean values for each treatment. Dietary supplementation with AURA had no effect on body weight or feed intake during any period of the study. For thigh muscle, kidney and skin the DHA increased linearly (P < 0.05) with increasing level of dietary AURA, whilst there was a quadratic response in uptake of DHA in breast muscle and liver. The study demonstrated the potential of efficiently enriching broiler meat and organs with DHA by feeding AURA.

Fads3 modulates docosahexaenoic acid in liver and brain

Fatty acid desaturase 3 (FADS3) is the third member of the FADS gene cluster. FADS1 and FADS2 code for enzymes required for highly unsaturated fatty acid (HUFA) biosynthesis, but FADS3 function remains elusive. We generated the first Fads3 knockout (KO) mouse with an aim to characterize its metabolic phenotype and clues to in vivo function. All mice (wild type (WT) and KO) were fed facility rodent chow devoid of HUFA. No differences in overt phenotypes (survival, fertility, growth rate) were observed. Docosahexaenoic acid (DHA, 22:6n-3) levels in the brain of postnatal day 1 (P1) KO mice were lower than the WT (P < 0.05). The ratio of docosapentaenoic acid (DPA, 22:5n-3) to DHA in P1 KO liver was higher than in WT suggesting lower desaturase activity. Concomitantly, 20:4n-6 was lower but its elongation product 22:4n-6 was greater in the liver of P1 KO mice. P1 KO liver Fads1 and Fads2 mRNA levels were significantly downregulated whereas expression levels of elongation of very long chain 2 (Elovl2) and Elovl5 genes were upregulated compared to age-matched WT. No Δ13-desaturation of vaccenic acid was observed in liver or heart in WT mice expressing FADS3 as was reported in vitro. Taken together, the fatty acid compositional results suggest that Fads3 enhances liver-mediated 22:6n-3 synthesis to support brain 22:6n-3 accretion before and during the brain growth spurt.

Maternal liver docosahexaenoic acid (DHA) stores are increased via higher serum unesterified DHA uptake in pregnant long Evans rats

Maternal docosahexaenoic acid (DHA, 22:6n-3) supplies the developing fetus during pregnancy; however, the mechanisms are unclear. We utilized pregnant rats to determine rates of DHA accretion, tissue unesterified DHA uptake and whole-body DHA synthesis-secretion. Female rats maintained on a DHA-free, 2% α-linolenic acid diet were either:1) sacrificed at 56 days for baseline measures, 2) mated and sacrificed at 14–18 days of pregnancy or 3) or sacrificed at 14–18 days as age-matched virgin controls. Maternal brain, adipose, liver and whole body fatty acid concentrations was determined for balance analysis, and kinetic modeling was used to determine brain and liver plasma unesterified DHA uptake and whole-body DHA synthesis-secretion rates. Total liver DHA was significantly higher in pregnant (95±5 μmol) versus non-pregnant (49±5) rats with no differences in whole-body DHA synthesis-secretion rates. However, liver uptake of plasma unesterified DHA was 3.8-fold higher in pregnant animals compared to non-pregnant controls, and periuterine adipose DHA was lower in pregnant (0.89±0.09 μmol/g) versus non-pregnant (1.26±0.06) rats. In conclusion, higher liver DHA accretion during pregnancy appears to be driven by higher unesterified DHA uptake, potentially via DHA mobilization from periuterine adipose for delivery to the fetus during the brain growth spurt.

Docosahexaenoic acid prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice

At a population level, dietary consumption of fish rich in docosahexaenoic acid (DHA) is associated with prevention of cognitive decline but this association is not clear in carriers of the apolipoprotein E epsilon 4 allele (E4). Plasma and liver DHA concentrations show significant alterations in E4 carriers, in part corrected by DHA supplementation. However, whether DHA sufficiency in E4 carriers has consequences on cognition is unknown. Mice expressing human E4 or apolipoprotein E epsilon 3 allele (E3) were fed either a control diet or a diet containing DHA for 8 months and cognitive performance was tested using the object recognition test and the Barnes maze test. In E4 mice fed the control diet, impaired memory was detected and arachidonic acid concentrations were elevated in the hippocampus compared to E3 mice fed the control diet. DHA consumption prevented memory decline and restored arachidonic acid concentrations in the hippocampus of E4 mice. Our results suggest that long-term high-dose DHA intake may prevent cognitive decline in E4 carriers.

Fatty acid and non-alcoholic fatty liver disease: Meta-analyses of case-control and randomized controlled trials

Blood and/or liver fatty acid contents of healthy subjects and non-alcoholic fatty liver disease (NAFLD) patients have shown inconsistent associations. In addition, the results of randomized controlled trials (RCTs) in relation to the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver fat, triglyceride (TAG) and fasting glucose levels are inconsistent. The present study aimed to investigate the differences of fatty acid content in the blood and/or liver tissue between healthy subjects and NAFLD patients, and to quantify the benefits of n-3 PUFA therapy in NAFLD patients. A systematic literature search was performed up to November 2016 using PubMed and Scopus databases. The differences of fatty acid content between cases and controls were calculated as weighted mean differences (WMD) by using a random-effects model. The intervention effects of RCTs were calculated as WMD for net changes in ALT, AST, liver fat, TAG and fasting glucose levels, respectively. Meta-regression with restricted maximum likelihood estimation was used to evaluate a potential linear relationship between confounding factors and effect sizes. Generalized least square was performed for dose-response analysis. Ten eligible case-control studies and 11 RCTs were included. The pooled estimates of case-control studies showed that blood and/or liver docosahexaenoic acid (DHA) content was significantly higher in the controls compared with cases. The pooled estimates of RCTs showed that n-3 PUFA supplementation significantly reduced the ALT (-7.53U/L; 95% CI:-9.98,-5.08U/L), ASL (-7.10U/L, 95% CI:-11.67,-2.52U/L) and TAG (-36.16mg/dL, 95% CI:-49.15,-23.18mg/dL) concentrations, and marginally reduced the liver fat content (-5.11%, 95% CI:-10.24, 0.02%, P=0.051), but not fasting glucose. Dose-response analysis of RCTs showed that 1g per day increment of eicosapentaenoic acid (EPA)+DHA was associated with a 3.14U/L, 2.43U/L, 2.74% and 9.97mg/dL reduction in ALT (95% CI:-5.25,-1.02U/L), AST (95% CI:-3.90,-0.90U/L), liver fat (95% CI:-4.32,-1.16%) and TAG (95% CI:-14.47,-5.48mg/dL) levels, respectively. The present meta-analysis provides substantial evidence that n-3 PUFA supplementation, especially DHA, has a favorable effect in treatment of NAFLD.

Vitamin B12 Deficiency Across Three Generations Adversely Influences Long-chain Polyunsaturated Fatty Acid Status and Cardiometabolic Markers in Rats

Vitamin B12 and omega-3 fatty acid deficiency is prevalent in the vegetarian population and is associated with adverse pregnancy outcomes and cardiometabolic risk. The present study investigates the long-term effects of vitamin B12 deficiency/supplementation in the presence of omega-3 fatty acids on cardiometabolic profile and long-chain polyunsaturated fatty acid levels (LCPUFA) in the F3 generation offspring. Three generations of rats were fed the following diets: control; vitamin B12 deficient; vitamin B12 supplemented; vitamin B12 deficient+omega-3 fatty acid supplemented; vitamin B12+omega-3 fatty acid supplemented. Animals were sacrificed at 3months of age. Vitamin B12 deficiency lowered (p <0.01 for both) plasma eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), liver DHA (p <0.05), plasma/liver omega-3 fatty acids (p <0.05 for both), increased triglycerides (p <0.05) and systolic BP (p <0.01) and lowered cholesterol levels (p <0.05) as compared to control. Vitamin B12 deficiency in the presence of omega-3 fatty acids improved plasma/liver EPA, DHA and omega-3 fatty acid profile and maintained cholesterol, triglyceride and BP levels. Vitamin B12 supplementation lowered liver DHA (p <0.05) and cholesterol (p<0.01), whereas BP was similar to control. Combined supplementation of vitamin B12 and omega-3 fatty acids improved omega-3 fatty acid profile, lowered cholesterol/triglyceride levels and maintained the BP similar to that of control. Vitamin B12 deficiency across three generations adversely affects LCPUFA and cardiometabolic profile in the adult offspring. This study provides clues for a combined supplementation of vitamin B12 and omega-3 fatty acids to reduce the risk for noncommunicable diseases.