Hypothyroidism Exacerbates Thrombophilia in Female Rats Fed with a High Fat Diet

Clotting abnormalities are discussed both in the context with thyroid dysfunctions and obesity caused by a high fat diet. This study aimed to investigate the impact of hypo-, or hyperthyroidism on the endogenous thrombin potential (ETP), a master indicator of clotting activation, on Sprague Dawley rats fed a normal or high fat diet. Female Sprague Dawley rats (n = 66) were grouped into normal diet (ND; n = 30) and high-fat diet (HFD; n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment ETP, body weight and food intake were analyzed. Successfully induced thyroid dysfunction was shown by T3 levels, both under normal and high fat diet. Thyroid dysfunction was accompanied by changes in calorie intake and body weight. In detail, compared to euthyroid controls, hypothyroid rats showed significantly increased—and hyperthyroid animals significantly decreased—ETP levels. High fat diet potentiated these effects in both directions. In summary, we are the first to show that hypothyroidism and high fat diet potentiate the thrombotic capacity of the clotting system in Sprague Dawley rats. This effect may be relevant for cardiovascular disease where thyroid function is poorly understood as a pathological contributor in the context of clotting activity and obesogenic nutrition.     

A Maternal High Fat Diet Has Long‐Lasting Effects on Skeletal Muscle Lipid and PLIN Protein Content in Rat Offspring at Young Adulthood

A maternal high fat diet (HFD) can have adverse effects on skeletal muscle development. Skeletal muscle PLIN proteins (PLIN2, 3 and 5) are thought to play critical roles in lipid metabolism, however effects of HFD on PLIN and lipases (HSL, ATGL, CGI‐58) in mothers as well as their offspring have yet to be investigated. The primary objective of this study was to determine whether maternal HFD would influence skeletal muscle lipase and PLIN protein content in offspring at weaning (19d) and young adulthood (3mo). Female rats (28d old, n = 9/group) were fed control (CON, AIN93G, 7 % soybean oil) or HFD (AIN93G, 20 % lard) for 10 weeks prior to mating and throughout pregnancy and lactation. All offspring were weaned to CON [n = 18/group, 1 female and 1 male pup per litter were studied at weaning (19d) and 3mo of age]. There was no effect of sex for the main outcomes measured in plantaris, therefore male and female data was combined. Maternal HFD resulted in higher triacylglycerol content in pups at 3mo (p < 0.05), as well as in the dams (p = 0.015). Maternal HFD resulted in higher PLIN5 content in pups at weaning and 3mo (p = 0.05). PLIN2 and PLIN5 content decreased at 3mo versus weaning (p < 0.001). HFD dams had a higher PLIN3 content (p = 0.016). Diet had no effect on ATGL, CGI‐58, or HSL content. In conclusion, exposure to a maternal HFD resulted in higher skeletal muscle lipid and PLIN5 content in plantaris of offspring through to young adulthood.     

Sprague Dawley Rats Show More Severe Bone Loss,Osteophytosis and Inflammation Compared to Wistar Han Rats in a High-Fat,High-Sucrose Diet Model of Joint Damage

In animal models, joint degeneration observed in response to obesogenic diet varies in nature and severity. In this study, we compare joint damage in Sprague Dawley and Wistar-Han rats in response to a high-fat, high-sucrose (HFS) diet groove model of osteoarthritis (OA). Wistar Han (n = 5) and Sprague Dawley (n = 5) rats were fed an HFS diet for 24 weeks. OA was induced 12 weeks after the diet onset by groove surgery in the right knee joint. The left knee served as a control. Outcomes were OARSI histopathology scoring, bone changes by µCT imaging, local (synovial and fat pad) and systemic (blood cytokine) inflammation markers. In both rat strains, the HFS diet resulted in a similar change in metabolic parameters, but only Sprague Dawley rats showed a large, osteoporosis-like decrease in trabecular bone volume. Osteophyte count and local joint inflammation were higher in Sprague Dawley rats. In contrast, cartilage degeneration and systemic inflammatory marker levels were similar between the rat strains. The difference in bone volume loss, osteophytosis and local inflammation suggest that both rat strains show a different joint damage phenotype and could, therefore, potentially represent different OA phenotypes observed in humans.     

Dietary Monounsaturated Fatty Acids but not Saturated Fatty Acids Preserve the Insulin Signaling Pathway via IRS-1/PI3K in Rat Skeletal Muscle

Saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) show different effects on the development of insulin resistance. In this study, we compared the effect of dietary SFA and MUFA on the insulin signaling pathway in the skeletal muscle of a type 2 diabetic animal model. Twenty-nine-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) rats were randomly divided into three groups and fed one of the following diets for 3 weeks; a normal chow diet, an SFA (lard oil) enriched or a MUFA (olive oil) enriched high-fat diet. The vastus lateralis muscle was used for analyses. Insulin tolerance test showed improved insulin sensitivity in rats fed the MUFA diet, as compared to those fed the SFA diet (p < 0.001). The SFA diet reduced IRS-1 expression and phosphorylated PI3K levels in skeletal muscle, as compared with a chow diet (p < 0.001, respectively). On the contrary, muscle IRS-2 expression and phosphorylated ERK1/2 was significantly increased in rats fed the SFA diet (p < 0.001, respectively). Membrane translocation of glucose transporter type 4 decreased in the skeletal muscle of rats fed the SFA diet, as compared to those fed a chow diet (p < 0.001). These changes in insulin signaling pathway in skeletal muscle were not observed in rats fed the MUFA diet. In conclusion, the beneficial effect of dietary MUFA on insulin sensitivity is associated with a conserved IRS-1/PI3K insulin signaling pathway which was altered by dietary SFA.     

Maternal High Folic Acid Supplement Promotes Glucose Intolerance and Insulin Resistance in Male Mouse Offspring Fed a High-Fat Diet

Maternal nutrition may influence metabolic profiles in offspring. We aimed to investigate the effect of maternal folic acid supplement on glucose metabolism in mouse offspring fed a high-fat diet (HFD). Sixty C57BL/6 female mice were randomly assigned into three dietary groups and fed the AIN-93G diet containing 2 (control), 5 (recommended folic acid supplement, RFolS) or 40 (high folic acid supplement, HFolS) mg folic acid/kg of diet. All male offspring were fed HFD for eight weeks. Physiological, biochemical and genetic variables were measured. Before HFD feeding, developmental variables and metabolic profiles were comparable among each offspring group. However, after eight weeks of HFD feeding, the offspring of HFolS dams (Off-HFolS) were more vulnerable to suffer from obesity (p = 0.009), glucose intolerance (p < 0.001) and insulin resistance (p < 0.001), compared with the controls. Off-HFolS had reduced serum adiponectin concentration, accompanied with decreased adiponectin mRNA level but increased global DNA methylation level in white adipose tissue. In conclusion, our results suggest maternal HFolS exacerbates the detrimental effect of HFD on glucose intolerance and insulin resistance in male offspring, implying that HFolS during pregnancy should be adopted cautiously in the general population of pregnant women to avoid potential deleterious effect on the metabolic diseases in their offspring.     

Dietary Supplementation with 22-<Emphasis Type="Italic">S</Emphasis>-Hydroxycholesterol to Rats Reduces Body Weight Gain and the Accumulation of Liver Triacylglycerol

This study explores the pharmacokinetics of 22-S-hydroxycholesterol (22SHC) in vivo in rats. We also carried out a metabolic study to explore whether the beneficial effects observed of 22SHC on glucose and lipid metabolism in vitro could be seen in vivo in rats. In the pharmacokinetic study, rats were given 50 mg/kg of [³H]22-S-hydroxycholesterol before absorption, distribution and excretion were monitored. In the metabolic study, the effect of 22SHC (30 mg/kg/day for 3 weeks) in rats on body weight gain [chow and high-fat diet (HFD)], serum lipids triacylglycerol (TAG) content and gene expression in liver and skeletal muscle were examined. Results showed that 22SHC was well absorbed after oral administration and distributed to most organs and mainly excreted in feces. Rats receiving 22SHC gained less body weight than their controls regardless whether the animals received chow diet or HFD. Moreover, we observed that animals receiving HFD had elevated levels of serum TAG while this was not observed for animals on HFD supplemented with 22SHC. The amount of TAG in liver was reduced after 22SHC treatment in animals receiving either chow diet or HFD. Gene expression analysis revealed that two genes (carnitine palmitoyltransferase 2 and uncoupling protein 3) involved in fatty acid oxidation and energy dissipation were increased in liver. Ucp3 expression (both protein and mRNA level) was increased in skeletal muscle, but insulin-stimulated glucose uptake and TAG content were unchanged. In conclusion, 22SHC seems to be an interesting model substance in the search of treatments for disorders involving aberrations in lipid metabolism.     

Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats

Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding) on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66) were grouped into normal diet (n = 30) and high-fat diet (n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL), malondialdehyde (MDA), 4-hydroxynonenal (HNE), the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats.     

Gut microbial fatty acid metabolites (KetoA and KetoC) affect the progression of nonalcoholic steatohepatitis and reverse cholesterol transport metabolism in mouse model

Nonalcoholic steatohepatitis (NASH) is a common liver disease that occurs in both alcoholics and nonalcoholics. Oxidative stress is a possible causative factor for liver diseases including NASH. Gut microorganisms, especially lactic acid bacteria, can produce unique fatty acids, including hydroxy, oxo, conjugated, and partially saturated fatty acids. The oxo fatty acid 10-oxo-11(E)-octadecenoic acid (KetoC) provides potent cytoprotective effects against oxidative stress through activation of Nrf2-ARE pathway. The aim of this study was to explore the preventive and therapeutic effects of gut microbial fatty acid metabolites in a NASH mouse model. The mice were divided into 3 experimental groups and fed as follows: (1) high-fat diet (HFD) (2) HFD mixed with 0.1% KetoA (10-oxo-12(Z)-octadecenoic acid), and (3) HFD mixed with 0.1% KetoC. After 3 weeks of feeding, plasma parameters, liver histology, and mRNA expression of multiple genes were assessed. There was hardly any difference in fat accumulation in the histological study; however, no ballooning occurred in 2/5 mice of KetoC group. Bridging fibrosis was not observed in the KetoA group, although KetoA administration did not significantly suppress fibrosis score (p = 0.10). In addition, KetoC increased the expression level of HDL related genes and HDL cholesterol levels in the plasma. These results indicated that KetoA and KetoC may partly affect the progression of NASH in mice models.     

High-Fat Diet Aggravates Cerebral Infarct,Hemorrhagic Transformation and Neuroinflammation in a Mouse Stroke Model

Background: Stroke in context of type 2 diabetes (T2D) is associated with a poorer outcome than in non-diabetic conditions. We aimed at creating a new reproducible mouse model of stroke in impaired glucose tolerance conditions induced by high-fat diet. Methods: Adult C57BL6 mice were fed for 2 months with either normal diet (ND) or high-fat diet (HFD). We used a model of Middle Cerebral Artery Occlusion (MCAO) for 90 min. Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT) were used to assess pre-diabetic status. Brain infarct volume, hemorrhagic transformation (HT) as well as systemic and cerebral inflammatory markers were evaluated. Results: HFD was associated with an increased body weight and glycemia following OGTT. The HFD group presented a significant increase in brain infarct volume (38.7 (IQR 30–46.7%) vs. 28.45 (IQR 21–30%); p = 0.016) and HT (HFD: 2 (IQR 1–5) vs. ND: 0 (IQR 0–1); p = 0.012) and higher levels of IL-6 and MCP-1 in infarcted hemisphere compared to the ND group. Conclusion: Two months of HFD in adult mice were sufficient to alter the lipid profile and the control of hyperglycemia. These metabolic perturbations were significantly associated with increased infarct volume and hemorrhagic complications.     

Effect of low intake of n−3 fatty acids during development on brain phospholipid fatty acid composition and exploratory behavior in rats

The effect of dietary restriction of n−3 fatty acids during development on brain phospholipid fatty acid composition and exploratory behavior has been studied in male Sprague Dawley rats. Female rats were fed semipurified diets containing either 5.5% safflower oil or 6% soybean oil for 6 wk prior to mating and throughout gestation and lactation. Control rats were maintained on laboratory chow. The male pups were weaned to the diets of the dams except for one group which was switched from safflower to soybean oil at weaning. Behavioral studies and brain phospholipid analyses were conducted at 16–18 wk of age. Rats fed safflower oil showed significantly lower levels of 22∶6n−3 in phospholipids of synaptic membranes and myelin than rats fed soybean oil or chow. The decrease in 22∶6n−3 was compensated for by an increase in 22∶5n−6, the total content of polyunsaturated fatty acids remaining approximately constant. The brain phospholipid fatty acid composition of rats switched from safflower to soybean oil at weaning was similar to that of rats fed soybean oil throughout the experiment. There was no difference in spontaneous locomotor activity among the different dietary groups. However, rats raised on safflower oil displayed a significantly lower exploratory activity (horizontal movements and rearings) in a novel environment than rats fed soybean oil or chow. In contrast to the brain phospholipid fatty acid composition, there was no recovery of exploratory behavior in rats raised on safflower oil and switched to soybean oil at weaning suggesting a specific requirement of n−3 fatty acids during development.     

Rice Bran Oil Improves Insulin Resistance by Affecting the Expression of Antioxidants and Lipid‐Regulatory Genes

The present study investigated the molecular effects of rice bran oil (RBO) on lipid‐regulatory genes (sterol regulatory element binding protein‐1 [Srebf1] and peroxisome proliferator‐activated receptors‐α [Ppara]) and the expression of catalase (CAT) and superoxide dismutase (SOD1) genes in insulin‐resistant rats. Rats were divided into five groups: animals that received standard diet (control); rats fed standard diet containing RBO as the sole source of fat (RBO); a high‐fructose diet (HFD) group, which was further divided into two subgroups: rats fed HFD either for only 1 month (HFD1) or for 2 months (HFD2) and rats fed HFD containing RBO for 1 month; while rats in the last group fed HFD for 30 days then treated with RBO for another 30 days. The HFD induced a state of insulin resistance (IR) as indicated by the hyperinsulinemia and elevated homeostasis model assessment insulin resistance index. Hepatic lipid levels and radical scavenging enzymes were altered by the HFD. Lipid‐regulatory genes, Srebf1 and Ppara, were upregulated while Sod1 and Cat were downregulated in insulin‐resistant rats. Addition of RBO to the two diet regimens alleviated the disorders of IR to some extent. RBO reduced the hepatic levels of triacylglycerol, malondialdehyde, SREBP, and PPAR‐α mRNA. Hepatic SOD and CAT were elevated at gene and protein levels. The HFD induces de novo lipogenesis by upregulating the lipid‐regulatory genes resulting in increased serum and hepatic triacylglycerol. Moreover, IR induced by the HFD caused a state of oxidative stress. Supplementation of RBO to fructose‐fed rats not only improves insulin resistance but also downregulates lipogenic genes and improves the unbalanced oxidative status.     

The Effect of a Sustained High-Fat Diet on the Metabolism of White and Brown Adipose Tissue and Its Impact on Insulin Resistance: A Selected Time Point Cross-Sectional Study

(1) Background: studies on the long-term dynamic changes in fat depot metabolism in response to a high-fat diet (HFD) on hepatic lipid deposition and insulin resistance are sparse. This study investigated the dynamic changes produced by HFD and the production of dysfunctional fat depots on insulin resistance and liver lipid metabolism. (2) Methods: mice fed a chow or HFD (45% kcal fat) diet had three fat depots, liver, and blood collected at 6, 10, 20, and 30 weeks. Anthropometric changes and gene markers for adipogenesis, thermogenesis, ECM remodeling, inflammation, and tissue insulin resistance were measured. (3) Results: early responses to the HFD were increased body weight, minor deposition of lipid in liver, increased adipocyte size, and adipogenesis. Later changes were dysfunctional adipose depots, increased liver fat, insulin resistance (shown by changes in ITT) accompanied by increased inflammatory markers, increased fibrosis (fibrosis > 2-fold, p < 0.05 from week 6), and the presence of crown cells in white fat depots. Later, changes did not increase thermogenic markers in response to the increased calories and decreased UCP1 and PRDM16 proteins in WAT. (4) Conclusions: HFD feeding initially increased adipocyte diameter and number, but later changes caused adipose depots to become dysfunctional, restricting adipose tissue expansion, changing the brown/beige ratios in adipose depots, and causing ectopic lipid deposition and insulin resistance.     

The Effect of Functional Fiber on Microbiota Composition in Different Intestinal Segments of Obese Mice

The gastrointestinal tract is a heterogeneous ecosystem with distinct, stratified environments, which leads to different microbial composition in different intestinal segments. The regional heterogeneity of intestinal microbiota complicates the relationship between diet and microbiota. Few studies have focused on the effects of different diets on microbiota in different intestinal segments. This study aimed to investigate the effects of functional fiber on the microbial composition in multiple intestinal segments from a high-fat diet compared with a normal chow diet. We found that the response of microbiota from different intestinal segments to diet was related to the intestinal physiologic function and the physicochemical properties of dietary nutrients. A high-fat diet drove changes in the microbial composition in the hindgut, possibly by affecting the digestive environment of the foregut, and increased the regional heterogeneity of the whole intestinal microbiota. The supplementation of functional fiber promoted the microbial transfer and colonization from the anterior to the posterior intestinal segments, and increased the regional similarity of intestinal microbiota accordingly, particularly within the hindgut. The gut fermentation of the functional fiber, which mainly occurred in the hindgut, resulted in a significant change in the microbial composition and metabolism in the cecum and colon, with richer carbohydrate metabolism-related bacteria, including Mucispirillum, Prevotella, Anaerostipes, Oscillospira, Ruminococcus, Bacteroides, Coprococcus, Ruminococcus (Lachnospiraceae), and Allobaculum, and higher production of acetate and butyrate. We concluded that multiple regulatory mechanisms of diets which affect microbiota composition exist, including microbial metabolism, microbial migration, and the regulation of the intestinal environment.     

Partial Deficiency of Zfp217 Resists High-Fat Diet-Induced Obesity by Increasing Energy Metabolism in Mice

Obesity-induced adipose tissue dysfunction and disorders of glycolipid metabolism have become a worldwide research priority. Zfp217 plays a crucial role in adipogenesis of 3T3-L1 preadipocytes, but about its functions in animal models are not yet clear. To explore the role of Zfp217 in high-fat diet (HFD)-induced obese mice, global Zfp217 heterozygous knockout (Zfp217^+/−) mice were constructed. Zfp217^+/− mice and Zfp217^+/+ mice fed a normal chow diet (NC) did not differ significantly in weight gain, percent body fat mass, glucose tolerance, or insulin sensitivity. When challenged with HFD, Zfp217^+/− mice had less weight gain than Zfp217^+/+ mice. Histological observations revealed that Zfp217^+/− mice fed a high-fat diet had much smaller white adipocytes in inguinal white adipose tissue (iWAT). Zfp217^+/− mice had improved metabolic profiles, including improved glucose tolerance, enhanced insulin sensitivity, and increased energy expenditure compared to the Zfp217^+/+ mice under HFD. We found that adipogenesis-related genes were increased and metabolic thermogenesis-related genes were decreased in the iWAT of HFD-fed Zfp217^+/+ mice compared to Zfp217^+/− mice. In addition, adipogenesis was markedly reduced in mouse embryonic fibroblasts (MEFs) from Zfp217-deleted mice. Together, these data indicate that Zfp217 is a regulator of energy metabolism and it is likely to provide novel insight into treatment for obesity.     

n-6 High Fat Diet Induces Gut Microbiome Dysbiosis and Colonic Inflammation

Background: Concerns are emerging that a high-fat diet rich in n-6 PUFA (n-6HFD) may alter gut microbiome and increase the risk of intestinal disorders. Research is needed to model the relationships between consumption of an n-6HFD starting at weaning and development of gut dysbiosis and colonic inflammation in adulthood. We used a C57BL/6J mouse model to compare the effects of exposure to a typical American Western diet (WD) providing 58.4%, 27.8%, and 13.7% energy (%E) from carbohydrates, fat, and protein, respectively, with those of an isocaloric and isoproteic soybean oil-rich n-6HFD providing 50%E and 35.9%E from total fat and carbohydrates, respectively on gut inflammation and microbiome profile. Methods: At weaning, male offspring were assigned to either the WD or n-6HFD through 10–16 weeks of age. The WD included fat exclusively from palm oil whereas the n-6HFD contained fat exclusively from soybean oil. We recorded changes in body weight, cyclooxygenase-2 (COX-2) expression, colon histopathology, and gut microbiome profile. Results: Compared to the WD, the n-6HFD increased plasma levels of n-6 fatty acids; colonic expression of COX-2; and the number of colonic inflammatory and hyperplastic lesions. At 16 weeks of age, the n-6HFD caused a marked reduction in the gut presence of Firmicutes, Clostridia, and Lachnospiraceae, and induced growth of Bacteroidetes and Deferribacteraceae. At the species level, the n-6HFD sustains the gut growth of proinflammatory Mucispirillum schaedleri and Lactobacillus murinus. Conclusions: An n-6HFD consumed from weaning to adulthood induces a shift in gut bacterial profile associated with colonic inflammation.     

The effect of linoleic,arachidonic and eicosapentaenoic acid supplementation on prostacyclin production in rats

We examined the effect of dietary supplementation of linoleic acid (LA), arachidonic acid (AA) or eicosapentaenoic acid (EPA) to rats fed a diet low in linoleic acid onin vitro andin vivo production of prostacyclin. Male Sprague Dawley rats were fed a high-fat diet (50% energy as fat, 1.5% linoleic acid) for two weeks. Three of the groups were then supplemented orally with either 90 mg/d of LA, AA or EPA, all as the ethyl esters, for a further two weeks while remaining on the high-fat diet. Forty-eight hour urine samples were collected at the end of the second and fourth weeks.In vivo prostacyclin production was determined by a stable isotope dilution, gas chromatography/mass spectrometry assay for the major urinary metabolite of prostacyclins (2,3-dinor-6-keto-PGF_1α or PGI₂-M and Δ¹⁷-2-3-dinor-6-keto-PGF_1α or PGI₃-M).In vitro prostacyclin production was determined by radioimmunoassay of the stable metabolite (6-keto-PGF_1α) following incubation of arterial tissue. Oral supplementation with AA resulted in a rise in plasma and aorta 20∶4n−6, and increasedin vitro prostacyclin and urinary PGI₂-M production. EPA supplementation resulted in a rise in plasma and aorta 20∶5n−3 and 22∶5n−3, and a decline in plasma 20∶4n−6, but not in the aorta. In the EPA-supplemented group, thein vitro prostacyclin and the urinary PGI₃-M increased, but urinary PGI₂-M decreased. The increase inin vitro prostacyclin production in the EPA-supplemented rats was unexpected and without obvious explanation. Supplementation with LA had minimal effect on fatty acid composition of plasma or aorta and caused no change in prostacyclin production with either method. Thein vivo measure of prostacyclin production was positively correlated with aorta AA levels, and negatively correlated with aorta levels of EPA. There was a significant positive correlation between thein vitro production of prostacyclin and thein vivo production (as measured by the urinary prostacyclin metabolite level), despite the differences observed in the EPA-fed group. There was a high inter-animal variability in prostacyclin production using either method. These results indicate that dietary AA stimulates and dietary EPA reducesin vivo PGI₂ production in the rat. An equivalent amount of dietary LA was without effect.     

n-3 Fatty Acids Abrogate Dyslipidemia-Induced Changes in Bile Acid Uptake,Synthesis, and Transport in Young and Aged Dyslipidemic Rats

In this study, the effect of n-3 fatty acids (FA) [α-linolenic acid (ALA) and eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] on the intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic bile acid transporters (BAT) was assessed in young and aged dyslipidemic rats. Dyslipidemia was induced in young and aged rats by feeding a high-fat (HF) diet. Experimental groups received diets containing canola oil (HF + CNO) and fish oil (HF + FO) as a source of ALA and EPA + DHA, respectively. After 60 days of feeding, intestinal BA uptake and expression of apical sodium-dependent bile acid transporter (Asbt), organic solute transporter-alpha/beta (Osta/b) messenger RNA (mRNA), and hepatic expression of Na⁺ taurocholate cotransporting polypeptide (Ntcp), bile salt export pump (Bsep), cholesterol 7-α hydroxylase A1 (Cyp7a1), Farnesoid X receptor (Fxr), small heterodimer partner-1 (Shp), liver receptor homolog-1 (Lrh-1), and hepatic nuclear factor-4 alpha (Hnf4a) mRNA were measured. Hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity and total BA in serum, liver, and feces were assessed. The dyslipidemic HF group had: (1) increased intestinal BA uptake and Asbt and Osta/b mRNA expression, (2) increased BA in serum, (3) decreased hepatic expression of Ntcp, Bsep, and Cyp7a1 mRNA, (4) increased activity of HMG-CoA reductase, (5) increased hepatic expression of Fxr and Shp mRNA, (6) decreased hepatic expression of Lrh-1 and Hnf4a mRNA, and (7) decreased BA in feces, when compared to control, HF + CNO, and HF + FO groups. Immunostaining revealed increased expression of intestinal Asbt and hepatic Ntcp protein in the HF group when compared to control, HF + CNO, and HF + FO groups. n-3 FA abrogated dyslipidemia-induced changes in the intestinal uptake, hepatic synthesis, and enterohepatic transporters of BA in both young and aged rats. EPA + DHA was more effective than ALA in modulating dyslipidemia-induced changes.     

n-3 Polyunsaturated Fatty Acids Improve Inflammation via Inhibiting Sphingosine Kinase 1 in a Rat Model of Parenteral Nutrition and CLP-Induced Sepsis

The sphingosine kinase 1 (SphK1)/sphingosine‐1‐phosphate (S1P) pathway plays a key role in inflammation. Parenteral nutrition containing n‐3 polyunsaturated fatty acids (n‐3 PUFA) may regulate inflammatory reactions. The aim of this study is to determine whether n‐3 PUFA may improve inflammatory responses by neutralizing SphK1 signaling. Rat models of parenteral nutrition, cecal ligation and puncture (CLP)‐induced sepsis were generated. Male Sprague–Dawley rats were operated for CLP on day 2 after venous catheterization. The rats were randomized to receive normal saline (NS; n = 20), parenteral nutrition (PN; n = 20), or PN + fish oil (FO; n = 20) for 5 days. The daily intake of fish oil (1.25–2.82 g EPA and 1.44–3.09 g DHA per 100 ml) in the FO group was approximately 1.8 g/kg body weight/day. Rats in the control group (n = 10) were subjected to sham operation and received a chow diet. Spleen tissues were collected for SphK1 and S1P receptor expression analysis. Our data showed that n‐3 PUFA ameliorated the survival rate. SphK1 expression and its enzymatic activity were significantly upregulated in sepsis rats. Furthermore, mRNA and protein levels of S1PR3, but not S1PR1, were also facilitated after CLP. However, PN + FO dramatically decreased SphK1 mRNA level and its enzymatic activity. S1PR3 expression was also attenuated by FO addition. In conclusion, the anti‐inflammatory effect of n‐3 PUFA may be linked to the inhibition of the SphK1/S1P pathway in a rat model of parenteral nutrition and CLP‐induced sepsis.