Inhibition of lncRNA TCONS_00077866 Ameliorates the High Stearic Acid Diet-Induced Mouse Pancreatic ß-Cell Inflammatory Response by Increasing miR-297b-5p to Downregulate SAA3 Expression.

Long-term consumption of a high-fat diet increases the circulating concentration of stearic acid (SA), which has a potent toxic effect on ß-cells, but the underlying molecular mechanisms of this action have not been fully elucidated. Here, we evaluated the role of long noncoding (lnc)RNA TCONS_00077866 (lnc866) in SA-induced ß-cell inflammation. lnc866 was selected for study because lncRNA high-throughput sequencing analysis demonstrated it to have the largest fold-difference in expression of five lncRNAs that were affected by SA treatment. Knockdown of lnc866 by virus-mediated shRNA expression in mice or by Smart Silencer in mouse pancreatic ß-TC6 cells significantly inhibited the SA-induced reduction in insulin secretion and ß-cell inflammation. According to lncRNA-miRNAs-mRNA coexpression network analysis and luciferase reporter assays, lnc866 directly bound to miR-297b-5p, thereby preventing it from reducing the expression of its target serum amyloid A3 (SAA3). Furthermore, overexpression of miR-297b-5p or inhibition of SAA3 also had marked protective effects against the deleterious effects of SA in ß-TC6 cells and mouse islets. In conclusion, lnc866 silencing ameliorates SA-induced ß-cell inflammation by targeting the miR-297b-5p/SAA3 axis. lnc866 inhibition may represent a new strategy to protect ß-cells against the effects of SA during the development of type 2 diabetes.

Dietary Saturated Fatty Acids Modulate Pain Behaviour in Trauma-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) is a degenerative condition of joints, causing pain and swelling, and can be caused or worsened by trauma and obesity. The objectives of this study were to determine whether pain behaviour and progression of OA were increased in rats with trauma-induced OA fed dietary saturated fatty acids (SFA). Male Wistar rats were fed either a corn starch diet (C) or high-carbohydrate high-fat diet (H) with either 20% beef tallow or SFA (lauric (HLA), myristic (HMA), palmitic (HPA) or stearic (HSA) acids) for 16 weeks prior to and 8 weeks after excision of the medial meniscus of right knee joint to initiate OA when pain behaviour, glial activity, progression of knee OA, inflammatory mediators and signs of metabolic syndrome were assessed. Rats fed beef tallow, palmitic or stearic acids showed increased pain symptoms characterised by decreased hind paw/limb withdrawal thresholds and grip strengths and increased spinal astrogliosis and microgliosis compared to rats fed lauric or myristic acids. However, the severity of OA joint damage was unchanged by these dietary manipulations. We conclude that pain symptoms of trauma-induced OA in rats worsen with increased dietary beef tallow or palmitic or stearic acids, but improve with lauric or myristic acids, despite unchanged OA cartilage damage.

Intake of dietary fat and fat subtypes and risk of premenstrual syndrome in the Nurses' Health Study II.

Approximately 8-20 % of reproductive-aged women experience premenstrual syndrome (PMS), substantially impacting quality of life. Women with PMS are encouraged to reduce fat intake to alleviate symptoms; however, its role in PMS development is unclear. We evaluated the association between dietary fat intake and PMS development among a subset of the prospective Nurses' Health Study II cohort. We compared 1257 women reporting clinician-diagnosed PMS, confirmed by premenstrual symptom questionnaire and 2463 matched controls with no or minimal premenstrual symptoms. Intakes of total fat, subtypes and fatty acids were assessed via FFQ. After adjustment for age, BMI, smoking, Ca and other factors, intakes of total fat, MUFA, PUFA and trans-fat measured 2-4 years before were not associated with PMS. High SFA intake was associated with lower PMS risk (relative risk (RR) quintile 5 (median=28·1 g/d) v. quintile 1 (median=15·1 g/d)=0·75; 95 % CI 0·58, 0·98; P trend=0·07). This association was largely attributable to stearic acid intake, with women in the highest quintile (median=7·4 g/d) having a RR of 0·75 v. those with the lowest intake (median=3·7 g/d) (95 % CI 0·57, 0·97; P trend=0·03). Individual PUFA and MUFA, including n-3 fatty acids, were not associated with risk. Overall, fat intake was not associated with higher PMS risk. High intake of stearic acid may be associated with a lower risk of developing PMS. Additional prospective research is needed to confirm this finding.

Stearic acid at physiologic concentrations induces in vitro lipotoxicity in circulating angiogenic cells.

BACKGROUND AND AIMS: Saturated free fatty acids (SFAs) can induce lipotoxicity in different cells. No studies have investigated the effects of SFA in circulating angiogenic cells (CACs), which play a key role in endothelial repair processes. The aim of the study was to assess the effects of SFAs, specifically stearic acid (SA), on viability and function of CACs and to investigate potential underlying molecular mechanisms. METHODS: CACs were isolated from healthy subjects by established methods. CACs were incubated with BSA-complexed stearate (100 µM) to assess the time course (from 8 to 24 h exposure) of the effects on viability and apoptosis (activation of caspases 3/7), angiogenic function (tube formation assay), pro-inflammatory cytokine (IL-1ß, IL-6, IL-8, MCP-1 and TNFα) gene expression (qPCR) and secretion (ELISA), activation of MAPK (JNK, p38 and Erk1/2) by Western blot and endoplasmic reticulum (ER) stress marker (CHOP, BIP, ATF4, XBP-1 and sXBP-1) gene expression by qPCR. RESULTS: Stearic acid activates effector caspases in CACs in a dose- and time-dependent manner. SA also impairs CAC function and increases pro-inflammatory molecule (IL-1ß, IL-6, IL-8, MCP-1 and TNFα) gene expression and secretion in CACs starting from 3 h of incubation. The activation of JNK by SA mediates pro-inflammatory response, but it may be not necessary for apoptosis. Moreover, SA induces the expression of ER stress markers across the three branches of the ER stress response. CONCLUSIONS: In humans, both function and viability of CACs are exquisitely vulnerable to physiologic concentrations of stearate; lipotoxic impairment of endothelial repair processes may be implicated in vascular damage caused by SFAs.

Saturated fatty acids induce development of both metabolic syndrome and osteoarthritis in rats.

The predominant saturated fatty acids (SFA) in human diets are lauric acid (LA, C12:0), myristic acid (MA, C14:0), palmitic acid (PA, C16:0) and stearic acid (SA, C18:0). The aim of this study was to investigate whether diets containing individual SFA together with excess simple carbohydrates induce osteoarthritis (OA)-like changes in knee joints and signs of metabolic syndrome in rats. Rats were given either a corn starch diet or a diet composed of simple carbohydrates together with 20% LA, MA, PA, SA or beef tallow for 16 weeks. Rats fed beef tallow, SA, MA or PA diets developed signs of metabolic syndrome, and also exhibited cartilage degradation and subchondral bone changes similar to OA. In contrast, replacement of beef tallow with LA decreased signs of metabolic syndrome together with decreased cartilage degradation. Furthermore, PA and SA but not LA increased release of matrix sulphated proteoglycans in cultures of bovine cartilage explants or human chondrocytes. In conclusion, we have shown that longer-chain dietary SFA in rats induce both metabolic syndrome and OA-like knee changes. Thus, diets containing SFA are strongly relevant to the development or prevention of both OA and metabolic syndrome.

Synthesis, self-assembly, and in vitro toxicity of fatty acids-modified Bletilla striata polysaccharide.

Hydrophobic modification of Bletilla striata polysaccharide (BSP) was performed by grafting fatty acids to BSP backbone and then characterized on their physicochemical properties. All neutral derivatives were able to self-assemble into spherical particles within the size range of 250-400 nm, their size and critical micelle concentration decreased with increasing hydrophobicity and substitution degree of the fatty acids. Also, the BSP-stearic acid conjugates showed a preferable performance on hemolysis test and cytotoxicity analysis on HepG2 cells, which suggested their potential application as a drug delivery vector.

Dietary fat and breast cancer mortality: A systematic review and meta-analysis.

BACKGROUND: The influence of dietary fat upon breast cancer mortality remains largely understudied despite extensive investigation into its influence upon breast cancer risk. OBJECTIVE: To conduct meta-analyses of studies to clarify the association between dietary fat and breast cancer mortality. DESIGN: MEDLINE and EMBASE were searched for relevant articles published up to March 2012. Risk of all-cause or breast-cancer-specific death was evaluated by combining multivariable adjusted estimates comparing highest versus lowest categories of intake; and per 20 g increase in intake of total and/or saturated fat (g/day) using random-effects meta-analyses. RESULTS: Fifteen prospective cohort studies investigating total fat and/or saturated fat intake (g/day) and breast cancer mortality were included. There was no difference in risk of breast-cancer-specific death (n = 6; HR = 1.14; 95% CI: 0.86, 1.52; p = 0.34) or all-cause death (n = 4; HR = 1.73; 95% CI: 0.82, 3.66; p = 0.15) for women in the highest versus lowest category of total fat intake. Breast-cancer-specific death (n = 4; HR = 1.51; 95% CI: 1.09, 2.09; p < 0.01) was higher for women in the highest versus lowest category of saturated fat intake. CONCLUSIONS: These meta-analyses have shown that saturated fat intake negatively impacts upon breast cancer survival.

Good Fats versus Bad Fats: A Comparison of Fatty Acids in the Promotion of Insulin Resistance, Inflammation, and Obesity.

Recently, debate has erupted in both the scientific community and throughout the lay public around whether a low-fat or low-carbohydrate diet is better for weight loss. In other words, is it better to cut fat or cut carbohydrate for weight loss. However, going beyond this debate (fat versus carbohydrate), are questions around whether certain fatty acids are worse for promoting insulin resistance, inflammation, and obesity. The overall evidence in the literature suggests that medium-chain saturated fats (such as lauric acid, found in coconut oil) and monounsaturated fat (oleic acid, found in olive oil) are less likely to promote insulin resistance, inflammation, and fat storage compared to long-chain saturated fatty acids (such as stearic acid found in large quantities in butter, but particularly palmitic acid found in palm oil) especially when consumed on top of a diet moderate in refined carbohydrates. Compared to long-chain saturated fats, lauric acid and oleic acid have an increased fatty acid oxidation rate, are more likely to be burned for energy and less likely to be stored in adipose tissue, and thus promote increased energy expenditure. Omega-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid, as found in vegetable oils may contribute to obesity, whereas omega-3 PUFA may be protective. Importantly, both olive oil as part of a Mediterranean diet, and omega-3 from fish and fish oil have been proven to reduce risk of cardiovascular (CV) events.

Fatty acids in a high-fat diet potentially induce gastric parietal-cell damage and metaplasia in mice.

BACKGROUND: Obesity is associated with risk of adenocarcinoma in the proximal stomach. We aimed to identify the links between dietary fat and gastric premalignant lesions. METHODS: C57BL/6 mice were fed high fat diet (HFD), and gastric mucosa was histologically analysed. Morphological changes were also analysed using an electron microscope. Transcriptome analysis of purified parietal cells was performed, and non-parietal gastric corpus epithelial cells were subjected to single-cell gene-expression profiling. Composition of gastric contents of HFD-fed mice was compared with that of the HFD itself. Lipotoxicity of free fatty acids (FFA) was examined in primary culture and organoid culture of mouse gastric epithelial cells in vitro, as well as in vivo, feeding FFA-rich diets. RESULTS: During ~8-20 weeks of HFD feeding, the parietal cells of the stomach displayed mitochondrial damage, and a total of 23% of the mice developed macroscopically distinct metaplastic lesions in the gastric corpus mucosa. Transcriptome analysis of parietal cells indicated that feeding HFD enhanced pathways related to cell death. Histological analysis and gene-expression profiling indicated that the lesions were similar to previously reported precancerous lesions identified as spasmolytic polypeptide-expressing metaplasia. FFAs, including linoleic acid with refluxed bile acids were detected in the stomachs of the HFD-fed mice. In vitro, FFAs impaired mitochondrial function and decreased the viability of parietal cells. In vivo, linoleic acid-rich diet, but not stearic acid-rich diet induced parietal-cell loss and metaplastic changes in mice. CONCLUSIONS: Dietary lipids induce parietal-cell damage and may lead to the development of precancerous metaplasia.

Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation.

Interesterified fats are currently being used to replace trans fatty acids. However, their impact on biological pathways involved in the atherosclerosis development was not investigated. Weaning male LDLr-KO mice were fed for 16weeks on a high-fat diet (40% energy as fat) containing polyunsaturated (PUFA), TRANS, palmitic (PALM), palmitic interesterified (PALM INTER), stearic (STEAR) or stearic interesterified (STEAR INTER). Plasma lipids, lipoprotein profile, arterial lesion area, macrophage infiltration, collagen content and inflammatory response modulation were determined. Macrophage cholesterol efflux and the arterial expression of cholesterol uptake and efflux receptors were also performed. The interesterification process did not alter plasma lipid concentrations. Although PALM INTER did not increase plasma cholesterol concentration as much as TRANS, the cholesterol enrichment in the LDL particle was similar in both groups. Moreover, PALM INTER induced the highest IL-1ß, MCP-1 and IL-6 secretion from peritoneal macrophages as compared to others. This inflammatory response elicited by PALM INTER was confirmed in arterial wall, as compared to PALM. These deleterious effects of PALM INTER culminate in higher atherosclerotic lesion, macrophage infiltration and collagen content than PALM, STEAR, STEAR INTER and PUFA. These events can partially be attributed to a macrophage cholesterol accumulation, promoted by apoAI and HDL2-mediated cholesterol efflux impairment and increased Olr-1 and decreased Abca1 and Nr1h3 expressions in the arterial wall. Interesterified fats containing palmitic acid induce atherosclerosis development by promoting cholesterol accumulation in LDL particles and macrophagic cells, activating the inflammatory process in LDLr-KO mice.

Potential cutaneous hypersensitivity reaction to an inactive ingredient of thyroid hormone supplements in a dog.

BACKGROUND: Although discussions about allergic reactions to thyroid supplements abound on professional forums, there is almost no information in the literature on these specific idiosyncratic drug reactions. ANIMAL: A dog with a history of hypothyroidism-associated weight gain and mild lethargy was prescribed levothyroxine tablets (0.018 mg/kg twice daily). After 19 days the dog developed a severe skin condition that was responsive to levothyroxine withdrawal, and antibiotic and glucocorticoid therapy. Three weeks later a different levothyroxine tablet was prescribed. Within 48 h the dog developed a more severe cutaneous reaction that resolved with drug discontinuation and appropriate topical care. OBJECTIVES: To confirm a possible hypersensitivity reaction and identify its chemical target. METHODS AND RESULTS: The two prescribed levothyroxine formulations shared two inactive ingredients: magnesium stearate and polyvinylpyrrolidone. Nine months after discontinuation of thyroid supplement, a formulation without either of these two compounds was used for a second re-challenge. There was no recurrence of the drug reaction and after 1.5 years of treatment the dog remains normal. CONCLUSIONS AND CLINICAL IMPORTANCE: These elements strongly suggest that this dog had an idiosyncratic reaction (likely immune-mediated) against one or both inactive ingredients in the first two formulations of levothyroxine. We are not aware of any previous confirmed delayed hypersensitivity to a thyroid supplement in a dog with the likely chemical trigger being an inactive ingredient rather than the therapeutic agent itself. We hope that this case will raise awareness about allergic reactions to thyroid supplements and allergic reactions to inactive formulation components.

Elaidic acid (EA) generates dysfunctional high-density lipoproteins and consumption of EA exacerbates hyperlipidemia and fatty liver change in zebrafish.

SCOPE: It is well known that trans-fatty acids have proatherogenic properties while HDL has antiatherogenic activities in plasma. However, there has been no report on the effects of trans-fat on the functional and structural properties of HDL. METHODS AND RESULTS: To compare physiological properties, we synthesized reconstituted HDL (rHDL) containing stearic acid (18:0), oleic acid (18:1, cis), or elaidic acid (EA, 18:1, trans). An rHDL containing EA (EA-rHDL) showed loss of antioxidant ability and induced the highest uptake of oxidized LDL into human macrophages. EA-rHDL caused the strongest cellular senescence in human dermal fibroblast cells along with the highest production of inflammatory species in macrophages co-treated with fructose. Injection of EA-rHDL into zebrafish embryos resulted in acute embryonic toxicity with the lowest survivability. Consumption of trans-fat for 20 weeks resulted in remarkable hyperlipidemia, elevation of serum cholesteryl ester transfer protein activity, hepatic inflammation, and fatty liver changes. CONCLUSION: Incorporation of EA impaired the beneficial effects of rHDL against atherogenesis. In zebrafish, EA-rHDL resulted in acute embryonic toxicity, and consumption of EA caused remarkable hyperlipidemia, inflammation, and fatty liver changes.

Stearic acids at sn-1, 3 positions of TAG are more efficient at limiting fat deposition than palmitic and oleic acids in C57BL/6 mice.

In the present study, we investigated the effect of long-acyl chain SFA, namely palmitic acid (16:0) and stearic acid (18:0), at sn-1, 3 positions of TAG on obesity. Throughout the 15 weeks of the experimental period, C57BL/6 mice were fed diets fortified with cocoa butter, sal stearin (SAL), palm mid fraction (PMF) and high-oleic sunflower oil (HOS). The sn-1, 3 positions were varied by 16:0, 18:0 and 18:1, whilst the sn-2 position was preserved with 18:1. The HOS-enriched diet was found to lead to the highest fat deposition. This was in accordance with our previous postulation. Upon normalisation of total fat deposited with food intake to obtain the fat:feed ratio, interestingly, mice fed the SAL-enriched diet exhibited significantly lower visceral fat/feed and total fat/feed compared with those fed the PMF-enriched diet, despite their similarity in SFA-unsaturated fatty acid-SFA profile. That long-chain SFA at sn-1, 3 positions concomitantly with an unsaturated FA at the sn-2 position exert an obesity-reducing effect was further validated. The present study is the first of its kind to demonstrate that SFA of different chain lengths at sn-1, 3 positions exert profound effects on fat accretion.

Combined effect of N-stearoyiletanolamine and ionizing radiation on hematological indices of peripheral blood in rats.

UNLABELLED: The study objective was to explore the peculiarities of peripheral blood values in rats under the combined influence of 10.0 mg/kg N-stearoylethanolamine (NSE) and 6.0 Gy dose of ionizing radiation to identify the radiomodifying properties of the drug. METHODS: hematological, statistical. RESULTS: it was found that NSE injection to irradiated rats leads to exacerbation of hematopoietic system disorders indicating to radiosensitizing effect of the substance. CONCLUSIONS: The radiosensitizing effect of the drug was established according to qualitative and quantitative abnormalities in peripheral blood values of the rats. Effect of the NSE drug on the rate of recovery processes (i.e. retardation) in the peripheral blood of rats after irradiation was established under these experimental conditions.

Avaliação comparativa do efeito dos ácidos graxos oléico, palmítico e esteárico sobre biomarcadores do processo aterosclerótico / Comparative evaluation of fatty acids, oleic, palmitic and stearic, effects on atherosclerosis biomarkers

A aterosclerose é classificada como enfermidade crônica não transmissível e é considerada uma das principais causas de morte e morbidade em vários países, incluindo o Brasil. Entre as possíveis causas de sua gênese está o hábito alimentar, especificamente o consumo de ácidos graxos, principalmente saturados e trans. Ácidos graxos saturados possuem características biológicas e fisico-químicas diferentes dos insaturados. Os mais abundantes na dieta humana são o palmítico e esteárico. Sua associação com acometimentos cardiovasculares vem sendo cada vez mais investigada, principalmente os que possuem mais de dez carbonos em sua cadeia interferindo no metabolismo de lipoproteínas podendo desencadear todo o processo aterosclerótico. A indústria de alimentos vem desenvolvendo algumas tecnologias opcionais para reduzir ou eliminar ácidos graxos trans, em especial, o elaídico, dentre elas a modificação no processo de hidrogenação que aumenta a quantidade de ácidos graxos saturados. Alguns alimentos industrializados necessitam de uma grande quantidade de ácidos graxos saturados promovendo um aumento no teor de ácido palmítico e esteárico, sendo este último considerado um ácido graxo saturado neutro, mas dependendo da concentração utilizada, pode contribuir no decréscimo da HDL-c (High Density Lipoprotein), dentre outras alterações deletérias. Desta forma, investigar as alterações de determinados parâmetros biológicos diante da mudança da proporção de ácidos graxos saturados, respeitando o teor total de lipídios de uma dieta é a base deste estudo. Foram realizados ensaios em material biológico para a determinação dos seguintes parâmetros: 1) Atividade de enzimas antioxidantes; 2) Peroxidação lipídica em tecidos; 3) Lipidograma; 4) Determinação do perfil de ácidos graxos de tecidos e rações e 5) Expressão de genes relacionados com o processo aterosclerótico (ICAM-1, VCAM-1, CD36 e MCP-1). A determinação da atividade de enzimas antioxidantes foi realizada considerando somente as enzimas Catalase (CAT) e Superóxido Dismutase (SOD), por se tratarem de enzimas com alteração expressiva no processo aterogênico, na ocorrência de disfunção endotelial. Neste trabalho, foi analisada a atividade das referidas enzimas no tecido hepático e cardíaco, onde não foram constatadas alterações. O mesmo processo biológico que estimula a produção excessiva de espécies reativas pode levar ao aumento da peroxidação lipídica, principalmente de ácidos graxos polinsaturados das membranas celulares, em tecidos como fígado, cérebro e coração. A peroxidação lipídica apresentou diferenças significativas no tecido hepático. O grupo alimentado com ração enriquecida com tripalmitato apresentou peroxidação lipídica aumentada em relação ao grupo controle. Correlacionando com o perfil de ácidos graxos do tecido hepático, notamos que houve maior incorporação de ácido palmítico nesse tecido, que por apresentar configuração linear, quando incorporado à membrana celular, pode levar à disfunção e possível suscetibilidade a danos, como a peroxidação. No tecido cardíaco e no tecido cerebral não foram observadas alterações e diferenças entre os tratamentos. O lipidograma consiste na quantificação de lipoproteínas e frações lipídicas, compondo o perfil lipídico no plasma sanguíneo. Os resultados obtidos mostraram que o colesterol total foi significativamente menor no grupo controle, assim como triacilglicerol e LDL colesterol (LDL-c). Já HDL colesterol (HDL-c) está reduzida no grupo que recebeu ração suplementada com ácido palmítico, assim como este grupo apresentou parâmetros aumentados nas dosagens de triacilglicerol e colesterol total. Os grupos alimentados com ração suplementada com triestearato e trioleato apresentaram resultados intermediários para a dosagem de HDL-c, com valores tendendo ao grupo suplementado com tripalmitato. Em relação à dosagem de LDL-c, foi constatada diferença entre os grupos suplementados e o grupo controle. Destaca-se que não houve diferença entre a dosagem entre os grupos suplementados. Portanto, o grupo alimentado com dieta enriquecida com ácido oleico (monoinsaturado) equipara-se aos grupos alimentados com dietas enriquecidas com ácido esteárico e palmítico (saturados). O perfil de ácidos graxos do tecido hepático mostrou uma porcentagem elevada de ácido palmítico no grupo alimentado com ração enriquecida com o mesmo ácido graxo, com diferença estatística em relação aos demais grupos. Já em relação ao ácido esteárico, não houve diferenças significativas entre os grupos. Em compensação, o teor de ácido oleico no grupo suplementado com este mesmo ácido graxo e com ácido palmítico foi significativamente diferente em relação aos demais, com valores superiores. Este resultado demonstra que não houve dessaturação do ácido esteárico a oleico, ao menos neste modelo. No tecido cardíaco, foi observado o mesmo comportamento. No tecido cardíaco não houve diferença estatística significativa da concentração de ácidos graxos, indicando que não houve incorporação ou dessaturação. Ressalta-se que de acordo com determinação realizada utilizando a técnica de cromatografia gasosa, as rações apresentavam em sua composição o teor de lipídios adequado ao modelo animal e as proporções de ácidos graxos alteradas como proposto no objetivo deste trabalho. Em relação às moléculas de adesão e quimiocinas (VCAM-1, ICAM-1, CD-36 e MCP-1) relacionadas com o processo aterosclerótico, houve somente alteração na molécula CD-36 no grupo alimentado com ração enriquecida com trioleato, com redução em relação aos demais. Mas, as moléculas de adesão relacionadas com o processo inicial da aterogênese, a expressão gênica realizada através da técnica de q-RT-PCR não foi relevante, não apresentando diferença entre os tratamentos. Conclui-se, portanto, que os tratamentos aplicados ao modelo animal selecionado possui o potencial de alterar lipoproteínas plasmáticas, mas não de manter a continuidade e desencadear o processo inflamatório relacionado à aterogênese

Atherosclerosis is chronic a non-communicable disease considered one of a major cause of morbidity and mortality in several countries, including Brazil. Among all the possible causes of their genesis the dietary habit of high fatty acid intake, especially saturated and trans fatty acids is the most important. Saturated and unsaturated fatty acids possess different biological and physicochemical characteristics. The most abundant fatty acid in the human diet are palmitic and stearic and they association with cardiovascular events has been increasingly investigated, especially those one with more than ten carbons in its chain which interfers in the lipoproteins metabolism and can initiate the atherosclerotic process. The food industry has developed some optional technologies to reduce or eliminate the presence of trans fatty acids in foods, in particular elaidic, which after the hydrogenation process increases the saturated fatty acids content. Some industrialized foods requires a large amount of saturated fatty acids that promote an increase of palmitic and stearic content, the last fatty acid mentioned is considered a neutral saturated fatty acid that can contribute to the decrease in HDL-c (High Density lipoprotein), depending on the concentration used, among other deleterious changes. Thus, investigate changes of specifics biological parameters in response to consumption of different saturated fatty acids, respecting the total content of lipids in a normolipidic diet is the aim of this study. Assays were conducted to determine the following parameters in the tissues: 1) Activity of antioxidant enzymes, 2) Lipid peroxidation, 3) Lipidogram; 4) Fatty acid composition 5) Expression of genes related the atherosclerotic process (ICAM-1, VCAM-1, CD36 and MCP- 1). The determination of the activity of antioxidant enzymes was carried out considering only the enzymes Catalase (CAT) and Superoxide Dismutase (SOD), because they are enzymes more sensitive and readily available in changes resulted of an atherosclerotic process with endothelial dysfunction. In the study, no changes were observed in activity of these enzymes in the liver and heart. The same biological process that stimulates the overproduction of reactive species can lead to increased lipid peroxidation, especially of polyunsaturated fatty acids present in cell membranes of tissues such as liver, brain and heart. The group fed with diet enriched with tripalmitate showed increased lipid peroxidation compared to control group. Correlating this information with the fatty acid profile in liver tissue, we noted that there was a greater incorporation of palmitic acid, which exhibit linear configuration when incorporated into the cell membrane and can lead to dysfunction and higher susceptibility to damages such as oxidation. No differences were observed in the others tissues analyzed. The lipidogram is the quantification of lipoprotein and lipid fractions, composing the lipid profile in blood plasma. The results showed that total cholesterol was significantly lower in the control group, as well triglyceride and LDL cholesterol (LDL-c). HDL cholesterol (HDL-C) concentration is reduced and triacylglycerol and cholesterol increased n the group fed with diet supplemented with palmitic. The groups fed with diets supplemented with tristearate and trioleate presented intermediate results for the measurement of HDL-c, with values tending to the group supplemented with tripalmitate. Regarding LDL-c levels, significant differences were observed between the supplemented groups and the control group. Emphasis that there was no difference between the dosage between the supplemented groups. Therefore, the group fed with oleic acid (monounsaturated) supplemented diet equates to the groups fed with diets enriched with stearic and palmitic acid (saturated). The fatty acid profile of liver tissue showed a high percentage of palmitic acid in the group fed with diet enriched with the same fatty acid, with a statistical difference compared to the other groups. In relation to stearic acid, there were no significant differences between groups. As compensation, the oleic acid content in the group supplemented with the same fatty acid and palmitic acid was significantly higher when compared to the others. This result demonstrates that no desaturation of stearic acid to oleic happened in this experimental model. In cardiac tissue there was no statistically significant difference in the concentration of fatty acids, indicating no incorporation or desaturation. Regarding adhesion molecules and chemokines (VCAM-1, ICAM- 1, CD-36 and MCP-1) related to the atherosclerotic process, there was only change in the gene expression of CD-36 molecule in the group fed diet enriched with trioleate, with reduction in relation to others. No other alterations were observed. In conclusion, we verified that the consumption of the different fatty acids in this experimental model has potential to alter lipoproteins levels but not to iniciate or maintain the inflammatory process associated with atherogenesis

Saturated fatty acids activate microglia via Toll-like receptor 4/NF-κB signalling.

Diets rich in SFA have been implicated in Alzheimer's disease (AD). There is strong evidence to suggest that microglial activation augments the progression of AD. However, it remains uncertain whether SFA can initiate microglial activation and whether this response can cause neuronal death. Using the BV-2 microglial cell line and primary microglial culture, we showed that palmitic acid (PA) and stearic acid (SA) could activate microglia, as assessed by reactive morphological changes and significantly increased secretion of pro-inflammatory cytokines, NO and reactive oxygen species, which trigger primary neuronal death. In addition, the mRNA level of these pro-inflammatory mediators determined by RT-PCR was also increased by PA and SA. We further investigated the intracellular signalling mechanism underlying the release of pro-inflammatory mediators from PA-activated microglial cells. The present results showed that PA activated the phosphorylation and nuclear translocation of the p65 subunit of NF-κB. Furthermore, pyrrolidine dithiocarbamate, a NF-κB inhibitor, attenuated the production of pro-inflammatory mediators except for IL-6 in PA-stimulated microglia. Administration of anti-Toll-like receptor (TLR)4-neutralising antibody repressed PA-induced NF-κB activation and pro-inflammatory mediator production. In conclusion, the present in vitro study demonstrates that SFA could activate microglia and stimulate the TLR4/NF-κB pathway to trigger the production of pro-inflammatory mediators, which may contribute to neuronal death.

Hematopoietic cell-restricted deletion of CD36 reduces high-fat diet-induced macrophage infiltration and improves insulin signaling in adipose tissue.

OBJECTIVE: The fatty acid translocase and scavenger receptor CD36 is important in the recognition and uptake of lipids. Accordingly, we hypothesized that it plays a role in saturated fatty acid-induced macrophage lipid accumulation and proinflammatory activation. RESEARCH DESIGN AND METHODS: In vitro, the effect of CD36 inhibition and deletion in lipid-induced macrophage inflammation was assessed using the putative CD36 inhibitor, sulfosuccinimidyl oleate (SSO), and bone marrow-derived macrophages from mice with (CD36KO) or without (wild-type) global deletion of CD36. To investigate whether deletion of macrophage CD36 would improve insulin sensitivity in vivo, wild-type mice were transplanted with bone marrow from CD36KO or wild-type mice and then fed a standard or high-fat diet (HFD) for 20 weeks. RESULTS: SSO treatment markedly reduced saturated fatty acid-induced lipid accumulation and inflammation in RAW264.7 macrophages. Mice harboring CD36-specific deletion in hematopoietic-derived cells (HSC CD36KO) fed an HFD displayed improved insulin signaling and reduced macrophage infiltration in adipose tissue compared with wild-type mice, but this did not translate into protection against HFD-induced whole-body insulin resistance. Contrary to our hypothesis and our results using SSO in RAW264.7 macrophages, neither saturated fatty acid-induced lipid accumulation nor inflammation was reduced when comparing CD36KO with wild-type bone marrow-derived macrophages. CONCLUSIONS: Although CD36 does not appear important in saturated fatty acid-induced macrophage lipid accumulation, our study uncovers a novel role for CD36 in the migration of proinflammatory phagocytes to adipose tissue in obesity, with a concomitant improvement in insulin action.

Inflammation of the hypothalamus leads to defective pancreatic islet function.

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic ß-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic ß-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.