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Background: Genetic risk scores (GRSs) have partially improved the understanding of the etiology of moderate hypertriglyceridemia (HTG), which until recently was mainly assessed by secondary predisposing causes. The main objective of this study was to assess whether this variability is due to the interaction between clinical variables and GRS. Methods: We analyzed 276 patients with suspected polygenic HTG. An unweighted GRS was developed with the following variants: c.724C > G (ZPR1 gene), c.56C > G (APOA5 gene), c.1337T > C (GCKR gene), g.19986711A > G (LPL gene), c.107 + 1647T > C (BAZ1B gene) and g.125478730A > T (TRIB gene). Interactions between the GRS and clinical variables (body mass index (BMI), diabetes mellitus, diet, physical activity, alcohol consumption, age and gender) were evaluated. Results: The GRS was associated with triglyceride (TG) concentrations. There was a significant interaction between BMI and GRS, with the intensity of the relationship between the number of alleles and the TG concentration being greater in individuals with a higher BMI. Conclusions: GRS is associated with plasma TG concentrations and is markedly influenced by BMI. This finding could improve the stratification of patients with a high genetic risk for HTG who could benefit from more intensive healthcare interventions.

[eng] Quality attributes of food products such as visual appearance, melting behavior, or shelf-life are strongly determined by the crystallization behavior of natural fats and oils within. In turn, this behavior depends on the polymorphism and the sort of mixing states (eutectic phase, solid solution phase, molecular compound formation) displayed by their major triacylglycerol components. Therefore, it becomes essential that studies regarding lipid crystallization cover from pure molecular components and their mixtures to real fats and oils. In connection with the above, this thesis focuses on gaining further fundamental knowledge about the polymorphism and crystalline behavior of lipid systems with varying degrees of complexity. Thus, the first stage of the research involved a study of pure triacylglycerols based on palmitic, lauric, and oleic acids (P, L, and O, respectively), which are typical of natural fats and oils such as lard and palm, olive, and coconut oils. During the second stage, binary and ternary mixtures including these triacylglycerols were examined to obtain an insight into their solid-state miscibility properties. Concretely, the mixtures were composed of a fully saturated triacylglycerol and one or two saturated-unsaturated triacylglycerols able to form a molecular compound. Despite the presumable crucial role of interactions including triacylglycerols forming molecular compound in the physical behavior of natural lipids and their blends, the phase behavior of triacylglycerol mixtures with such configuration is barely known. Finally, the third stage consisted of a more applied investigation of the crystalline and thermal properties of blends including natural fats. More specifically, binary blends of cocoa butter and shea butter stearin. Regarding the investigation of pure TAGs, calorimetric and X-ray diffraction techniques were used to examine the polymorphic occurrence and transformation behavior of PPP, LLL, OPO, and PPO during the application of dynamic thermal treatments at varying cooling and heating rates. The results showed that the polymorphic occurrence on cooling, as well as the sequence and type of transformations during heating, were influenced by the rate of the thermal treatments applied. However, it was also found that the extent of the kinetic influence depended on the intrinsic properties of triacylglycerols such as the length of the fatty acid chains or the characteristic polymorphism. The mixtures under examination during the phase behavior studies included the binary systems PPP/POP, PPP/PPO, PPP/OPO, LLL/POP, and LLL/PPO, and the ternary systems PPP/POP/OPO, PPP/POP/PPO, and LLL/POP/PPO (keeping an equimolecular ratio of POP/OPO or POP/PPO to favor molecular compound formation). Eutectic behavior with partial miscibility was observed under metastable and stable conditions. Furthermore, the results obtained for stable binary mixtures showed that the degree of miscibility was primarily influenced by the oleic acid content of the unsaturated component, as well as the differences in the size of the triacylglycerols within the mixture. From the solid-state miscibility observed in ternary systems containing LLL or PPP, it was concluded that third components may affect the mixing interactions associated with molecular compound formation. In addition, the results suggested that the ternary interactions studied may help to explain the crystallization behavior of edible lipids like palm oil and be useful in fat structuring applications. As a case study of real fat blends, combinations of cocoa butter and shea butter stearin at varying proportions were examined through calorimetric, X-ray diffraction, spectroscopic, and microscopic techniques. These made possible to characterize the effect of composition on the polymorphic crystallization and transformation properties, the melting profile, and the microstructural development. The results obtained for some of the parameters under study suggested that specific combinations might be considered for its application in chocolate-type confectionery products., [spa] Atributos de calidad de productos alimentarios con base lipídica, como la apariencia visual, el perfil de fusión o la vida útil, están determinados por el comportamiento cristalino de las grasas, polimorfismo y del estado de mezcla (fases eutécticas, fase de solución sólida, formación de compuesto molecular) de sus triacilgliceroles mayoritarios. Por tanto, los estudios en cristalografía de lípidos deben abarcar desde componentes moleculares puros y sus mezclas hasta grasas y aceites reales. En línea con esto, la presente tesis se centra en el estudio del polimorfismo y comportamiento cristalino de sistemas lipídicos atendiendo a los diferentes grados de complejidad. Por un lado, se ha investigado la cristalización y transformación polimórfica bajo condiciones dinámicas de temperatura de triacilgliceroles basados en ácidos palmítico, láurico y oleico (P, L y O, respectivamente), comunes en la manteca y los aceites de palma, oliva y coco. Además, se han estudiado mezclas binarias y ternarias incluyendo estos triacilgliceroles para determinar sus propiedades de miscibilidad en estado sólido. Específicamente, las mezclas han consistido en un triacilglicerol trisaturado y uno o dos triacilgliceroles con cierto grado de insaturación capaces de formar un compuesto molecular. A pesar del rol fundamental de las interacciones entre triacilgliceroles capaces de formar un compuesto molecular y otros componentes en las propiedades físicas de lípidos naturales y sus combinaciones, el comportamiento de fase de mezclas de triacilgliceroles con esta configuración apenas se ha investigado con anterioridad. Por último, esta tesis también recoge un estudio de carácter más aplicado sobre las propiedades térmicas y cristalinas de mezclas de grasas naturales. Más concretamente, de mezclas binarias de manteca de cacao y estearina de karité. El interés de este estudio reside en la importancia a nivel económico de los productos relacionados con el chocolate y en la necesidad de encontrar nuevas mezclas lipídicas que permitan satisfacer la creciente demanda global de manteca de cacao u obtener nuevas funcionalidades en los productos finales.

© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim We report lipase-based nanomotors that are capable of enhanced Brownian motion over long periods of time in triglyceride solution and of degrading triglyceride droplets that mimic “blood lipids”. We achieved about 40 min of enhanced diffusion of lipase-modified mesoporous silica nanoparticles (MSNPs) through a biocatalytic reaction between lipase and its corresponding water-soluble oil substrate (triacetin) as fuel, which resulted in an enhanced diffusion coefficient (ca. 50 % increase) at low triacetin concentration (

SLE is associated with increased cardiovascular risk. The objective of this study was to determine the prevalence of asymptomatic carotid atherosclerosis to analyze its relationship with dyslipidemia and related genetic factors in a population of patients with SLE. Seventy-one SLE female patients were recruited. Carotid ultrasound, laboratory profiles, and genetic analysis of the ZPR1, APOA5, and GCKR genes were performed. SLE patients were divided into two groups according to the presence or absence of carotid plaques. Patients with carotid plaque had higher plasma TG (1.5 vs. 0.9 mmol/L, p = 0.001), Non-HDL-C (3.5 vs. 3.1 mmol/L, p = 0.025), and apoB concentrations (1.0 vs. 0.9 g/L, p = 0.010) and a higher prevalence of hypertension (80 vs. 37.5%, p = 0.003) than patients without carotid plaque. The GCKR C-allele was present in 83.3% and 16.7% (p = 0.047) of patients with and without carotid plaque, respectively. The GCKR CC genotype (OR = 0.026, 95% CI: 0.001 to 0.473, p = 0.014), an increase of 1 mmol/L in TG concentrations (OR = 12.550, 95% CI: 1.703 to 92.475, p = 0.013) and to be hypertensive (OR = 9.691, 95% CI: 1.703 to 84.874, p = 0.040) were independently associated with carotid atherosclerosis. In summary, plasma TG concentrations, CGKR CC homozygosity, and hypertension are independent predictors of carotid atherosclerosis in women with SLE.

Treballs Finals de Grau de Nutrició Humana i Dietètica, Facultat de Farmàcia i Ciències de l'Alimentació, Campus de l'Alimentació de Torribera, Universitat de Barcelona. Curs: 2020-2021. Tutor: Carmen Escolano Mirón, [spa] La dieta cetogénica es un régimen dietético basado en la formación de cuerpos cetónicos y sus beneficios para la salud. A lo largo de los años, esta ha sido empleada en el tratamiento de enfermedades neurodegenerativas como la enfermedad de Alzheimer (AD) y la epilepsia. Existen varios tipos de dieta cetogénica, pero ¿son todos tan eficaces en el tratamiento de dichas enfermedades? Esta revisión evalúa el efecto de la dieta suplementada con triglicéridos de cadena media (MCT) en sujetos con AD y epilepsia. AD y epilepsia son enfermedades en las que la captación y metabolización de la glucosa se ven afectadas, por ello, la dieta MCT se propone como un tratamiento eficaz. En AD la mayoría de los estudios concluyen que la suplementación con MCT es un tratamiento eficaz para evitar un mayor deterioro cognitivo. Mientras que, en epilepsia, la evidencia consultada no muestra resultados significativos por lo que es necesaria la aparición de más estudios para determinar si realmente tiene o no efectos positivos. En conclusión, se recomienda que este régimen dietético se aplique siempre bajo supervisión de Dietista-Nutricionista y teniendo en cuenta posibles efectos secundarios y deficiencias nutricionales., [eng] The ketogenic diet is a dietary regime based on the formation of ketone bodies and their health benefits. Over the years, it has been used in the treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and epilepsy. There are many different types of ketogenic diet, but are they all as effective in the treatment of these diseases? This review evaluates the effect of diet supplemented with medium-chain triglycerides (MCT) in subjects with AD and epilepsy. AD and epilepsy are diseases in which glucose uptake and metabolism are impaired, so the MCT diet is proposed as an effective treatment. In AD, most studies conclude that MCT supplementation is an effective treatment to prevent further cognitive decline. In epilepsy, however, the evidence consulted does not show significant results and more studies are needed to determine whether or not it really has positive effects. In conclusion, it is recommended that this dietary regime should always be applied under the supervision of a dietician-nutritionist and taking into account possible side effects and nutritional deficiencies.

Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease (NAFLD), is defined as the presence of hepatic steatosis with inflammation, hepatocyte injury, and different degrees of fibrosis. Although NASH affects 2–5% of the global population, no drug has been specifically approved to treat the disease. Fibroblast growth factor 21 (FGF21) and its analogs have emerged as a potential new therapeutic strategy for the treatment of NASH. In fact, FGF21 deficiency favors the development of steatosis, inflammation, hepatocyte damage, and fibrosis in the liver, whereas administration of FGF21 analogs ameliorates NASH by attenuating these processes. We review mechanistic insights into the beneficial and potential side effects of therapeutic approaches targeting FGF21 for the treatment of NASH.

Critically increasing high demands for trans-free and reduction of saturated fats have been asking lipid researchers to develop novel ideas of materials designs of hard stocks for various edible fats.

The purpose of this study was to identify circulating biomarkers of recurrent non-infectious anterior uveitis (NIAU), and to address the anti-inflammatory effects of triglyceride containing docosahexaenoic acid (DHA-TG). A prospective multicenter study was conducted in 72 participants distributed into: patients diagnosed with recurrent NIAU in the quiescence stage (uveitis group (UG), n = 36) and healthy controls (control group (CG), n = 36). Each group was randomly assigned to the oral supplementation of one pill/day (+) containing DHA-TG (n = 18) or no-pill condition (−) (n = 17) for three consecutive months. Data from demographics, risk factors, comorbidities, eye complications and therapy were recorded. Blood was collected and processed to determine pro-inflammatory biomarkers by bead-base multiplex assay. Statistical processing with multivariate statistical analysis was performed. The mean age was 50, 12 (10, 31) years. The distribution by gender was 45% males and 55% females. The mean number of uveitis episodes was 5 (2). Higher plasma expression of interleukin (IL)-6 was detected in the UG versus the CG (p = 5 × 10−5). Likewise, significantly higher plasma levels were seen for IL-1β, IL-2, INFγ (p = 10−4), and TNFα (p = 2 × 10−4) in the UG versus the CG. Significantly lower values of the above molecules were found in the +DHA-TG than in the -DHA-TG subgroups, after 3 months of follow-up, TNFα (p = 10−7) and IL-6 (p = 3 × 10−6) being those that most significantly changed. Signatures of circulating inflammatory mediators were obtained in the quiescent stage of recurrent NIAU patients. This 3-month follow-up strongly reinforces that a regular oral administration of DHA-TG reduces the inflammatory load and may potentially supply a prophylaxis-adjunctive mediator for patients at risk of uveitis vision loss.

We examined the influence of dynamic thermal treatment (variation of cooling/heating rates) on the polymorphic crystallization and transformation pathways of 1-palmitoyl-2,3-dioleoyl glycerol (POO), 1-stearoyl-2,3-dioleoyl glycerol (SOO), and 1-palmitoyl-2-oleoyl-3-linoleoyl glycerol (POL), which are major saturated-unsaturated-unsaturated (SUU) triacylglycerols (TAGs) of vegetable oils and animal fats (e.g., palm oil, olive oil, and Iberian ham fat). Using mainly a combination of differential scanning calorimetry (DSC) and synchrotron radiation X-ray diffraction (SR-XRD), we analyzed the polymorphic behavior of TAGs when high (15 °C min− 1), intermediate (2 °C min− 1), and low (0.5 °C min− 1) cooling and heating rates were applied. Multiple polymorphic forms were detected in POO, SOO, and POL (sub-α, α, β'2, and β'1). Transient disordered phases, defined as kinetic liquid crystal (KLC) phases, were determined in POO and SOO for the first time. The results demonstrated that more stable forms were directly obtained from the melt by decreasing the cooling rates, whereas less stable forms predominated at high cooling rates, as confirmed in our previous work. Regarding heating rate variation, we confirmed that the nature of the polymorphic transformations observed (solid-state, transformation through KLC phase, or melt-mediation) depended largely on the heating rate. These results were discussed considering the activation energies involved in each process and compared with previous studies on TAGs with different saturated-unsaturated structures (1,3-dioleoyl-2-palmitoylglycerol, 1,3-dipalmitoyl-2-oleoyl-glycerol, trioleoyl glycerol, and 1,2-dioleoyl-3-linoleoyl glycerol).

The polymorphic crystallization and transformation behavior of extra virgin olive oil (EVOO) was examined by using differential scanning calorimetry (DSC) and X-ray diffraction with both laboratory-scale (XRD) and synchrotron radiation source (SR-XRD). The complex behavior observed was studied by previously analyzing mixtures composed by its main 2 to 6 triacylglycerol (TAG) components. Thus, component TAGs were successively added to simulate EVOO composition, until reaching a 6 TAGs mixture, composed by trioleoyl glycerol (OOO), 1-palmitoyl-2,3-dioleoyl glycerol (POO), 1,2-dioleoyl-3-linoleoyl glycerol (OOL), 1-palmitoyl-2-oleoyl-3-linoleoyl glycerol (POL), 1,2-dipalmitoyl-3-oleoyl glycerol (PPO) and 1-stearoyl-2,3-dioleoyl glycerol (SOO). Molten samples were cooled from 25 °C to − 80 °C at a controlled rate of 2 °C/min and subsequently heated at the same rate. The polymorphic behavior observed in multicomponent TAG mixtures was interpreted by considering three main groups of TAGs with different molecular structures: triunsaturated OOO and OOL, saturated-unsaturated-unsaturated POO, POL and SOO, and saturated-saturated-unsaturated PPO. As confirmed by our previous work, TAGs belonging to the same structural group displayed a highly similar polymorphic behavior. EVOO exhibited two different β'-2 L polymorphic forms (β'2-2 L and β'1-2 L), which transformed into β'-3 L when heated. Equivalent polymorphic pathways were detected when the same experimental conditions were applied to the 6 TAG components mixture. Hence, minor components may not exert a strong influence in this case.

[Background]: Rhodococcus jostii RHA1 and other actinobacteria accumulate triglycerides (TAG) under nutrient starvation. This property has an important biotechnological potential in the production of sustainable oils. [Results]: To gain insight into the metabolic pathways involved in TAG accumulation, we analysed the transcriptome of R jostii RHA1 under nutrient-limiting conditions. We correlate these physiological conditions with significant changes in cell physiology. The main consequence was a global switch from catabolic to anabolic pathways. Interestingly, the Entner-Doudoroff (ED) pathway was upregulated in detriment of the glycolysis or pentose phosphate pathways. ED induction was independent of the carbon source (either gluconate or glucose). Some of the diacylglycerol acyltransferase genes involved in the last step of the Kennedy pathway were also upregulated. A common feature of the promoter region of most upregulated genes was the presence of a consensus binding sequence for the cAMP-dependent CRP regulator. [Conclusion]: This is the first experimental observation of an ED shift under nutrient starvation conditions. Knowledge of this switch could help in the design of metabolomic approaches to optimize carbon derivation for single cell oil production., This work was financed by Grants BIO2010-14809 from the Spanish Ministry of Science and Innovation and BFU2014-55534-C2-2-P from the Spanish Ministry of Economy and Competitiveness to GM. H.M. Alvarez is a career investigator of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.

Importance Hypertriglyceridemia is the most frequent and limiting adverse effect of bexarotene therapy in cutaneous T-cell lymphoma (CTCL). Despite standard prophylactic measures, there is a wide variability in the severity of this complication, which could be associated with both genetic and environmental factors. Objectives To analyze the association between genetic polymorphisms of apolipoprotein genes APOA5, APOC3, and APOE and the severity of hypertriglyceridemia during bexarotene therapy and to optimize patient selection for bexarotene therapy based on adverse effect profile. Design, Setting, and Participants This case series study was conducted in 12 university referral hospitals in Spain from September 17, 2014, to February 6, 2015. One hundred twenty-five patients with a confirmed diagnosis of CTCL who had received bexarotene therapy for at least 3 months were enrolled. Nine patients were excluded owing to missing analytic triglyceride level data, leaving a study group of 116 patients. Data on demographic and cardiovascular risk factor were collected, and a complete blood analysis, including lipid profile and genetic analysis from a saliva sample, was performed. Main Outcomes and Measures Primary outcomes were the maximal triglyceride levels reported in association with the minor alleles of the polymorphisms studied. Results Among 116 patients, the mean (SD) age was 61.2 (14.7) years, 69 (59.5%) were men, and 85 (73.2%) had mycosis fungoides, the most prevalent form of CTCL. During bexarotene therapy, 96 patients (82.7%) experienced hypertriglyceridemia, which was severe or extreme in 8 of these patients (8.3%). Patients who carried minor alleles of the polymorphisms did not show significant differences in baseline triglyceride concentrations. After bexarotene treatment, carriers of at least 1 of the 2 minor alleles of APOA5 c.-1131T>C and APOC3 c.*40C>G showed lower levels of triglycerides than noncarriers (mean [SD], 241.59 [169.91] vs 330.97 [169.03] mg/dL, respectively; P = .02). Conclusions and Relevance These results indicate that the screening of APOA5 and APOC3 genotypes may be useful to estimate changes in triglyceride concentrations during bexarotene treatment in patients with CTCL and also to identify the best candidates for bexarotene therapy based on the expected adverse effect profile.

The epicuticular wax (EW) layer is located on the surface of most of plants organs. It provides the cuticle with most of its properties and is the primary barrier against biotic and abiotic stress. Despite the importance of Olea europaea cultivation, few studies have characterized the EW covering leaves and olives, which could be involved in resistance to both infection and environmental conditions. In the present study, wide-ranging screening was carried out using direct-injection electrospray ionisation coupled to high-resolution mass spectrometry to analyse EW in developing olives of nine varieties. The proportions of EW fractions (wax esters (WEs), diacylglycerols, triacylglycerols (TAGs), triterpenic acids and aldehydes) strongly depended on the olive cultivar, and in only a few cases were they influenced by the sampling date. The specific compositions of the major fractions, WEs and TAGs, were strictly related to the cultivar, while the degree of unsaturation and the chain length of the WEs evolved throughout the four weeks prior to the olive colour turning.

Triheptanoin-enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30–40% of the daily caloric intake. However, pre-clinical studies using triheptanoin-rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. Practical applications: This work provides a complete description of (i) an efficient and cost-effective synthesis of triheptanoin and (ii) its formulation as a solid, stable, and palatable ketogenic diet (triheptanoin-rich; 39% of the caloric intake) for rodents. Triheptanoin-rich diets will be helpful on pre-clinical experiments testing the therapeutic efficacy of triheptanoin in different rodent models of human diseases. In addition, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study their dosage and long-term effects on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.

We systematically examined the phase behavior of binary mixtures of mixed-acid triacylglycerols (TAGs) containing palmitic and oleic acid moieties 1,3-dioleoyl-2-palmitoyl-glycerol (OPO), 1,2-dipalmitoyl-3-oleoyl-rac-glycerol (PPO), and 1,2-dioleoyl-3-palmitoyl-rac-glycerol (OOP), which are widely present in natural fats and are employed in the food, pharmaceutical, and cosmetic industries. Differential scanning calorimetry and X-ray diffraction methods were applied to observe the mixing behavior of PPO/OPO, OOP/OPO, and PPO/OOP under metastable and stable conditions. The results led to three conclusions: (1) Eutectic behavior was observed in PPO/OPO. (2) Molecular compound (MC) crystals were formed in the mixtures of OOP/OPO and PPO/OOP. (3) However, the MC crystals occurred only under metastable conditions and tended to separate into component TAGs to form eutectic mixture systems after 17 months of incubation. These results were contrary to those of previous studies on 1,3-dipalmitoyl-2-oleoyl glycerol (POP)/OPO and POP/PPO in which the MC crystals were thermodynamically stable. We determined that specific molecular interactions may cause this different phase behavior (stability of POP/OPO and POP/PPO MC crystals and metastability of OOP/OPO and PPO/OOP MC crystals). All results confirm the significant effects of molecular structures of glycerol groups, interactions of fatty acid chains, and polymorphism of the component TAGs on the mixing behavior of mixed-acid TAGs.

Apolipoprotein CIII (apoCIII) plays an important role in plasma triglyceride and remnant lipoprotein metabolism. Because hypertriglyceridemia is an independent risk factor in coronary artery disease and the presence in plasma of triglyceride-rich remnant lipoproteins is correlated with atherosclerosis, considerable research efforts have been focused on the identification of factors regulating apoCIII gene expression to decrease its production. Here we report that the orphan nuclear hormone receptor Rev-erbalpha regulates the human apoCIII gene promoter. In apoCIII expressing human hepatic HepG2 cells, transfection of Rev-erbalpha specifically repressed apoCIII gene promoter activity. We determined by deletion and site-directed mutagenesis experiments that Rev-erbalpha dependent repression is mainly due to an element present in the proximal promoter of the apoCIII gene. In contrast, we found no functional Rev-erbalpha response elements in the convergently transcribed human apoAI gene or the common regulatory enhancer. The identified Rev-erbalpha response element coincides with a RORalpha1 element, and in the present study we provide evidence that functional cross-talk between these orphan receptors modulates the apoCIII promoter. In vitro binding analysis showed that monomers of Rev-erbalpha bound this element but not another upstream RORalpha1 response element. In addition, we showed that the closely related nuclear orphan receptor RVR also specifically repressed the human apoCIII gene. These studies underscore a novel physiological role for members of the Rev-erb family of nuclear receptors in the regulation of genes involved in triglyceride metabolism and the pathogenesis of atherosclerosis.

[spa] Esta tesis se basa fundamentalmente en el estudio in situ del polimorfismo de triacilgliceroles (TAGs) mayoritarios de aceites y grasas alimentarios, la determinación del comportamiento de fases de algunas de sus mezclas binarias, y la aplicación del polimorfismo como herramienta para la autentificación de productos alimentarios. Se ha llevado a cabo la caracterización polimórfica de los TAGs POP, OPO, POO, POL, SOO, OOO y OOL, básicamente utilizando una combinación de calorimetría diferencial de barrido y difracción de rayos X con radiación sincrotrón (SAXD y WAXD). Así, se han podido monitorizar los procesos dinámicos de cristalización y las transiciones polimórficas cuando las muestras se sometían a diferentes velocidades de enfriamiento y calentamiento. Los resultados obtenidos son directamente aplicables a procesos de cristalización de aceites y grasas alimentarios, con la finalidad de obtener las propiedades deseadas del producto final, utilizando los tratamientos térmicos más eficientes. Para comprender las interacciones intermoleculares que tienen lugar entre TAGs, se ha determinado los diagramas de fases de las mezclas PPO-OPO, PPO-POO y POO-OPO. Se ha observado un comportamiento eutéctico para el sistema PPO-OPO, mientras que en los sistemas PPO-POO y POO-OPO se formaba un compuesto molecular (co-cristal) metaestable, que tendía a separarse en los componentes de origen. Mediante el uso de difracción de rayos X con micro-haz de radiación sincrotrón, se han analizado las microestructuras heterogenias de mezclas de POP-OPO. El estudio de estos agregados cristalinos esferulíticos es directamente aplicable a procesos de fraccionamiento del aceite de palma. Con la finalidad de comprender muestras grasas más complejas, se ha caracterizado el complejo comportamiento polimórfico de mezclas multi-componente de 3 a 6 TAGs. Para el caso particular del aceite de oliva, el comportamiento polimórfico viene básicamente determinado por los TAGs mayoritarios, mientras que los componentes minoritarios parecen desarrollar un papel menos crucial. Finalmente, se ha aplicado el comportamiento polimórfico como herramienta para la autentificación y detección de fraudes en productos alimentarios. Ha sido posible determinar adiciones fraudulentas de aceite de avellana en aceite de oliva virgen extra en concentraciones inferiores al 5%, y se han podido establecer diferencias muy significativas en grasas de jamones Ibéricos de las categorías cebo y bellota., [eng]Lipids, together with proteins and carbohydrates are major nutrients and also employed as lipophilic materials in food, cosmetic and pharmaceutical industries. Alimentary and industrial fats and oils (such as vegetable oils, margarine, chocolate, and confectionery fats) mainly consist of triacylglycerols (TAGs), whose molecules involve different types of fatty acid moieties. TAGs show a complicated crystallization behavior. The physicochemical properties of a TAG molecule are determined by the nature and compositions of the three fatty acid moieties. These properties must be studied not only in their pure systems but also in mixed systems. In particular, studies on binary mixture systems provide valuable information about molecular interactions among different lipid materials. This PhD thesis is based on the study of the in situ polymorphic characterization of the main TAGs of some vegetable and animal fats and oils, some of their mixtures and the use of the polymorphic behavior of edible fats and oils as a tool to determine their authentication. The polymorphic study of the triacylglycerols POP, OPO, POO, POL, SOO, OOO and OOL was in situ characterized by mainly using differential scanning calorimetry (DSC) and synchrotron radiation X-ray diffraction (SR-XRD) with SAXD and WAXD simultaneous measurement. The combined usage of DSC and SR-XRD or laboratory-scale X-ray diffraction enabled us to monitor the occurrence and transformation behavior at different rates of cooling and heating. The results obtained are closely related to actual crystallization processes of edible fats and oils, in which most functional polymorphic forms can be obtained by applying the most efficient thermal treatments. We also determined the phase behavior of binary mixtures of mixed-acid TAGs containing palmitic and oleic fatty acids (i.e. PPO-OPO, PPO-POO and POO-OPO). PPO-OPO system revealed an eutectic behavior, whereas PPO-POO and POO-OPO were molecular compound-forming. Long incubation periods were needed in order to thermodynamically stabilize the binary mixtures, and the results demonstrated that molecular compounds of PPO-POO and POO-OPO were metastable and tended to separate into the pure TAG components. On the other hand, microstructures of spherulites of POP-OPO binary mixtures were analyzed in neat liquid and solution (n-dodecane) systems by using synchrotron radiation microbeam X-ray diffraction (SR-mu-XRD). Due to a molecular compound formation at the 50:50 concentration ratio, 75POP:25OPO and 25POP:75OPO compositions were characterized to study how the microstructures of spherulites of the TAGs mixtures are determined when the molecular compound crystals and POP or OPO component crystals can be formed competitively. Studies of these heterogeneous microstructures in neat liquid and solution are applicable to palm oil fractionation processes by dry and solvent methods. In an attempt to make an approach to complex natural fatty samples, such as olive oil, the polymorphism of multicomponent mixtures (from 3 to 6 TAG components) was analyzed and discussed. Thus, we observed that the polymorphic behavior of an extra virgin olive oil from the Arbequina olive variety was mainly influenced by its main TAGs, whereas apparently minor components did not develop a crucial role. Furthermore, we also used the polymorphic behavior of natural fat and oils (virgin and extra virgin olive oil, and Iberian ham fat) as a tool to determine authenticity (different ham categories depending on the fattening system used) and detection of adulterations (fraudulent additions of hazelnut oil in olive oil). The combined use of DSC and preliminary chemometric calculations permitted determining fraudulent additions of raw hazelnut oil in an extra virgin olive oil (Arbequina) at concentrations below 5%. On the other hand, highly significant differences were detected in the polymorphic behavior of Iberian ham fat from the bellota and cebo categories.

This study examined the influence of different thermal treatments on the crystallization and transformation of trioleoyl glycerol (OOO) and 1,2-dioleoyl-3-rac-linoleoyl glycerol (OOL). Two triacylglycerol (TAG) samples were cooled at 0.5-15 °C·min(-1) and heated at 2 and 15 °C·min(-1). The polymorphic characteristics of the two TAGs were analyzed in situ using differential scanning calorimetry, Raman spectroscopy, and synchrotron radiation X-ray diffraction. Multiple polymorphic forms were identified in OOO (α, β'2, β'1, β2, and β1) and OOL (α, β'2, and β'1). Larger quantities of more stable forms (e.g., β2 and β1 of OOO and β'1 of OOL) were obtained when the samples were slowly cooled and heated. In contrast, less stable polymorphs were obtained with increased cooling and heating rates. Polymorphic transformations occurred in either solid-state or melt-mediation and were influenced by heating rates. The results were analyzed by considering the activation energies for crystallization and transformation of stable and less stable polymorphic forms in comparison with previous studies on 1,3-dipalmitoyl-2-oleoyl-glycerol and 1, 3-dioleoyl-2-palmitoyl-glycerol.

The low-grade inflammation observed in obesity has been associated with a high-fat diet, though this relation is not fully understood. Bacterial endotoxin, produced by gut microbiota, may be the linking factor. However, this has not been confirmed in obese patients. To study the relationship between a high-fat diet and bacterial endotoxin, we analyzed postprandial endotoxemia in morbidly obese patients after a fat overload. The endotoxin levels were determined in serum and the chylomicron fraction at baseline and 3 h after a fat overload in 40 morbidly obese patients and their levels related with the degree of insulin resistance and postprandial hypertriglyceridemia. The morbidly obese patients with the highest postprandial hypertriglyceridemia showed a significant increase in lipopolysaccharide (LPS) levels in serum and the chylomicron fraction after the fat overload. Postprandial chylomicron LPS levels correlated positively with the difference between postprandial triglycerides and baseline triglycerides. There were no significant correlations between C-reactive protein (CRP) and LPS levels. The main variables contributing to serum LPS levels after fat overload were baseline and postprandial triglyceride levels but not glucose or insulin resistance. Additionally, superoxide dismutase activity decreased significantly after the fat overload. Postprandial LPS increase after a fat overload is related to postprandial hypertriglyceridemia but not to degree of insulin resistance in morbidly obese patients.

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.

La malaltia cardiovascular és responsable d'un elevat nombre de morts en els països industrialitzats. La seva alta prevalença és deguda, principalment, a factors ambientals com l'estil de vida sedentari, el tipus de dieta rica en greixos i hàbits com el tabaquisme, que si s'afegeixen a una predisposició genètica pot resultar en un major risc de malaltia. Un dels factors determinants del desenvolupament de malaltia són els lípids, que en circulació són guiats per les apolipoproteïnes (APO). El mal funcionament d'aquestes proteïnes degut a variants genètiques pot influir, per exemple, en la quantitat de lípids i el temps que estiguin en circulació. L'APOA5 és clau en la modulació del metabolisme dels triglicèrids (TG) i la nostra hipòtesi és que l'APOA5 també pot modificar els nivells d'altres components del metabolisme altament lligats als TG, influint el procés de síntesi i secreció de partícules riques en TG.Utilitzant la variabilitat genètica de l'APOA5 en una població formada per homes sans i en una formada per pacients diabètics tipus 2, hem pogut descriure que els portadors de la variant -1131T>C presenten un augment de més del 15% en els nivells de TG, i que aquest efecte és principalment degut a un major contingut de TG en les partícules VLDL que trobem en circulació. També hem descrit que aquest variant afecta les concentracions de vitamina E en ambdues poblacions fent que augmentin els seus nivells circulants. Tot i que la vitamina E és un potent antioxidant, aquesta variant no afecta l'estat oxidatiu dels individus perquè els seus nivells augmenten en la mateixa mesura que ho fan els TG. Com que els nivells circulants de TG es poden veure influenciats per altres aspectes com el tractament farmacològic (p. ex. els inhibidors de la proteasa emprats pel tractament del la SIDA indueixen hipertrigliceridemia), vam estudiar el paper del gen en una població de pacients infectats pel virus VIH, i vam veure que en els individus tractats amb inhibidors de la proteasa, ser portador de la variant -1131T>C del gen APOA5 pot fer que els augmentin els nivells de TG més del 40%. També els augmenten els nivells de colesterol total en plasma, i això resulta en la presència d'un perfil lipídic pro-aterogènic.Per a aprofundir en els mecanismes d'acció de l'APOA5 hem utilitzat un model animal d'arteriosclerosi, el ratolí deficient en APOE. Disposàvem de diferents grups d'animals segons si rebien dieta convencional o rebien una dieta rica en greix saturat, suplementada o no amb colesterol, i els animals van ser sacrificats a diferents edats (16, 24 i 32 setmanes). Hem descobert que l'expressió del gen APOA5 en fetge es troba reprimida pel greix saturat de la dieta, arribant a disminuir fins un 75%. A més, l'expressió del gen en fetge augmenta significativament amb l'edat dels animals. També hem publicat que l'expressió hepàtica d'APOA5 correlaciona amb l'àrea de la lesió arterioscleròtica i el grau d'inflamació en aquests animals.Fins ara es creia que el gen només s'expressava en fetge. El fetge és un dels principals òrgans reguladors del metabolisme lipídic i és el responsable de la síntesi de partícules riques en TG d'origen endogen, però no és l'únic. L'intestí també s'encarrega de sintetitzar partícules riques en TG d'origen exogen. En aquest treball també hem demostrat que el gen APOA5 no s'expressa únicament en fetge en humans, sinó que també es troba en intestí. Per a dur a terme aquests experiments, vam utilitzar un model cel·lular d'intestí humà (cèl·lules TC7/ Caco2), i tot i que s'expressa a baixos nivells, hem pogut descriure que la seva expressió a l'intestí es veu modulada per components de la dieta (àcids grassos de cadena llarga i de cadena curta) i fàrmacs hipolipemiants (agonista PPARα).Conclusió: l'APOA5 és un gen clau modulant els nivells circulants de TG, tant en homes sans com en pacients dislipèmics (diabètics o pacients VIH sota tractament antiretroviral), i la seva expressió es veu alterada per components de la dieta, tant en fetge com en intestí, i per fàrmacs hipolipemiants., Cardiovascular disease is the main cause of mortality in industrialised countries. Its high prevalence is mainly due to environmental factors (sedentary lifestyle, saturated fat rich diet and tobacco consumption, among others), which together with genetic predisposition could result in increased disease risk. One of the key factors in the development of atherosclerosis are circulating lipids which are guided by the apolipoproteins (APO). The malfunctioning of these proteins due to genetic variants could affect, for example, the concentration and circulating time of lipids. The APOA5 is a key gene modulating triglyceride (TG) metabolism, and our hypothesis is that APOA5 may also modify the circulating levels of other metabolic components highly linked to TG by influencing the synthesis and secretion of TG-rich particles.Using the genetic variability of the APOA5 gene in two populations, healthy men and type 2 diabetic patients, we have described that carriers of the -1131T>C variant present with more than 15% higher TG levels, being this effect mainly due to a greater TG content in circulating VLDL particles. We have also described that this variant affects vitamin E concentrations in both populations, increasing its levels in circulation. Vitamin E is a potent antioxidant, but this variant does not affect the oxidative status of the subjects, because its levels rise in the same proportion than TG do.Since the circulating TG levels can be affected by other factors such as the pharmacological treatment (for example, the protease inhibitors used for the AIDS therapy induce hypertriglyceridemia), we studied the role of APOA5 in a population of patients infected by the VIH virus, and we found that in the group of subjects treated with protease inhibitors, carrying the -1131C variant could increase more than 40% the levels of circulating TG. They also present with increased plasma total cholesterol levels, resulting in the presence of a pro-atherogenic lipid profile.To go deeper in the mechanisms of APOA5 we have used an animal model for atherosclerosis, the APOE-deficient mouse. We had different groups of animals depending on whether they received conventional diet or a saturated fat rich diet supplemented or not with cholesterol. The animals were sacrificed at different ages (16, 24 and 32 weeks). We have demonstrated that the hepatic expression of the APOA5 gene is repressed by dietary saturated fat, reaching a 75% descent. Furthermore, the hepatic expression of APOA5 increases with the age of the animals. We have also published that the expression of APOA5 correlates with the atherosclerotic lesion area and the degree of inflammation in those animals. Till date, it has been published that the gene was only expressed in the liver. The liver is one of the main organs regulating lipid metabolism and is responsible of the synthesis of particles rich in TG from an endogenous origin, but is not the only tissue capable of doing that. The intestine is also involved in the synthesis of TG-rich particles from exogenous origin. We have also demonstrated that APOA5 is not only expressed in the liver in humans, but also in the intestine. For that purpose we used a human intestine cell model (TC-7/ Caco2 cells), and although it is expressed at low levels, we have been able to describe that its intestinal expression is modified by dietary components (long- and short-chain fatty acids) and by hypolipemiant drugs (a PPARα agonist).Conclusion: APOA5 is a key gene modulating circulating TG levels, in dislipemic patients (diabetics or HIV patients under antiretroviral treatment) and even in healthy men, and its expression is affected by dietary components, in the liver and in the intestine, and also by hypolipemiant drugs.

ANTECEDENTS:L'ApoA-II és la segona proteïna més abundant en l'HDL. La proteïna transferidora d' èsters de colesterol (CETP) actúa intercanviant èsters de colesterol per triglicèrids entre les partícules d'HDL i les lipoproteïnes que contenen apoB. El transportador ABCA1 és una proteïna reguladora del flux de colesterol. El transportador ABCG5-G8 és una proteïna reguladora de l'excreció biliar. Totes aquestes son proteïnes que intervenen en la estructura i metabolisme de l'HDL, però es desconeix el seu paper en el transport revers de colesterol específic de macròfags (TRC). HIPÒTESI DEL TREBALL:Estudis clínics i epidemiològics han demostrat l'existència d'una relació inversa entre la concentració en plasma de colesterol HDL i el risc de patir malalties cardiovasculars aterotrombòtiques. Aquest efectes cardioprotectors son atribuïts al paper de l'HDL en el TRC, i especialment el transport revers de colesterol específic de macròfags. L'expressió i/o inactivació selectiva de gens en ratolins ha permès d'obtenir una valuosa informació sobre el paper fisiològic d'aquestes proteïnes involucrades en aquest mecanisme potencial de prevenció de l'aterogènesi per part de les HDL. Així la modificació d'aquestes proteïnes en ratolins modificats genèticament ens permetrà estudiar com afecta el TRC i explicar així el paper aterogènic d'aquests ratolins.CONCLUSIONS:Del primer article vam concloure que malgrat la deficiència d'HDL que presentaven els ratolins transgènics d'apoA-II humana, el TRC des de macròfags a femtes in vivo funcionava de forma efectiva. Els nostres resultats també suggereixen que l'augment de les lesions arterioscleròtiques trobades en els ratolins transgènics d'apoA-II alimentats amb dieta rica en greixos no són degudes al bloqueig del TRC específic de macròfags. Resultats previs suggereixen que l'apoA-II podria exercir el seu efecte proaterogènic reduint les propietats antioxidants de l'HDL.Del segon article vam concloure que la deficiència del transportador ABCA-1 en ratolins knockout reduïa el TRC específic de macròfags in vivo. Aquest resultats demostren la importància d'ABCA-1 en aquesta funció antiaterogènica de les HDL i, demostren la possible relació entre la disminució del TRC depenent de macròfags i l'augment de la susceptibilitat a l'arteriosclerosi.Del tercer article vam concloure que l'expressió de CETP de macaco o humana en ratolins transgènics no afectava al TRC específic de macròfags in vivo ni les propietats antioxidants de l'HDL. L'efecte proaterogènic de l'expressió de CETP en ratolins sembla doncs degut a mecanismes independents d'aquestes dues funcions antiaterogèniques de les HDL.I finalment, en l'últim article vam concloure que la deficiència del transportador ABCG5/G8 en ratolins knockout no alterava el TRC des de macròfags a femtes in vivo. Tanmateix, l'expressió ABCG5/G8 és necessària per a la inducció del TRC específic de macròfags induït pels agonistes de LXR. Els nostres resultats donen suport a la hipòtesi que aquests transportadors tenen un paper determinant en la fase final d'aquesta via i els confirmen com a dianes moleculars de gran interès per a prevenir o tractar l'arteriosclerosi., Epidemiological studies have demonstrated that increased HDL is a protective factor against atherosclerotic cardiovascular disease. The evaluation of antiatherogenic functions of HDL is an important area of research which includes the role of HDL in reverse cholesterol transport (RCT), especially macrophage-specific RCT, and its antioxidant and antiinflammatory roles.The development of transgenic and knockout mice provides us a lot of information about the role of some proteins that are important in these potencial antiatherogenic mechanisms.We studied four proteins that are important in the HDL metabolism: apoA-II is the second major HDL protein. The action of CETP results in a heteroexchange between HDL cholesteryl ester and VLDL- or chymolicron -triglycerides. The ABCA-1 transporter is a protein that regulates the cholesterol efflux. The ABCG5/G8 transporter is a crucial protein for hepatobiliary and intestinal sterol excretion. Thus, the modification of these proteins in genetical modified mice and the development of a new strategy to mesure the macrophage-specific RCT in vivo permit us to know the atherogenic role of these mice. We concluded that human apoA-II maintains effective RCT from macrophages to feces in vivo despite an HDL deficiency. These findings suggest that the increased atherosclerotic lesions observed in apoA-II transgenic mice fed an atherogenic diet are not due to impairment in macrophage-specific RCT. The results of the study with ABCA-1 knockout mice provide definitive in vivo evidence of the crucial role of ABCA1 in macrophage-specific RCT. This fact may also indicate, together with previous works, that ABCA1 exerts, at least in part, its antiatherogenic effect by promoting macrophage-specific RCT. The CETP overexpression in transgenic mice does not affect RCT from macrophages to feces in vivo or the protection conferred by HDL against LDL oxidative modification. Finally, the results of the study with ABCG5/G8 demonstrate that the presence of ABCG5/G8 transporters is required for LXR-mediated induction of macrophage-specific RCT, and support the hypothesis that these transporters play a key role in the final step of this pathway. These data also suggest that upregulation of ABCG5/G8 may be an effective strategy to increase macrophage-specific RCT and reduce atherosclerosis.

The apolipoprotein AV gene (APOA5) is a key determinant of plasma triglyceride levels, a major risk factor for coronary artery disease and a biomarker for the metabolic syndrome. Since thyroid hormones influence very low density lipoprotein triglyceride metabolism and clinical studies have demonstrated an inverse correlation between thyroid status and plasma triglyceride levels, we examined whether APOA5 is regulated by thyroid hormone. Here we report that 3,5,3'-triiodo-L-thyronine (T3) and a synthetic thyroid receptor beta (TRbeta) ligand increase APOA5 mRNA and protein levels in hepatocytes. Our data revealed that T3-activated TR directly regulates APOA5 promoter through a functional direct repeat separated by four nucleotides (DR4). Interestingly, we show that upstream stimulatory factor 1, a transcription factor associated with familial combined hyperlipidemia and elevated triglyceride levels in humans, and upstream stimulatory factor 2 cooperate with TR, resulting in a synergistic activation of APOA5 promoter in a ligand-dependent manner via an adjacent E-box motif. In rats, we observed that apoAV levels declines with thyroid hormone depletion but returned to normal levels upon T3 administration. In addition, treatments with a TRbeta-selective agonist increased apoAV and diminished triglyceride levels. The identification of APOA5 as a T3 target gene provides a new potential mechanism whereby thyroid hormones can influence triglyceride homeostasis. Additionally, these data suggest that TRbeta may be a potential pharmacological target for the treatment of hypertriglyceridemia.

The effects of medium chain triglycerides (MCT) on jejunal mucosa mass and protein synthesis were compared with results from previous experiments with rats fed by parenteral nutrition or enteral nutrition. Other published studies have also been analysed. Three experimental models were studied. In the traumatic model, production of a femoral fracture was followed by Kirschner pin insertion into the medullary canal of both fragments at reduction. (Forty ras were fed enteral nutrition and 93 were given parenteral nutrition.) A second model entailed resection under ether anaesthesia using the technique described by Higgins. (Fifty five rats were fed enteral nutrition and 28 with parenteral nutrition.) A third model entailed a terminolateral portocaval shunt under anaesthesia with pentobarbital. (Sixty nine rats were treated this way and then given enteral nutrition.) Proportions of medium chain/long chain triglycerides (LCT) were as follows: 0/100, 20/80, 40/60, 50/50, and 92/8 for enteral nutrition and 0/100, 30/70, 50/50, and 70/30 for parenteral nutrition. Faecal losses of alpha amino nitrogen, protein, total fats, and free fatty acids were analysed together with the quantitative intake, weight gain of the rats, jejunal mucosal mass, and protein synthesis in relation to the MCT proportion ingested or given by enteral nutrition or parenteral nutrition. From analysis of our results and those of others, several conclusions could be drawn. Firstly, the route of administration of MCT is extremely important and enterocytes might be considered one of the main target sites. Secondly, a high proportion of MCT (more than 80%) offers no advantage for jejunal mucosa and produces undesirable side effects. Thirdly, the effect of MCT on jejunal mucosal protein synthesis depends on the metabolic state. Finally, an increase in jejunal mucosal mass directly correlated with MCT concentrations, but no correlation was found between mass and protein synthesis. A positive correlation, however, between MCT proportion and enzyme activity (alkaline phosphatase and sucrase) in the brush border membrane was seen as well as a positive correlation with the concentration of phospholipids in the microvilli.

We observed microstructures of spherulites made of two triacylglycerols (TAGs) (POP (1,3-dipalmitoyl-2-oleoyl-sn-glycerol) and OPO (1,3-dioleoyl-2-palmitoyl-sn-glycerol)), which exhibit the mixing behavior of a molecular compound (MC) formation at a ratio of POP : OPO = 50 : 50, using synchrotron radiation microbeam (beam area of 5 × 5 μm2) X-ray diffraction (SR-μ-XRD). The spherulites were grown from neat liquid, and from solution containing 50% n-dodecane and 50% POP + OPO. SR-μ-XRD analysis revealed heterogeneous distributions of MCPOP:OPO and component TAGs in every spherulite; TAG compositions in the inner and outer areas differed when the relative ratios of POP and OPO were changed. In the 75POP : 25OPO spherulites, MCPOP:OPO always occupied the inner areas and POP dominated the outer areas as a result of different rates of crystallization of MCPOP:OPO and POP in the spherulite. In contrast, in the 25POP : 75OPO spherulites, the entire area was homogeneously occupied either with almost all OPO or with coexisting MCPOP:OPO and OPO. The microstructures of the spherulites grown from n-dodecane solutions demonstrated basically the same characteristics as those grown from the neat liquid both for 75POP : 25OPO and 25POP : 75OPO. SR-μ-XRD also clarified that the lamellar planes of the crystals are directed parallel to the radial direction from the central to the outer regions of the spherulites.

Se realiza un estudio prospectivo, randomizado, doble ciego en pacientes quirúrgicos que requieren nutrición parenteral durante un período de diez días y estén en ayuno completo. Los pacientes deben tener una función hepática normal medida por gamma-GT, fosfatasa alcalina (FA), bilirrubina y ALT normales. Se estudia la evolución de los parámetros de colestasis los días O, 1, 3, 8 y 1 O. Se observa un aumento de la gammaGT en las de grupos, pero mucho más marcado en el grupo con LCT (p < 0,005) al décimo día que en el grupo MCT/LCT. La FA aumenta sólo en el grupo LCT, siendo estadísticamente significativo (p < 0,001) al décimo día respecto al grupo MCT/LCT

Here we report that in skeletal muscle cells the contribution to insulin resistance and inflammation of two common dietary long-chain fatty acids depends on the channeling of these lipids to distinct cellular metabolic fates. Exposure of cells to the saturated fatty acid palmitate led to enhanced diacylglycerol levels and the consequent activation of the protein kinase C theta/nuclear factor kappa B pathway, finally resulting in enhanced interleukin 6 secretion and down-regulation of the expression of genes involved in the control of the oxidative capacity of skeletal muscle (peroxisome proliferator-activated receptor (PPAR)gamma-coactivator 1 alpha) and triglyceride synthesis (acyl-coenzyme A: diacylglycerol acyltransferase 2). In contrast, exposure to the monounsaturated fatty acid oleate did not lead to these changes. Interestingly, co-incubation of cells with palmitate and oleate reversed both inflammation and impairment of insulin signaling by channeling palmitate into triglycerides and by up-regulating the expression of genes involved in mitochondrial beta-oxidation, thus reducing its incorporation into diacylglycerol. Our findings support a model of cellular lipid metabolism in which oleate protects against palmitate-induced inflammation and insulin resistance in skeletal muscle cells by promoting triglyceride accumulation and mitochondrial beta-oxidation through PPAR alpha- and protein kinase A-dependent mechanisms.