RESUMO
Excessive levels of saturated fatty acids are toxic to cells, although the basis for this lipotoxicity remains incompletely understood. Here, we analyzed the transcriptome, lipidome, and genetic interactions of human leukemia cells exposed to palmitate. Palmitate treatment increased saturated glycerolipids, accompanied by a transcriptional stress response, including upregulation of the endoplasmic reticulum (ER) stress response. A comprehensive genome-wide short hairpin RNA (shRNA) screen identified >350 genes modulating lipotoxicity. Among previously unknown genetic modifiers of lipotoxicity, depletion of RNF213, a putative ubiquitin ligase mutated in Moyamoya vascular disease, protected cells from lipotoxicity. On a broader level, integration of our comprehensive datasets revealed that changes in di-saturated glycerolipids, but not other lipid classes, are central to lipotoxicity in this model. Consistent with this, inhibition of ER-localized glycerol-3-phosphate acyltransferase activity protected from all aspects of lipotoxicity. Identification of genes modulating the response to saturated fatty acids may reveal novel therapeutic strategies for treating metabolic diseases linked to lipotoxicity.
Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Glicerídeos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Palmítico/toxicidade , Aciltransferases/genética , Aciltransferases/metabolismo , Adenosina Trifosfatases/metabolismo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/genética , Regulação Enzimológica da Expressão Gênica , Células HeLa , Células Hep G2 , Humanos , Células K562 , Metabolismo dos Lipídeos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Transcriptoma , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Diacylglycerol kinase (DGK) α, which is a key enzyme in the progression of cancer and, in contrast, in T-cell activity attenuation, preferentially produces saturated fatty acid (SFA)- and/or monounsaturated fatty acid (MUFA)-containing phosphatidic acids (PAs), such as 16:0/16:0-, 16:0/18:0-, and 16:1/16:1-PA, in melanoma cells. In the present study, we searched for the target proteins of 16:0/16:0-PA in melanoma cells and identified heat shock protein (HSP) 27, which acts as a molecular chaperone and contributes to cancer progression. HSP27 more strongly interacted with PA than other phospholipids, including phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, cardiolipin, phosphatidylinositol, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-bisphosphate. Moreover, HSP27 is more preferentially bound to SFA- and/or MUFA-containing PAs, including 16:0/16:0- and 16:0/18:1-PAs, than PUFA-containing PAs, including 18:0/20:4- and 18:0/22:6-PA. Furthermore, HSP27 and constitutively active DGKα expressed in COS-7 cells colocalized in a DGK activity-dependent manner. Notably, 16:0/16:0-PA, but not phosphatidylcholine or 16:0/16:0-phosphatidylserine, induced oligomer dissociation of HSP27, which enhances its chaperone activity. Intriguingly, HSP27 protein was barely detectable in Jurkat T cells, while the protein band was intensely detected in AKI melanoma cells. Taken together, these results strongly suggest that SFA- and/or MUFA-containing PAs produced by DGKα selectively target HSP27 and regulate its cancer-progressive function in melanoma cells but not in T cells.
Assuntos
Ácidos Graxos , Melanoma , Humanos , Ácidos Graxos/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Proteínas de Choque Térmico HSP27/genética , Ácidos Fosfatídicos/metabolismo , Fosfatidilserinas , Fosfatidilinositóis , Fosfatidilcolinas , Melanoma/metabolismoRESUMO
Chronic low-grade inflammation is a central component in the pathogenesis of obesity-related expansion of adipose tissue and complications in other metabolic tissues. Five different signaling pathways are defined as dominant determinants of adipose tissue inflammation: These are increased circulating endotoxin due to dysregulation in the microbiota-gut-brain axis, systemic oxidative stress, macrophage accumulation, and adipocyte death. Finally, the nucleotide-binding and oligomerization domain (NOD) leucine-rich repeat family pyrin domain-containing 3 (NLRP3) inflammasome pathway is noted to be a key regulator of metabolic inflammation. The NLRP3 inflammasome and associated metabolic inflammation play an important role in the relationships among fatty acids and obesity. Several highly active molecules, including primarily leptin, resistin, adiponectin, visfatin, and classical cytokines, are abundantly released from adipocytes. The most important cytokines that are released by inflammatory cells infiltrating obese adipose tissue are tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2), and IL-1. All these molecules mentioned above act on immune cells, causing local and then general inflammation. Three metabolic pathways are noteworthy in the development of adipose tissue inflammation: toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, endoplasmic reticulum (ER) stress-derived unfolded protein response (UPR), and inhibitor of nuclear factor kappa-B kinase beta (IKKß)-nuclear factor kappa B (NF-κB) pathway. In fact, adipose tissue inflammation is an adaptive response that contributes to a visceral depot barrier that effectively filters gut-derived endotoxin. Excessive fatty acid release worsens adipose tissue inflammation and contributes to insulin resistance. However, suppression of adipose inflammation in obesity with anti-inflammatory drugs is not a rational solution and paradoxically promotes insulin resistance, despite beneficial effects on weight gain. Inflammatory pathways in adipocytes are indeed indispensable for maintaining systemic insulin sensitivity. Cannabinoid type 1 receptor (CB1R) is important in obesity-induced pro-inflammatory response; however, blockade of CB1R, contrary to anti-inflammatory drugs, breaks the links between insulin resistance and adipose tissue inflammation. Obesity, however, could be decreased by improving leptin signaling, white adipose tissue browning, gut microbiota interactions, and alleviating inflammation. Furthermore, capsaicin synthesized by chilies is thought to be a new and promising therapeutic option in obesity, as it prevents metabolic endotoxemia and systemic chronic low-grade inflammation caused by high-fat diet.
Assuntos
Tecido Adiposo , Inflamação , Obesidade , Transdução de Sinais , Humanos , Obesidade/metabolismo , Obesidade/imunologia , Obesidade/patologia , Tecido Adiposo/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Animais , Inflamação/metabolismo , Inflamação/patologia , Citocinas/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mediadores da Inflamação/metabolismoRESUMO
Due to deleterious health effects, consumption of trans fat containing fried foods is a major concern. The present study has assessed total fat, SFA, cis-UFA and TFA content of Indian fried foods-French fries, Poori, Potato chips, Bread Pakora and Mathri (on dry weight basis), at varying number of frying cycles/temperatures as well as composition of the oils extracted from the foods and the oils used for frying. Total fat in the food items was significantly higher at 32nd (xÌ27.4%) versus the 1st frying cycle (xÌ22.5%; p < 0.05). Progressive frying cycles (1st vs. 32nd)/temperatures demonstrated declining levels of cis-UFAs (at 180 °C: xÌ16.33% vs. xÌ11.29%; at 160 °C: xÌ19.54% vs. xÌ13.81%) with concomitant increase in SFA (at 180 °C: xÌ4.97% vs. xÌ14.97%; at 160 °C: xÌ5.19% vs. xÌ13.79%) and TFA content (at 180 °C: xÌ0.05% vs. xÌ0.89%; at 160 °C: xÌ0.04% vs. xÌ0.17%). Compared to the unheated oil, at 32nd frying cycle (irrespective of the frying temperatures), oils extracted from fried foods registered a significant decrease in cis-UFA (xÌ17.41%) coupled with an increase in SFA (xÌ63.74%) and an exponential increase in TFA (39-301 folds); however, the change was slightly lesser in oils used for frying (cis-UFA: xÌ15.06%; SFA: xÌ53.75%; TFA: 20-264 folds). To curb TFA in fried foods, necessary regulations are needed for restricting the number of frying cycles as well as the frying temperatures along with awareness generation regarding appropriate frying practices. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-024-05989-z.
RESUMO
The FA Elongase-4 (ELOVL4) enzyme mediates biosynthesis of both very long chain (VLC)-PUFAs and VLC-saturated FA (VLC-SFAs). VLC-PUFAs play critical roles in retina and sperm function, whereas VLC-SFAs are predominantly associated with brain function and maintenance of the skin permeability barrier. While some ELOVL4 mutations cause Autosomal Dominant Stargardt-like Macular Dystrophy (STGD3), other ELOVL4 point mutations, such as L168F and W246G, affect the brain and/or skin, leading to Spinocerebellar Ataxia-34 (SCA34) and Erythrokeratodermia variabilis. The mechanisms by which these ELOVL4 mutations alter VLC-PUFA and VLC-SFA biosynthesis to cause the different tissue-specific pathologies are not well understood. To understand how these mutations alter VLC-PUFA and VLC-SFA biosynthesis, we expressed WT-ELOVL4, L168F, and W246G ELOVL4 variants in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. Total lipids were extracted, converted to FA methyl esters, and quantified by gas chromatography. We showed that L168F and W246G mutants were capable of VLC-PUFA biosynthesis. W246G synthesized and accumulated 32:6n3, while L168F exhibited gain of function in VLC-PUFA biosynthesis as it made 38:5n3, which we did not detect in WT-ELOVL4 or W246G-expressing cells. However, compared with WT-ELOVL4, both L168F and W246G mutants were deficient in VLC-SFA biosynthesis, especially the W246G protein, which showed negligible VLC-SFA biosynthesis. These results suggest VLC-PUFA biosynthetic capabilities of L168F and W246G in the retina, which may explain the lack of retinal phenotype in SCA34. Defects in VLC-SFA biosynthesis by these variants may be a contributing factor to the pathogenic mechanism of SCA34 and Erythrokeratodermia variabilis.
Assuntos
Eritroceratodermia Variável , Ataxias Espinocerebelares , Masculino , Humanos , Sêmen/metabolismo , Ácidos Graxos Insaturados/metabolismo , Mutação , Proteínas do Olho/genética , Proteínas de Membrana/metabolismoRESUMO
Due to their high energy demands and characteristic morphology, retinal photoreceptor cells require a specialized lipid metabolism for survival and function. Accordingly, dysregulation of lipid metabolism leads to the photoreceptor cell death and retinal degeneration. Mice bearing a frameshift mutation in the gene encoding lysophosphatidylcholine acyltransferase 1 (Lpcat1), which produces saturated phosphatidylcholine (PC) composed of two saturated fatty acids, has been reported to cause spontaneous retinal degeneration in mice; however, the mechanism by which this mutation affects degeneration is unclear. In this study, we performed a detailed characterization of LPCAT1 in the retina and found that genetic deletion of Lpcat1 induces light-independent and photoreceptor-specific apoptosis in mice. Lipidomic analyses of the retina and isolated photoreceptor outer segment (OS) suggested that loss of Lpcat1 not only decreased saturated PC production but also affected membrane lipid composition, presumably by altering saturated fatty acyl-CoA availability. Furthermore, we demonstrated that Lpcat1 deletion led to increased mitochondrial reactive oxygen species levels in photoreceptor cells, but not in other retinal cells, and did not affect the OS structure or trafficking of OS-localized proteins. These results suggest that the LPCAT1-dependent production of saturated PC plays critical roles in photoreceptor maturation. Our findings highlight the therapeutic potential of saturated fatty acid metabolism in photoreceptor cell degeneration-related retinal diseases.
Assuntos
1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Células Fotorreceptoras de Vertebrados/citologia , Espécies Reativas de Oxigênio/metabolismo , Degeneração Retiniana , 1-Acilglicerofosfocolina O-Aciltransferase/genética , Animais , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Camundongos , Fosfatidilcolinas/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Degeneração Retiniana/metabolismoRESUMO
Previous investigations mainly focused on the associations of dietary fatty acids with colorectal cancer (CRC) risk, which ignored gene-environment interaction and mechanisms interpretation. We conducted a case-control study (751 cases and 3058 controls) and a prospective cohort study (125 021 participants) to explore the associations between dietary fatty acids, genetic risks, and CRC. Results showed that high intake of saturated fatty acid (SFA) was associated with a higher risk of CRC than low SFA intake (HR =1.22, 95% CI:1.02-1.46). Participants at high genetic risk had a greater risk of CRC with the HR of 2.48 (2.11-2.91) than those at low genetic risk. A multiplicative interaction of genetic risk and SFA intake with incident CRC risk was found (PInteraction = 7.59 × 10-20 ), demonstrating that participants with high genetic risk and high SFA intake had a 3.75-fold greater risk of CRC than those with low genetic risk and low SFA intake. Furthermore, incorporating PRS and SFA into traditional clinical risk factors improved the discriminatory accuracy for CRC risk stratification (AUC from 0.706 to 0.731). Multi-omics data showed that exposure to SFA-rich high-fat dietary (HFD) can responsively induce epigenome reprogramming of some oncogenes and pathological activation of fatty acid metabolism pathway, which may contribute to CRC development through changes in gut microbiomes, metabolites, and tumor-infiltrating immune cells. These findings suggest that individuals with high genetic risk of CRC may benefit from reducing SFA intake. The incorporation of SFA intake and PRS into traditional clinical risk factors will help improve high-risk sub-populations in individualized CRC prevention.
Assuntos
Neoplasias Colorretais , Gorduras na Dieta , Humanos , Estudos Prospectivos , Estudos de Casos e Controles , Gorduras na Dieta/efeitos adversos , Fatores de Risco , Ácidos Graxos/efeitos adversos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/induzido quimicamenteRESUMO
BACKGROUND: It has been well documented that metabolic syndrome (MetS) increases severity of periodontitis. In this study, we determined the effect of high-fat diet (HFD)-induced MetS on alveolar bone loss in a mouse model with ligature-induced periodontitis. To understand how MetS increases bone loss, we tested our hypothesis that palmitic acid (PA), a most abundant saturated fatty acid in the HFD, interacts with lipopolysaccharide (LPS) to promote osteoclastogenesis. METHODS: We induced MetS by feeding mice HFD for 18 weeks and induced periodontitis with ligature placement. After treatments, we assessed alveolar bone loss using micro-computed tomography and determined osteoclastogenesis using tartrate-resistant acid phosphatase (TRAP) staining. To explore the mechanisms, we treated macrophages with PA, LPS or both and analyzed the osteoclast formation and cytokine expression in macrophages. RESULTS: While ligature robustly induced periodontitis in mice with or without MetS, the mice with MetS had more bone loss than those without MetS. PA and LPS cooperatively induced osteoclast formation and stimulated the expression of inflammatory cytokines involved in osteoclastogenesis potentially via a FAT/CD36-dependent mechanism in macrophages. CONCLUSIONS: HFD-induced MetS increases alveolar bone loss in mice with ligature-induced periodontitis, and PA and LPS cooperatively stimulate osteoclast formation and proinflammatory gene expression in macrophages.
Assuntos
Perda do Osso Alveolar , Síndrome Metabólica , Periodontite , Animais , Camundongos , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/genética , Citocinas , Dieta Hiperlipídica , Lipopolissacarídeos/farmacologia , Síndrome Metabólica/complicações , Osteoclastos/metabolismo , Periodontite/complicações , Microtomografia por Raio-XRESUMO
Aging continues to be the main cause of the development of Alzheimer's, although it has been described that certain chronic inflammatory pathologies can negatively influence the progress of dementia, including obesity and hyperlipidemia. In this sense, previous studies have shown a relationship between low-density lipoprotein receptor (LDLR) and the amyloid-beta (Aß) binding activity, one of the main neuropathological features of Alzheimer's disease (AD). LDLR is involved in several processes, including lipid transport, regulation of inflammatory response and lipid metabolism. From this perspective, LDLR-/- mice are a widely accepted animal model for the study of pathologies associated with alterations in lipid metabolism, such as familial hypercholesterolemia, cardiovascular diseases, metabolic syndrome, or early cognitive decline. In this context, we induced hyperlipidemia in LDLR-/- mice after feeding with a high-saturated fatty acid diet (HFD) for 44 weeks. LDLR-/--HFD mice exhibited obesity, hypertriglyceridemia, higher glucose levels, and early hepatic steatosis. In addition, HFD increased plasmatic APOE and ubiquitin 60S levels. These proteins are related to neuronal integrity and health maintenance. In agreement, we detected mild cognitive dysfunctions in mice fed with HFD, whereas LDLR-/--HFD mice showed a more severe and evident affectation. Our data suggest central nervous system dysfunction is associated with a well-established metabolic syndrome. As a late consequence, metabolic syndrome boots many behavioral and pathological alterations recognized in dementia, supporting that the control of metabolic parameters could improve cognitive preservation and prognosis.
Assuntos
Doença de Alzheimer , Hiperlipidemias , Síndrome Metabólica , Camundongos , Animais , Síndrome Metabólica/genética , Síndrome Metabólica/complicações , Dieta Hiperlipídica , Doença de Alzheimer/patologia , Obesidade/complicações , Hiperlipidemias/complicações , Cognição , Ácidos Graxos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Modelos Animais de DoençasRESUMO
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises a spectrum of liver diseases, ranging from liver steatosis to metabolic dysfunction-associated steatohepatitis (MASH), increasing the risk of developing cirrhosis and hepatocellular carcinoma (HCC). Fibrosis within MASLD is critical for disease development; therefore, the identification of fibrosis-driving factors is indispensable. We analyzed the expression of interleukin 32 (IL-32) and chemokine CC ligand 20 (CCL20), which are known to be linked with inflammation and fibrosis, and for their expression in MASLD and hepatoma cells. RT-PCR, ELISA and Western blotting analyses were performed in both human liver samples and an in vitro steatosis model. IL-32 and CCL20 mRNA expression was increased in tissues of patients with NASH compared to normal liver tissue. Stratification for patatin-like phospholipase domain-containing protein 3 (PNPLA3) status revealed significance for IL-32 only in patients with I148M (rs738409, CG/GG) carrier status. Furthermore, a positive correlation was observed between IL-32 expression and steatosis grade, and between IL-32 as well as CCL20 expression and fibrosis grade. Treatment with the saturated fatty acid palmitic acid (PA) induced mRNA and protein expression of IL-32 and CCL20 in hepatoma cells. This induction was mitigated by the substitution of PA with monounsaturated oleic acid (OA), suggesting the involvement of oxidative stress. Consequently, analysis of stress-induced signaling pathways showed the activation of Erk1/2 and p38 MAPK, which led to an enhanced expression of IL-32 and CCL20. In conclusion, cellular stress in liver epithelial cells induced by PA enhances the expression of IL-32 and CCL20, both known to trigger inflammation and fibrosis.
Assuntos
Fígado Gorduroso , Hepatócitos , Doenças Metabólicas , Humanos , Carcinoma Hepatocelular/genética , Quimiocina CCL20/genética , Quimiocinas , Hepatócitos/metabolismo , Ligantes , Cirrose Hepática/genética , Neoplasias Hepáticas/genética , Ácido Palmítico , Regulação para Cima , Gorduras Insaturadas/metabolismoRESUMO
PURPOSE: An optimal diet for lowering the risk of gestational diabetes mellitus (GDM) is still to be defined, but may comprise of nutrient intakes, dietary patterns, diet quality, and eating frequency. This study was designed to investigate the contribution of diet in developing GDM in a comprehensive way. METHODS: The dietary intake of overweight or obese women, a risk group for GDM (n = 351), was assessed using 3-day food diaries and diet quality questionnaires in early pregnancy. Eating frequency and nutrient intakes were calculated, and dietary patterns identified using principal component analysis. The inflammatory potential of the diet was determined by calculating the dietary inflammatory index (DII®) and energy-adjusted DII (E-DII™). GDM was diagnosed with an oral glucose tolerance test at 24-28 gestational weeks. RESULTS: Higher adherence to 'healthier dietary pattern' characterized by consumptions of vegetables and rye bread associated with a reduced risk of GDM (adjusted OR 0.27, 95% CI 0.11-0.70). Higher E-DII score, indicating pro-inflammatory diet, was associated with a 27% higher risk of GDM (adjusted OR 1.27; 95% CI 1.08-1.49) for each E-DII point. In the evaluation of nutrient intakes, total fat, saturated fatty acids (SFAs), and trans fatty acids were higher and fiber lower in women developing GDM compared to women not developing GDM (all p < 0.05). Intakes of total fat, SFAs, and trans fatty acids were also significant predictors for GDM (all p < 0.05). CONCLUSIONS: The results emphasize the importance of an overall healthy diet and limitation of foods with SFAs, and other nutrients with a high inflammatory potential in reducing the risk of GDM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922791, August 14, 2013.
Assuntos
Diabetes Gestacional , Diabetes Gestacional/epidemiologia , Diabetes Gestacional/prevenção & controle , Dieta , Registros de Dieta , Fibras na Dieta , Feminino , Teste de Tolerância a Glucose , Humanos , GravidezRESUMO
AIMS: The aim of the present study was to investigate the gastrointestinal (GI) microbiota and bacterium-specific fatty acid occurrence in the muscle and hepatic lipids of rainbow trout Oncorhynchus mykiss (Walbaum, 1792), both healthy and those naturally infected with bacterial pathogens. METHODS AND RESULTS: From June 2017 (L1) to September 2018 (L8), 74 specimens of rainbow trout Oncorhynchus mykiss (with an average weight from 139.2 ± 7.1 g (L1) to 2191.7 ± 85.1 g (L8)) were studied. Amplicon sequencing targeted to the V3-V4 region of 16S rRNA gene fragments is used for the identification of the taxonomic composition of gut bacterial communities. Firmicutes, Bacteroidetes, Proteobacteria, Tenericutes and Fusobacteria were the major phyla. Besides behavioural and physiological manifestations of the bacterial mixed disease (yersiniosis, pseudomonosis and flavobacteriosis), some disorders induced by both the infection and followed antibiotic treatment were detected in the host organism, including (1) a progressive decrease in the content of odd-chain saturated fatty acids of bacterial origin within the trout lipid molecules and (2) abnormalities in trout GI tract microbiota, such as the elimination of LAB and progressive occurrence of certain bacterial taxa, particularly Mycoplasmataceae. CONCLUSIONS: The GI bacterial flora varied principally due to Mycoplasmataceae and Lactobacillaceae, which could be considered in the search for bioindicators. The content of specific bacterium-derived fatty acids incorporated into the lipids of trout muscle and hepatic seems to be related to the prevalence of bacterial taxa, and their deficit could be regarded as an early warning sign of microbiota disturbance. SIGNIFICANCE AND IMPACT OF STUDY: Our results demonstrated that infectious disease and antibiotic treatment of reared species can cause a pertinent imbalance in their gut microbiota and reduce the abundance of specific fatty acids. This can be useful for the sustainable aquaculture industry due to the development of early indication technologies for rapid disease diagnosis.
Assuntos
Microbioma Gastrointestinal , Oncorhynchus mykiss , Animais , Antibacterianos/farmacologia , Bactérias/genética , Ácidos Graxos , Músculos , Oncorhynchus mykiss/microbiologia , RNA Ribossômico 16S/genéticaRESUMO
BACKGROUND: Preeclampsia is a complication during pregnancy characterised by new-onset hypertension and proteinuria that develops after 20 weeks of gestation. Dyslipidemia in pregnancy is correlated with an increased risk of preeclampsia. However, the dynamic changes in lipid metabolic product, particularly fatty acid fraction, in preeclampsia maternal circulation, are not well understood. This study aimed to investigate fatty acid fraction in preeclampsia maternal blood compared with normotensive normal pregnancy. METHODS: A total of 34 women who developed preeclampsia and 32 women with normotensive normal pregnancy were included in our case-control study. Maternal blood samples were collected for serum fatty acid fractions analysis and other biochemical parameters. Serum fatty acid fractions included long-chain polyunsaturated fatty acid (LCPUFA), monounsaturated fatty acid (MUFA), saturated fatty acid, and total fatty acid, measured with gas chromatography-mass spectrometry (GC-MS). The mean difference of fatty acid level was analysed using parametric and non-parametric bivariate analysis based on normality distributed data, while the risk of preeclampsia based on fatty acid fraction was analysed using a logistic regression model. RESULTS: Women with preeclampsia have lower high-density lipoprotein (53.97 ± 12.82 mg/dL vs. 63.71 ± 15.20 mg/dL, p = 0.006), higher triglyceride (284.91 ± 97.68 mg/dL vs. 232.84 ± 73.69 mg/dL, p = 0.018) than that in the normotensive group. Higher palmitoleic acid was found in women with preeclampsia compared to normotensive normal pregnancy (422.94 ± 195.99 vs. 325.71 ± 111.03 µmol/L, p = 0.037). The binary logistic regression model showed that pregnant women who had total omega-3 levels within the reference values had a higher risk of suffering preeclampsia than those with the higher reference value (odds ratio OR (95% CI): 8,5 (1.51-48.07), p = 0.015). Pregnant women who have saturated fatty acid within reference values had a lower risk for suffering preeclampsia than those in upper reference value (OR (95% CI): 0.21 (0.52-0.88), p = 0.032). CONCLUSION: Overall, palmitoleic acid was higher in women with preeclampsia. Further analysis indicated that reference omega-3 in and high saturated fatty acid serum levels are characteristics of women with preeclampsia.
Assuntos
Ácidos Graxos/sangue , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Adulto , Estudos de Casos e Controles , Ácidos Graxos Monoinsaturados/análise , Ácidos Graxos Ômega-3/análise , Ácidos Graxos Ômega-6/análise , Ácidos Graxos Insaturados/análise , Feminino , Humanos , Análise Multivariada , Gravidez , Valores de ReferênciaRESUMO
BACKGROUND: Metabolic disorder is considered a well-established risk factor for endometrial carcinoma (EC). However, the mechanism remains unclear. Insulin resistance and excessive flux of free fatty acids serve as fundamental pathogenic factors in metabolic disorders, including obesity and type 2 diabetes. The aim of this study was to test the correlation between insulin resistance and dyslipidaemia in EC and to determine the effect of insulin and saturated fatty acids on EC cells. METHODS: A retrospective study on the medical records of patients with EC and RNA-seq from the TCGA database analysed with edgR and Gene Ontology (GO) were used to assess the correlation of dyslipidaemia and diabetes as well as obesity. Crystal violet assays and CCK-8 assays were used to detect the proliferation of EC cells, and Annexin V-PI was used to examine apoptosis. Transient changes in mitochondrial Ca2+ and reactive oxygen species (ROS) were monitored via confocal microscopy. DNA damage was assessed by comet assays. Changes in signalling pathways were detected via phospho-kinase array. western blotting was used to assess the molecular changes in endoplasmic reticulum (ER) stress and DNA damage. RESULTS: We found that glucose metabolism disorders accompanied dyslipidaemia in patients with EC. As a key regulator of glucose metabolism disorders, insulin promoted DNA damage, ROS and Ca2+ homoeostasis imbalance in a panel of established EC cell lines. Interestingly, excessive insulin boosted saturated fatty acid-induced pro-apoptotic effects in EC cells. Furthermore, our data showed that insulin synergised with saturated fatty acids to activate the mechanistic target of rapamycin kinase/70 kDa ribosomal protein S6 kinase (mTOR/p70S6K) pathway and ER stress, resulting in Ca2+ release from ER and unfolded protein response (UPR) activation, which contributed to combined insulin and saturated fatty acid treatment-induced apoptosis and tumour progression. CONCLUSIONS: Our data are the first to illustrate that impaired glucose metabolism accelerates dyslipidaemia-promoted EC progression, which is attributed to hyperinsulinaemia and saturated fatty acid-induced Ca2+ dyshomoeostasis and UPR activation in EC cells via ER stress.
Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias do Endométrio , Resistência à Insulina , Insulinas , Humanos , Feminino , Espécies Reativas de Oxigênio/metabolismo , Estudos Retrospectivos , Estresse do Retículo Endoplasmático , Apoptose , Ácidos Graxos/farmacologia , Obesidade , Insulinas/farmacologiaRESUMO
Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with a fish oil diet (FOD). High gut microbial divergency resulted from difference in diets, and the abundance of several bacterial species, such as in the orders Clostridiales and Lactobacillales, was markedly altered in the feces of LD- or FOD-fed mice. The proportion of the order Lactobacillales in the gut was negatively involved in SMFA-induced body weight gain and PCa progression. We found the modulation of lipid metabolism and cholesterol biosynthesis pathways with three and seven commonly up- and downregulated genes in PCa tissues, and some of them correlated with the abundance of the order Lactobacillales in mouse gut. The expression of sphingosine 1-phosphate receptor 2, which is associated with the order Lactobacillales and cancer progression in mouse models, was inversely associated with aggressive phenotype and weight gain in patients with PCa using the NCBI Gene Expression Omnibus database. Therefore, SMFA may promote PCa progression with the abundance of specific gut microbial species and overexpression of lipogenic genes in PCa. Therapeutics with alteration of gut microbiota and candidate genes involved in diet-induced PCa progression may be attractive in PCa.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Neoplasias da Próstata/microbiologia , Neoplasias da Próstata/fisiopatologia , Animais , Clostridiales/fisiologia , Gorduras Insaturadas na Dieta/metabolismo , Ácidos Graxos/metabolismo , Fezes/microbiologia , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/fisiopatologia , Neoplasias da Próstata/metabolismo , Aumento de Peso/fisiologiaRESUMO
BACKGROUND: Plasma phospholipid fatty acids (FAs) in early and mid-pregnancy have been prospectively related to gestational diabetes mellitus (GDM) risk. Yet, changes of FAs following GDM diagnosis and treatment and their implications for glucose metabolism and control remain understudied. METHODS: From the Eunice Kennedy Shriver National Institute Child Health and Human Development Fetal Growth Studies-Singleton Cohort of 2802 pregnant women, we ascertained 85 GDM cases using the Carpenter and Coustan criteria and 85 non-GDM controls after exclusion. Using plasma collected before (23-31 weeks) and after GDM diagnosis (33-39 weeks), we quantified 25 saturated, poly- and monounsaturated FAs levels. We estimated the fold change of FAs before and after GDM diagnosis, using multiple linear mixed models adjusting for confounders. RESULTS: Eight FAs showed significant fold changes from the baseline values (23-31 weeks) among GDM cases as compared to women without GDM. Five FAs showed reduced fold changes [myristic acid (14:0): ß: -0.22 (95% CI: -0.30, -0.14), palmitic acid (16:0): ß: -0.02 (95% CI: -0.04, -0.01), cis-palmitoleic acid (16:1n7): ß: -0.15 (95% CI: -0.24, -0.05), alpha-linolenic acid (18:3n3): ß: -0.19 (95% CI: -0.31, -0.07], and dihomo-gamma-linoleic acid (20:3n6): ß:-0.16; 95% CI: -0.21, -0.11)], whereas 3 showed increases [heptadecanoic acid (17:0): ß: 0.17 (95% CI: 0.11, 0.22), cis-vaccenic acid (18:1n7): ß: 0.06 (95% CI: 0.03, 0.10), and arachidonic acid (20:4n6): ß: 0.10 (95% CI: 0.06, 0.13)]. CONCLUSIONS: Our study identified 8 FAs with unique patterns of change before and after GDM diagnosis that differed significantly between women with and without GDM. Our findings may shed light on the role of FA metabolism in the pathophysiology and disease management and progression of GDM. CLINICAL TRIAL REGISTRY: NCT00912132.
Assuntos
Diabetes Gestacional , Criança , Estudos de Coortes , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/terapia , Ácidos Graxos , Feminino , Humanos , Fosfolipídeos , GravidezRESUMO
Saturated fatty acids, whose circulating levels are markedly increased in the body, significantly affect the growth and functions of skeletal muscle. These fatty acids may exert a detrimental effect on the undifferentiated skeletal myoblasts that may adversely affect their differentiation. In the present study, the exposure of myoblasts to excess palmitic acid caused an elevation of tumor necrosis factor-α expression and an increase in reactive oxygen species levels consistent with the enhanced inflammation and oxidative stress. Various concentrations of palmitic acid significantly decreased the mitochondrial membrane potential, induced the programmed cell death by an increase in the caspase-3 expression, and DNA fragmentation in the myoblasts. These findings suggest that the increased concentrations of saturated fatty acid in the myoblasts increase lipotoxicity by increasing inflammation and oxidative stress, decreasing the mitochondrial function, and inducing apoptosis.
Assuntos
Caspase 3/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Mioblastos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/toxicidade , Fator de Necrose Tumoral alfa/biossíntese , Linhagem Celular , Fragmentação do DNA/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Musculares/patologia , Mioblastos/patologiaRESUMO
Background: A body of epidemiological, clinical and preclinical studies suggest increased risk for cerebro- and cardio-vascular disease associated with dietary ingestion of long-chain saturated fatty acids (LCSFA). In wild-type rodent models, chronic ingestion of LCSFA diets are associated with increased cerebral capillary permeability, heightened neurovascular inflammation and poorer cognitive performance. However, recent studies suggest that diets enriched in fat may paradoxically attenuate elements of the ageing phenotype via a caloric support axis.Objective: The purpose of this study was to explore the effects of dietary LCSFA on cerebral capillary integrity and neurovascular inflammation in an established model of accelerated ageing, Senescence-Accelerated-Murine-Prone Strain 8 (SAMP8) mice.Methods: From 6 weeks of age, SAMP8 mice and age-matched controls were randomised to either normal chow, or to an LCSFA-enriched diet, for either 12 or 34 weeks. An additional group of SAMP8 mice were provided the LCSFA-enriched diet for 12 weeks followed by the provision of ordinary low-fat chow for 22 weeks. Ex vivo measures of cerebrovascular integrity, neurovascular inflammation and astrocytic activation, were determined via 3-dimensional immunofluorescent confocal microscopy methodologies.Results: LCSFA-fed SAMP8 mice had markedly attenuated cerebral capillary dysfunction concomitant with reduced microglial activation. In SAMP8 mice transiently maintained on an LCSFA diet for 12 weeks, suppression of neurovascular inflammation persisted. Marked hippocampal astrogliosis was evident in LCSFA-fed mice when compared to SAMP8 mice maintained on ordinary chow.Conclusion: The findings from this study support the notion that high-fat, potentially ketogenic diets, may confer neuroprotection in SAMP8 mice through a vascular-support axis.
Assuntos
Envelhecimento/fisiologia , Córtex Cerebral/irrigação sanguínea , Dieta Hiperlipídica , Encefalite/fisiopatologia , Envelhecimento/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Ácidos Graxos/administração & dosagem , Masculino , CamundongosRESUMO
AIM: To examine the relationship between dietary fat intake and breast cancer (BC) development. METHOD: This case-control study included 473 women with breast cancer (pathologically confirmed) and 501 healthy subjects matched by age and residency. Dietary intakes of different types and sources of fatty acids were assessed using a validated food frequency questionnaire. The association between dietary fats and odds of BC was assessed using a logistic regression model in crude and multivariable-adjusted models. P values below 0.05 were regarded as statistically significant. RESULTS: Participants' age and body mass index were 44.0 ± 10.8 years and 28.4 ± 5.6 kg/m2, respectively. Individuals with the highest quartile of total fat intake and polyunsaturated fatty acid (PUFA) intake were 1.50 times more at risk to develop BC than others. A positive significant association was observed between animal fat (Q4 vs. Q1, OR = 1.89, 95 % CI = 0.93-3.81), saturated fatty acid (SFA) (Q4 vs. Q1, OR = 1.70, 95 % CI = 0.88-3.30), monounsaturated fatty acid (MUFA) (Q4 vs. Q1 OR = 1.85, 95 % CI = 0.95-3.61) and PUFA intake (Q4 vs. Q1, OR = 2.12, 95 % CI = 1.05-4.27) with BC risk in postmenopausal women. However, there was no association in premenopausal women. CONCLUSIONS: Total dietary fat and its subtypes might increase the risk of BC, especially in postmenopausal women. This observational study confirms the role of dietary fat in breast cancer development. Intervention studies involving different estrogen receptor subgroups are needed.
Assuntos
Neoplasias da Mama/etiologia , Gorduras na Dieta/efeitos adversos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Estudos de Casos e Controles , Inquéritos sobre Dietas , Gorduras na Dieta/administração & dosagem , Ácidos Graxos/administração & dosagem , Ácidos Graxos/efeitos adversos , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos Insaturados/efeitos adversos , Feminino , Humanos , Irã (Geográfico)/epidemiologia , Modelos Logísticos , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
Previous studies have revealed that a high-fat diet is one of the key contributors to the progression of liver fibrosis, and increasing studies are devoted to analyzing the different influences of diverse fat sources on the progression of non-alcoholic steatohepatitis. When we treated three types of isocaloric diets that are rich in cholesterol, saturated fatty acid (SFA) and trans fatty acid (TFA) with hepatitis C virus core gene transgenic mice that spontaneously developed hepatic steatosis without apparent fibrosis, TFA and cholesterol-rich diet, but not SFA-rich diet, displayed distinct hepatic fibrosis. This review summarizes the recent advances in animal and cell studies regarding the effects of these three types of fat on liver fibrogenesis.