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1.
Molecules ; 26(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361783

RESUMO

Amber-the fossilized resin of trees-is rich in terpenoids and rosin acids. The physiological effects, such as antipyretic, sedative, and anti-inflammatory, were used in traditional medicine. This study aims to clarify the physiological effects of amber extract on lipid metabolism in mouse 3T3-L1 cells. Mature adipocytes are used to evaluate the effect of amber extract on lipolysis by measuring the triglyceride content, glucose uptake, glycerol release, and lipolysis-related gene expression. Our results show that the amount of triacylglycerol, which is stored in lipid droplets in mature adipocytes, decreases following 96 h of treatment with different concentrations of amber extract. Amber extract treatment also decreases glucose uptake and increases the release of glycerol from the cells. Moreover, amber extract increases the expression of lipolysis-related genes encoding perilipin and hormone-sensitive lipase (HSL) and promotes the activity of HSL (by increasing HSL phosphorylation). Amber extract treatment also regulates the expression of other adipocytokines in mature adipocytes, such as adiponectin and leptin. Overall, our results indicate that amber extract increases the expression of lipolysis-related genes to induce lipolysis in 3T3-L1 cells, highlighting its potential for treating various obesity-related diseases.


Assuntos
Adipócitos/efeitos dos fármacos , Âmbar/farmacologia , Misturas Complexas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipolipemiantes/farmacologia , Lipólise/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Âmbar/química , Animais , Diferenciação Celular , Misturas Complexas/química , Etanol/química , Glucose/metabolismo , Glicerol/metabolismo , Hipolipemiantes/química , Leptina/genética , Leptina/metabolismo , Gotículas Lipídicas/química , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Camundongos , Perilipina-1/genética , Perilipina-1/metabolismo , Fosforilação/efeitos dos fármacos , Esterol Esterase/genética , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo
2.
Nutrients ; 13(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34371841

RESUMO

Excessive liver lipid deposition is a vital risk factor for the development of many diseases. Here, we fed Sprague-Dawley rats with a control or α-lipoic acid-supplemented diet (0.2%) for 5 weeks to elucidate the effects of α-lipoic acid on preventive ability, hepatic lipid metabolism-related gene expression, and the involved regulatory mechanisms. In the current study, α-lipoic acid supplementation lowered plasma triglyceride level and hepatic triglyceride content. Reduced hepatic lipid deposition was closely associated with inhibiting fatty acid-binding protein 1 and fatty acid synthase expression, as well as increasing phosphorylated hormone-sensitive lipase expression at the protein level in α-lipoic acid-exposed rats. Hepatic miRNA sequencing revealed increased expression of miR-3548 targeting the 3'untranslated region of Fasn mRNA, and the direct regulatory link between miRNA-3548 and FASN was verified by dual-luciferase reporter assay. Taken together, α-lipoic acid lowered hepatic lipid accumulation, which involved changes in miRNA-mediated lipogenic genes.


Assuntos
Suplementos Nutricionais , Ácido Graxo Sintase Tipo I/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , MicroRNAs/metabolismo , Ácido Tióctico/farmacologia , Animais , Ácido Graxo Sintases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica/efeitos dos fármacos , Lipogênese/genética , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Triglicerídeos/metabolismo
3.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205604

RESUMO

Rutin (R) and quercetin (Q) are two widespread dietary flavonoids. Previous studies regarding the plasma cholesterol-lowering activity of R and Q generated inconsistent results. The present study was therefore carried out to investigate the effects of R and Q on cholesterol metabolism in both HepG2 cells and hypercholesterolemia hamsters. Results from HepG2 cell experiments demonstrate that both R and Q decreased cholesterol at doses of 5 and 10 µM. R and Q up-regulated both the mRNA and protein expression of sterol regulatory element binding protein 2 (SREBP2), low-density lipoprotein receptor (LDLR), and liver X receptor alpha (LXRα). The immunofluorescence study revealed that R and Q increased the LDLR expression, while only Q improved LDL-C uptake in HepG2 cells. Results from hypercholesterolemia hamsters fed diets containing R (5.5 g/kg diet) and Q (2.5 g/kg diet) for 8 weeks demonstrate that both R and Q had no effect on plasma total cholesterol. In the liver, only Q reduced cholesterol significantly. The discrepancy between the in vitro and in vivo studies was probably due to a poor bioavailability of flavonoids in the intestine. It was therefore concluded that R and Q were effective in reducing cholesterol in HepG2 cells in vitro, whereas in vivo, the oral administration of the two flavonoids had little effect on plasma cholesterol in hamsters.


Assuntos
Colesterol/sangue , Colesterol/metabolismo , Quercetina/farmacologia , Rutina/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Cricetinae , Flavonoides/farmacologia , Células Hep G2 , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Receptores de LDL/sangue , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacos
4.
Molecules ; 26(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209258

RESUMO

Tripalmitin-(PPP, 81.2%), 1,3-dipalmitoyl-2-oleoylglycerol-(POP, 64.4%), 1,2-dipalmitoyl-3-oleoylglycerol-(PPO, 86.5%), and 1,3-dioleoyl-2-palmitoylglycerol-(OPO, 50.2%)-rich lipids with different regiospecific positions of palmitic acid (P) were synthesized via acetone fractionation and lipase-catalyzed acidolysis, and their physicochemical and hydrolytic characteristics were compared. Triacylglycerols (TAGs) with higher content of P, wherein P was at the sn-1 (or 3) position, had higher melting points, crystallization temperatures, and packing densities of fat crystals compared to those with a lower content of P, and with P at the sn-2 position. The in vitro digestion degree calculated as released fatty acid (FA) (%) at 30, 60, and 120 min was in the following order: OPO-rich > PPO-rich > POP-rich lipids. At 120 min, in vitro digestion of the OPO-rich lipid released 92.6% of fatty acids, resulting in the highest digestibility, while 89.7% and 87.2% of fatty acids were released from the OPO-rich and PPO-rich lipids, respectively. Over the digestion period, the TAG and monoacylglycerol (MAG) contents decreased, while the diacylglycerol (DAG) content initially increased and then decreased, and the 1,2-DAG content exceeded the 1,3-DAG content. Therefore, the content and stereospecific position of P attached to a specific TAG affected the physicochemical and in vitro digestion characteristics of the lipids.


Assuntos
Lipase/química , Ácido Palmítico/química , Triglicerídeos/química , Digestão , Monoglicerídeos/química , Monoglicerídeos/metabolismo , Ácido Palmítico/metabolismo , Triglicerídeos/metabolismo
5.
Nutrients ; 13(6)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207558

RESUMO

Hypercholesterolemia can cause many diseases, but it can effectively regulated by Lactobacillus. This study aimed to evaluate the cholesterol-lowering mechanism of Enterococcus faecium strain 132 and Lactobacillusparacasei strain 201. These results showed that both the strains decreased serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), liver TC and TG and increased fecal TC, TG and total bile acid (TBA) levels. Additionally, both strains also reduced glutamic-pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST) and levels of tissue inflammation levels to improve the lipid profile, and they reduced fat accumulation partially by alleviating inflammatory responses. Furthermore, both strains regulated the expression of the CYP8B1, CYP7A1, SREBP-1, SCD1 and LDL-R gene to promote cholesterol metabolism and reduce TG accumulation. Interventions with both strains also altered the gut microbiota, and decreasing the abundance of Veillonellaceae, Erysipelotrichaceae and Prevotella. Furthermore, fecal acetic acid and propionic acid were increased by this intervention. Overall, the results suggested that E. faecium strain 132 and L. paracasei strain 201 can alleviate hypercholesterolemia in rats and might be applied as a new type of hypercholesterolemia agent in functional foods.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Enterococcus faecium , Hipercolesterolemia/microbiologia , Lactobacillus paracasei , Probióticos/farmacologia , Ácido Acético/análise , Animais , Colesterol 7-alfa-Hidroxilase/metabolismo , LDL-Colesterol/metabolismo , Modelos Animais de Doenças , Fezes/química , Fezes/microbiologia , Alimento Funcional/microbiologia , Microbioma Gastrointestinal/fisiologia , Humanos , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Fígado/microbiologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Propionatos/análise , Ratos , Estearoil-CoA Dessaturase/metabolismo , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
6.
Aging (Albany NY) ; 13(13): 17489-17498, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34232916

RESUMO

BACKGROUND AND PURPOSE: Obesity is becoming a major global health issue and is mainly induced by the accumulation of adipose tissues mediated by adipogenesis, which is reported to be regulated by peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα). Trichostatin A (TSA) is a novel histone deacetylase inhibitor (HDACI) that was recently reported to exert multiple pharmacological functions. The present study will investigate the inhibitory effect of TSA on adipogenesis, as well as the underlying mechanism. METHODS: The adipogenesis of 3T3-L1 cells was induced by stimulation with a differentiation cocktail (DMI) medium for 8 days. MTT assay was used to measure the cell viability and Oil Red O staining was used to evaluate the adipogenesis of 3T3-L1 cells. The total level of triglyceride and released glycerol were detected to evaluate the lipolysis during 3T3-L1 adipogenesis. The expression levels of Leptin, fatty acid-binding protein 4 (FABP4), and sterol regulatory element-binding protein (SREBP1C) were determined by qRT-PCR. qRT-PCR assay was utilized to detect the expression levels of PPARγ and C/EBPα in 3T3-L1 cells. A high-fat diet (HFD) was used to construct an obese mice model, followed by the treatment with TSA. HE staining was conducted to evaluate the pathological state of adipose tissues. Body weights and the weights of adipose tissues were recorded to evaluate the anti-obesity property of TSA. RESULTS: Firstly, the promoted lipid accumulation induced by DMI incubation was significantly reversed by the treatment with TSA in a dose-dependent manner. The elevated expression levels of Leptin, FABP4, SREBP1C, PPARγ, and C/EBPα induced by the stimulation with DMI incubation were dramatically inhibited by the introduction of TSA, accompanied by the upregulation of phosphorylated AMP-activated protein kinase (p-AMPK). Secondly, the inhibitory effect of TSA against the expression level of PPARγ and lipid accumulation was greatly abolished by an AMPK inhibitor. Lastly, the increased body weights and visceral adipocyte tissue weight, as well as the enlarged size of adipocytes induced by HFD were pronouncedly reversed by the administration of TSA. CONCLUSION: TSA inhibited adipogenesis in 3T3-L1 preadipocytes by activating the AMPK pathway.


Assuntos
Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Células 3T3-L1 , Tecido Adiposo/patologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Proteínas de Ligação a Ácido Graxo/genética , Glicerol/metabolismo , Leptina/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Obesos , Obesidade/genética , Triglicerídeos/metabolismo
7.
Nutrients ; 13(7)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202724

RESUMO

BACKGROUND: A low-sodium (LS) diet reduces blood pressure, contributing to the prevention of cardiovascular diseases. However, intense dietary sodium restriction impairs insulin sensitivity and worsens lipid profile. Considering the benefits of aerobic exercise training (AET), the effect of LS diet and AET in hepatic lipid content and gene expression was investigated in LDL receptor knockout (LDLr-KO) mice. METHODS: Twelve-week-old male LDLr-KO mice fed a normal sodium (NS) or LS diet were kept sedentary (S) or trained (T) for 90 days. Body mass, plasma lipids, insulin tolerance testing, hepatic triglyceride (TG) content, gene expression, and citrate synthase (CS) activity were determined. Results were compared by 2-way ANOVA and Tukey's post-test. RESULTS: Compared to NS, LS increased body mass and plasma TG, and impaired insulin sensitivity, which was prevented by AET. The LS-S group, but not the LS-T group, presented greater hepatic TG than the NS-S group. The LS diet increased the expression of genes related to insulin resistance (ApocIII, G6pc, Pck1) and reduced those involved in oxidative capacity (Prkaa1, Prkaa2, Ppara, Lipe) and lipoprotein assembly (Mttp). CONCLUSION: AET prevented the LS-diet-induced TG accumulation in the liver by improving insulin sensitivity and the expression of insulin-regulated genes and oxidative capacity.


Assuntos
Dieta Hipossódica/efeitos adversos , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Condicionamento Físico Animal/fisiologia , Receptores de LDL/deficiência , Animais , Peso Corporal , Citrato (si)-Sintase/metabolismo , Expressão Gênica , Lipídeos/sangue , Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout , Sódio na Dieta/metabolismo , Triglicerídeos/metabolismo
8.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208400

RESUMO

BACKGROUND: Obesity is a state of excess energy storage resulting in body fat accumulation, and postmenopausal obesity is a rising issue. In this study using ovariectomized (OVX) rats, we mimicked low estrogen levels in a postmenopausal state in order to investigate the effects of different amounts and types of dietary fatty acids on body fat accumulation and body lipid metabolism. METHODS: At 9 weeks of age, rats (n = 40) were given an ovariectomy, eight of which were sham-operated to serve as a control group (S). We then divided OVX rats into four different intervention groups: diet with 5% soybean oil (C), and diet with 5% (L), 15% (M), and 20% (H) (w/w) experimental oil, containing 60% monounsaturated fatty acids (MUFAs) and with a polyunsaturated/saturated fatty acid (P/S) ratio of 5. RESULTS: After OVX, compared to the S group, the C group showed significantly higher body weight, and insulin and leptin levels. Compared to the C group, the H group had lower hepatic triglyceride level and FAS enzyme activity, and higher hepatic ACO and CPT-1 gene expressions and enzyme activities. CONCLUSIONS: An OVX leads to severe weight gain and lipid metabolism abnormalities, while according to previous studies, high fat diet may worsen the situation. However, during our experiment, we discovered that the experimental oil mixture with 60% MUFAs and P/S = 5 may ameliorate these imbalances.


Assuntos
Tecido Adiposo , Gorduras Insaturadas na Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Ácidos Graxos Insaturados/administração & dosagem , Ácidos Graxos/administração & dosagem , Metabolismo dos Lipídeos , Animais , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Ácido Graxo Sintases/metabolismo , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Insulina/sangue , Leptina/sangue , Fígado/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Óleo de Soja/administração & dosagem , Triglicerídeos/metabolismo , Ganho de Peso
9.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202179

RESUMO

The progression of non-alcoholic fatty liver (NAFL) into non-alcoholic steatohepatitis implicates multiple mechanisms, chief of which is mitochondrial dysfunction. However, the sequence of events underlying mitochondrial failure are still poorly clarified. In this work, male C57BL/6J mice were fed with a high-fat plus high-sucrose diet for 16, 20, 22, and 24 weeks to induce NAFL. Up to the 20th week, an early mitochondrial remodeling with increased OXPHOS subunits levels and higher mitochondrial respiration occurred. Interestingly, a progressive loss of mitochondrial respiration along "Western diet" feeding was identified, accompanied by higher susceptibility to mitochondrial permeability transition pore opening. Importantly, our findings prove that mitochondrial alterations and subsequent impairment are independent of an excessive mitochondrial reactive oxygen species (ROS) generation, which was found to be progressively diminished along with disease progression. Instead, increased peroxisomal abundance and peroxisomal fatty acid oxidation-related pathway suggest that peroxisomes may contribute to hepatic ROS generation and oxidative damage, which may accelerate hepatic injury and disease progression. We show here for the first time the sequential events of mitochondrial alterations involved in non-alcoholic fatty liver disease (NAFLD) progression and demonstrate that mitochondrial ROS are not one of the first hits that cause NAFLD progression.


Assuntos
Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antioxidantes/metabolismo , Autofagia , Ésteres do Colesterol/metabolismo , Biologia Computacional/métodos , Suscetibilidade a Doenças , Fibrose , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Camundongos , Mitocôndrias/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução , Estresse Oxidativo , Triglicerídeos/metabolismo
10.
Nutrients ; 13(6)2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34203094

RESUMO

The burden of cognitive disorders is huge and still growing, however the etiology and the degree of cognitive impairment vary considerably. Neurodegenerative and vascular mechanisms were most frequently assessed in patients with dementia. Recent studies have shown the possible involvement of triglycerides levels in cognitive function through putative mechanisms such as brain blood barrier dysfunction or amyloid metabolism imbalance, but not all research in the field found this association. Several clinical studies evaluated the relationship between different forms of cognitive decline and levels of serum triglycerides, independent of other cardiovascular risk factors. This review focuses on the role of triglycerides in cognitive decline, cerebral amyloidosis and vascular impairment. Considering that the management of hypertriglyceridemia benefits from lifestyle modification, diet, and specific drug therapy, future studies are requested to appraise the triglycerides-cognitive impairment relationship.


Assuntos
Disfunção Cognitiva/etiologia , Triglicerídeos/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/etiologia , Amiloidose/diagnóstico , Barreira Hematoencefálica/metabolismo , Encefalopatias/diagnóstico , Transtornos Cerebrovasculares/diagnóstico , Cognição , Transtornos Cognitivos/sangue , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Dieta , Feminino , Humanos , Hipertrigliceridemia/terapia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Triglicerídeos/líquido cefalorraquidiano , Triglicerídeos/metabolismo
11.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199317

RESUMO

Empagliflozin, an established treatment for type 2 diabetes (T2DM), has shown beneficial effects on liver steatosis and fibrosis in animals and in humans with T2DM, non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). However, little is known about the effects of empagliflozin on liver function in advanced NASH with liver fibrosis and without diabetes. This study aimed to assess the effects of empagliflozin on hepatic and metabolic outcomes in a diet-induced obese (DIO) and insulin-resistant but non-diabetic biopsy-confirmed mouse model of advanced NASH. Male C57BL/6JRj mice with a biopsy-confirmed steatosis and fibrosis on AMLN diet (high fat, fructose and cholesterol) for 36-weeks were randomized to receive for 12 weeks: (a) Empagliflozin (10 mg/kg/d p.o.), or (b) vehicle. Metabolic outcomes, liver pathology, markers of Kupffer and stellate cell activation and lipidomics were assessed at the treatment completion. Empagliflozin did not affect the body weight, body composition or insulin sensitivity (assessed by intraperitoneal insulin tolerance test), but significantly improved glucose homeostasis as assessed by oral glucose tolerance test in DIO-NASH mice. Empagliflozin improved modestly the NAFLD activity score compared with the vehicle, mainly by improving inflammation and without affecting steatosis, the fibrosis stage and markers of Kupffer and stellate cell activation. Empagliflozin reduced the hepatic concentrations of pro-inflammatory lactosylceramides and increased the concentrations of anti-inflammatory polyunsaturated triglycerides. Empagliflozin exerts beneficial metabolic and hepatic (mainly anti-inflammatory) effects in non-diabetic DIO-NASH mice and thus may be effective against NASH even in non-diabetic conditions.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Glucosídeos/uso terapêutico , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Antígenos CD/metabolismo , Compostos Benzidrílicos/farmacologia , Biópsia , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Glucose/metabolismo , Glucosídeos/farmacologia , Homeostase/efeitos dos fármacos , Resistência à Insulina , Lactosilceramidas/metabolismo , Lipidômica , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismo
12.
Molecules ; 26(13)2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34203276

RESUMO

Regioisomers (or positional isomers) of triacylglycerols (TAGs) of milk are known to show differential outcome in relation to human absorption. Quantitation of TAG regioisomers remains a big challenge due to the lack of facile chromatographic separation technique. The feasibility of using fragment ion intensity ratio to determine the ratio of co-eluting AAB/ABA-type regioisomer pairs was confirmed in this study. The ability of C30 stationary phase in resolving interfering TAG isomers was demonstrated for the first time. This allowed us to reveal the complexity of using fragment ion intensity to quantify 1,2-olein-3-palmitin (OOP), 1,3-olein-2-palmitin (OPO), 1,2-olein-3-stearin (OOS), and 1,3-olein-2-stearin (OSO) regioisomers in milk samples. A novel algorithm was proposed to consider the contribution of OPO/OOP and OSO/OOS double bond (DB)-isomers and to eliminate the interference of isobaric ions from other isomers, an aspect overlooked in previous studies. This liquid chromatography-mass spectrometry method that requires no pre-fractioning and a moderate chromatographic separation time of 36 min is simple and, thus, suitable for screening a large number of samples for genetic analysis of this trait. Preliminary results using a small cohort of animals showed that OPO/OOP ratio differs significantly between Jersey and Holstein cows, and a large variation was also observed across individual Holstein cows.


Assuntos
Cruzamento , Leite/metabolismo , Triglicerídeos/metabolismo , Animais , Bovinos , Cromatografia Líquida de Alta Pressão , Feminino , Estereoisomerismo , Triglicerídeos/química , Triglicerídeos/isolamento & purificação
13.
Toxicology ; 459: 152857, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34273450

RESUMO

In real life, organisms are exposed to complex mixtures of chemicals at low concentration levels, whereas research on toxicological effects is mostly focused on single compounds at comparably high doses. Mixture effects deviating from the assumption of additivity, especially synergistic effects, are of concern. In an adverse outcome pathway (AOP)-guided manner, we analyzed the accumulation of triglycerides in human HepaRG liver cells by a mixture of eight steatotic chemicals (amiodarone, benzoic acid, cyproconazole, flusilazole, imazalil, prochloraz, propiconazole and tebuconazole), each present below its individual effect concentration at 1-3 µM. Pronounced and significantly enhanced triglyceride accumulation was observed with the mixture, and similar effects were seen at the level of pregnane-X-receptor activation, a molecular initiating event leading to hepatic steatosis. Transcript pattern analysis indicated subtle pro-steatotic changes at low compound concentrations, which did not exert measurable effects on cellular triglycerides. Mathematical modeling of mixture effects indicated potentially more than additive behavior using a model for compounds with similar modes of action. The present data underline the usefulness of AOP-guided in vitro testing for the identification of mixture effects and highlight the need for further research on chemical mixtures and harmonization of data interpretation of mixture effects.


Assuntos
Misturas Complexas/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Triglicerídeos/metabolismo , Algoritmos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Marcadores Genéticos , Humanos , Modelos Teóricos , Receptor de Pregnano X/metabolismo , Transcrição Genética
14.
Cell Rep ; 36(5): 109479, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34320401

RESUMO

Coronaviruses rely on host membranes for entry, establishment of replication centers, and egress. Compounds targeting cellular membrane biology and lipid biosynthetic pathways have previously shown promise as antivirals and are actively being pursued as treatments for other conditions. Here, we test small molecule inhibitors that target the PI3 kinase VPS34 or fatty acid metabolism for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity. Our studies determine that compounds targeting VPS34 are potent SARS-CoV-2 inhibitors. Mechanistic studies with compounds targeting multiple steps up- and downstream of fatty acid synthase (FASN) identify the importance of triacylglycerol production and protein palmitoylation as requirements for efficient viral RNA synthesis and infectious virus production. Further, FASN knockout results in significantly impaired SARS-CoV-2 replication that can be rescued with fatty acid supplementation. Together, these studies clarify roles for VPS34 and fatty acid metabolism in SARS-CoV-2 replication and identify promising avenues for the development of countermeasures against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , COVID-19/virologia , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Metabolismo dos Lipídeos/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Replicação Viral/efeitos dos fármacos , Aminopiridinas/farmacologia , Animais , Células CACO-2 , Linhagem Celular , Chlorocebus aethiops , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Ácido Graxo Sintases/efeitos dos fármacos , Ácido Graxo Sintases/genética , Técnicas de Inativação de Genes , Humanos , Lipoilação/efeitos dos fármacos , Pirimidinas/farmacologia , RNA Viral/metabolismo , Triglicerídeos/metabolismo , Células Vero
15.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298967

RESUMO

Pathological fibrosis of the liver is a landmark feature in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Diagnosis and assessment of progress or treatment efficacy today requires biopsy of the liver, which is a challenge in, e.g., longitudinal interventional studies. Molecular imaging techniques such as positron emission tomography (PET) have the potential to enable minimally invasive assessment of liver fibrosis. This review will summarize and discuss the current status of the development of innovative imaging markers for processes relevant for fibrogenesis in liver, e.g., certain immune cells, activated fibroblasts, and collagen depositions.


Assuntos
Imagem Molecular/tendências , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Alarminas/metabolismo , Animais , Aquaporinas/análise , Colágeno/análise , Meios de Contraste , Citocinas/metabolismo , Técnicas de Imagem por Elasticidade/métodos , Endopeptidases/análise , Ácidos Graxos/metabolismo , Fibroblastos/química , Fibroblastos/ultraestrutura , Radioisótopos de Flúor , Radioisótopos de Gálio , Células Estreladas do Fígado/química , Células Estreladas do Fígado/ultraestrutura , Hepatócitos/metabolismo , Humanos , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Proteínas de Membrana/análise , Camundongos , Imagem Molecular/métodos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Ratos , Receptores CCR2/análise , Triglicerídeos/metabolismo
16.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299218

RESUMO

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a new class of endogenous lipids with interesting physiological functions in mammals. Despite their structural diversity and links with nuclear factor erythroid 2-related factor 2 (NRF2) biosynthesis, FAHFAs are less explored as NRF2 activators. Herein, we examined for the first time the synthetic docosahexaenoic acid esters of 12-hydroxy stearic acid (12-DHAHSA) or oleic acid (12-DHAHOA) against NRF2 activation in cultured human hepatoma-derived cells (C3A). The effect of DHA-derived FAHFAs on lipid metabolism was explored by the nontargeted lipidomic analysis using liquid chromatography-mass spectrometry. Furthermore, their action on lipid droplet (LD) oxidation was investigated by the fluorescence imaging technique. The DHA-derived FAHFAs showed less cytotoxicity compared to their native fatty acids and activated the NRF2 in a dose-dependent pattern. Treatment of 12-DHAHOA with C3A cells upregulated the cellular triacylglycerol levels by 17-fold compared to the untreated group. Fluorescence imaging analysis also revealed the suppression of the degree of LDs oxidation upon treatment with 12-DHAHSA. Overall, these results suggest that DHA-derived FAHFAs as novel and potent activators of NRF2 with plausible antioxidant function.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Ácidos Graxos/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Oleico/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Ácidos Docosa-Hexaenoicos/síntese química , Ácidos Docosa-Hexaenoicos/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Triglicerídeos/metabolismo , Células Tumorais Cultivadas
17.
Chem Biol Interact ; 346: 109595, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34302803

RESUMO

Glycyrrhizic acid (GA), a major constituent of the root of licorice (Glycyrrhiza glabra), and has various biological activities, including anti-obesity property. However, the molecular mechanism of anti-adipogenic effect of GA is still unclear. In this study, we investigated the anti-adipogenic effects of GA in mouse adipocytic 3T3-L1 cells and elucidated its underlying molecular mechanism. GA decreased the intracellular triglyceride level. The expression levels of the adipogenic and lipogenic genes were lowered by treatment with GA in a concertation-dependent manner. In contrast, GA did not affect the lipolytic gene expression and the released glycerol level. GA suppressed the early stage of adipogenesis when it was added for 0-3 h after initiation of adipogenesis. Moreover, GA reduced the mRNA levels of CCAAT/enhancer binding protein (C/EBP) ß and C/EBPδ, both of which activate the early stage of adipogenesis. Furthermore, GA decreased phosphorylation of extracellular signal-regulated kinase [ERK: p44/42 mitogen-activated protein kinase (MAPK)] in the early stage of adipogenesis. In addition, a MAPK kinase (MEK) inhibitor, PD98059 reduced the C/EBPß and C/EBPδ gene expression. These results indicate that GA suppressed the early stage of adipogenesis through repressing the MEK/ERK-mediated C/EBPß and C/EBPδ expression in 3T3-L1 cells. Thus, GA has an anti-adipogenic ability and a possible agent for treatment of obesity.


Assuntos
Adipogenia/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Células 3T3-L1 , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína delta de Ligação ao Facilitador CCAAT/genética , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Flavonoides/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Lipólise/efeitos dos fármacos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , PPAR gama/metabolismo , Fosforilação/efeitos dos fármacos , Triglicerídeos/metabolismo
18.
Int J Mol Sci ; 22(14)2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34298929

RESUMO

Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to understand the metabolic mechanisms underlying dyslipidemia to develop effective strategies against ASCVDs. Angiopoietin-like 3 (ANGPTL3), a member of the angiopoietin-like protein family exclusively synthesized in the liver, has been demonstrated to be a critical regulator of lipoprotein metabolism to inhibit lipoprotein lipase (LPL) activity. Genetic, biochemical, and clinical studies in animals and humans have shown that loss of function, inactivation, or downregulated expression of ANGPTL3 is associated with an obvious reduction in plasma levels of TGs, LDL-C, and high-density lipoprotein-cholesterol (HDL-C), atherosclerotic lesions, and the risk of cardiovascular events. Therefore, ANGPTL3 is considered an alternative target for lipid-lowering therapy. Emerging studies have focused on ANGPTL3 inhibition via antisense oligonucleotides (ASOs) and monoclonal antibody-based therapies, which have been carried out in mouse or monkey models and in human clinical studies for the management of dyslipidemia and ASCVDs. This review will summarize the current literature on the important role of ANGPTL3 in controlling lipoprotein metabolism and dyslipidemia, with an emphasis on anti-ANGPTL3 therapies as a potential strategy for the treatment of dyslipidemia and ASCVDs.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Dislipidemias/metabolismo , Lipoproteínas/metabolismo , Animais , Aterosclerose/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol , Humanos , Triglicerídeos/metabolismo
19.
Toxicol Appl Pharmacol ; 426: 115644, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34252412

RESUMO

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPARα)-expressing mice fed an American diet. Mice were exposed to PFOA (3.5 mg/L) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 µg/ml. In male and female hPPARα mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of PPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in PPARα null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results of our study and others reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.


Assuntos
Caprilatos/toxicidade , Dieta Ocidental , Dislipidemias/induzido quimicamente , Fluorcarbonetos/toxicidade , Fígado/efeitos dos fármacos , PPAR alfa/genética , Animais , Peso Corporal/efeitos dos fármacos , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Genótipo , Lipidômica , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Estados Unidos
20.
Plant Cell Rep ; 40(9): 1647-1663, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34215912

RESUMO

KEY MESSAGE: AIL7 over-expression modulates fatty acid biosynthesis and triacylglycerol accumulation in Arabidopsis developing seeds through the transcriptional regulation of associated genes. Seed fatty acids (FAs) and triacylglycerol (TAG) contribute to many functions in plants, and seed lipids have broad food, feed and industrial applications. As a result, an enormous amount of attention has been dedicated towards uncovering the regulatory cascade responsible for the fine-tuning of the lipid biosynthetic pathway in seeds, which is regulated in part through the action of LEAFY COTYLEDON1, ABSCISSIC ACID INSENSITIVE 3, FUSCA3 and LEC2 (LAFL) transcription factors. Although AINTEGUMENTA-LIKE 7 (AIL7) is involved in meristematic function and shoot phyllotaxy, its effect in the context of lipid biosynthesis has yet to be assessed. Here, we generated AIL7 seed-specific over-expression lines and found that they exhibited significant alterations in FA composition and decreased total lipid accumulation in seeds. Seeds and seedlings from transgenic lines also exhibited morphological deviations compared to wild type. Correspondingly, RNA-Seq analysis demonstrated that the expression of many genes related to FA biosynthesis and TAG breakdown were significantly altered in developing siliques from transgenic lines compared to wild-type plants. The seed-specific over-expression of AIL7 also altered the expression profiles of many genes related to starch metabolism, photosynthesis and stress response, suggesting further roles for AIL7 in plants. These findings not only advance our understanding of the lipid biosynthetic pathway in seeds, but also provide evidence for additional functions of AIL7, which could prove valuable in downstream breeding and/or metabolic engineering endeavors.


Assuntos
Proteínas de Arabidopsis/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Ligação a DNA/genética , Ácidos Graxos/biossíntese , Sementes/metabolismo , Fatores de Transcrição/genética , Proteínas de Arabidopsis/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ácidos Graxos/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Óleos Vegetais/metabolismo , Plantas Geneticamente Modificadas , Plântula/genética , Plântula/crescimento & desenvolvimento , Sementes/genética , Sementes/crescimento & desenvolvimento , Amido/genética , Amido/metabolismo , Fatores de Transcrição/metabolismo , Triglicerídeos/metabolismo
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