RESUMO
Nonalcoholic steatohepatitis (NASH) is an emerging health problem worldwide. However, efficacious pharmacological treatment for NASH is lacking. A major issue for preclinical evaluation of potential therapeutics for NASH is the limited number of appropriate animal models, i.e., models that do not require long-term dietary intervention and adequately mimic disease progression in humans. The present study aimed to evaluate a 3-wk dietary mouse model of NASH and validate it by studying the effects of liraglutide, a compound in advanced clinical development for NASH. C57BL6/J mice were fed a diet high in fat (60%), cholesterol (1.25%), and cholic acid (0.5%), along with 2% hydroxypropyl-ß-cyclodextrin in drinking water (HFCC-CDX diet). Histological and biological parameters were measured at 1 and 3 wk. After 1-wk diet induction, liraglutide was administrated daily for 2 wk and then NASH-associated phenotypic aspects were evaluated in comparison with control mice. Prior to treatment with liraglutide, mice fed the HFCC-CDX diet for 1 wk developed liver steatosis and had increased levels of oxidative-stress markers and hepatic and systemic inflammation. For mice not treated with liraglutide, these aspects were even more pronounced after 3 wk of the dietary period, with additional liver insulin resistance and fibrosis. Liraglutide treatment corrected the diet-induced alterations in glucose metabolism and significantly reduced hepatic steatosis and inflammation. This study provides a novel 3-wk dietary model of mice that rapidly develop NASH features, and this model will be suitable for evaluating the therapeutic efficacy of compounds in preclinical drug development for NASH.NEW & NOTEWORTHY We propose a diet high in fat (60%), cholesterol (1.25%), and cholic acid (0.5%) along with 2% hydroxypropyl-ß-cyclodextrin in drinking water (HFCC-CDX diet) as a new dietary model of nonalcoholic steatohepatitis. We used the HFCC-CDX model to reproduce the main features of disease development in humans for the purpose of facilitating the rapid screening of drug candidates and prioritizing the more promising candidates for advanced preclinical assessment and subsequent clinical trials.
Assuntos
Hipoglicemiantes/farmacologia , Liraglutida/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , 2-Hidroxipropil-beta-Ciclodextrina , Animais , Colesterol na Dieta , Ácido Cólico/metabolismo , Dieta , Dieta Hiperlipídica , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/patologiaRESUMO
OBJECTIVE: Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. APPROACH AND RESULTS: Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1, and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. CONCLUSIONS: Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
Assuntos
Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Ácidos e Sais Biliares/metabolismo , Hipercolesterolemia/metabolismo , Metilaminas/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Animais , Animais Recém-Nascidos , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/patologia , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Feminino , Vesícula Biliar/metabolismo , Predisposição Genética para Doença , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Fígado/metabolismo , Masculino , Camundongos Knockout , Oxigenases/genética , Oxigenases/metabolismo , Fenótipo , Placa Aterosclerótica , Gravidez , Regiões Promotoras Genéticas , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismoRESUMO
Consumers are exposed to succinate dehydrogenase inhibitor (SDHI) pesticides through their diet. A cumulative dietary risk assessment for the French population has been performed with French monitoring data (2017-2021) and consumption data from INCA3. The calculation followed a two-tiered approach, using deterministic then probabilistic methods. It was carried out, using European health based guidance values (HBGV) derived for each active substance to characterise their toxicity. In Tier I, the calculated hazard index of 0.12 was below the threshold of 1 and in Tier II, the total margin of exposure at percentile 99.9 remains above the trigger value of 100 (1798 [1631-2311]). In Tier II, the three main risk drivers identified at the upper tail of the distribution were strawberries-fluopyram (19.1%), peaches-fluopyram (14.1%) and table grapes-boscalid (10.5%). Finally, the impact of the major sources of uncertainties was qualitatively evaluated. All together, they were considered of low impact on the outcomes. This work demonstrates the absence of unacceptable chronic risk related to the cumulative exposure of SDHI for French consumers during the 2017-2021 period.
Assuntos
Praguicidas , Succinato Desidrogenase , Humanos , França , Medição de Risco , Praguicidas/toxicidade , Succinato Desidrogenase/antagonistas & inibidores , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Exposição Dietética , Feminino , Masculino , Contaminação de Alimentos/análise , Adolescente , Idoso , Criança , Inibidores Enzimáticos/toxicidade , Pré-EscolarRESUMO
This abstract presents a report on the proposed work programme, focus on cumulative risk assessment (CRA) for chemical risks, specifically pesticide residues in food. While not a scientific publication, this technical report aims to provide insights without including the fellow's data to avoid publication restrictions. This report focuses on addressing the question concerning the trigger value to perform a prospective CRA in case of a new maximum residue level (MRL) setting. The 1,000 margin of exposure (MOE) threshold value was tested and compared to preliminary ANSES results. Alternative thresholds were calculated and explored. The EU-FORA fellow selected two cumulative assessment groups (CAGs) related to acute craniofacial alterations and chronic thyroid effects. The fellow performed exposure assessments, integrating effects data, French monitoring data, processing factors, agricultural uses, MRLs and extrapolations into Monte Carlo risk assessment (MCRA). Retrospective cumulative exposures using MCRA were conducted for children, adults and a vulnerable group of childbearing women based on the French survey INCA3, identifying background levels at P99.9. The fellow also performed prospective assessments with MCRA, analysing results at P99.9 to evaluate the adequacy of the 1,000 MOE threshold. Alternative thresholds are discussed and proposed.
RESUMO
In humans and animal models, intermittent fasting (IF) interventions promote body weight loss, improve metabolic health, and are thought to lower cardiovascular disease risk. However, there is a paucity of reports on the relevance of such nutritional interventions in the context of dyslipidemia and atherosclerotic cardiovascular diseases. The present study assessed the metabolic and atheroprotective effects of intermittent fasting intervention (IF) in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice. Groups of male and female Apoe-/- mice were fed a regular (chow) or atherogenic (high-fat, high-cholesterol, HFCD) diet for 4 months, either ad libitum or in an alternate-day fasting manner. The results show that IF intervention improved glucose and lipid metabolism independently of sex. However, IF only decreased body weight gain in males fed chow diet and differentially modulated adipose tissue parameters and liver steatosis in a diet composition-dependent manner. Finally, IF prevented spontaneous aortic atherosclerotic lesion formation in mice fed chow diet, irrespective of sex, but failed to reduce HFCD-diet-induced atherosclerosis. Overall, the current work indicates that IF interventions can efficiently improve glucose homeostasis and treat atherogenic dyslipidemia, but a degree of caution is warranted with regard to the individual sex and the composition of the dietary regimen.
Assuntos
Aterosclerose , Dislipidemias , Hipercolesterolemia , Hiperlipidemias , Humanos , Masculino , Feminino , Camundongos , Animais , Jejum Intermitente , Dieta , Aterosclerose/metabolismo , Dislipidemias/metabolismo , Glucose , Apolipoproteínas E , ApolipoproteínasRESUMO
Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE-/-) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.
Assuntos
Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/prevenção & controle , Daucus carota , Suplementos Nutricionais , Placa Aterosclerótica/terapia , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Débito Cardíaco , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/genética , Ceco/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Peroxidação de Lipídeos , Lipogênese , Lipoproteínas VLDL/sangue , Camundongos , Camundongos Knockout , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Propionatos/metabolismo , Triglicerídeos/sangue , Aumento de PesoRESUMO
Epidemiological studies describe the association between apple consumption and improved cardiovascular and metabolic dysfunction. Our recent multiparametric screening on cellular model studies has shown that apples exhibit vascular tropism including Granny Smith (GS) variety independently of the storage condition. The present study aimed to evaluate the cardiovascular and metabolic protection of supplementation of GS variety after storage in classic cold (GSCC) and extreme ultra-low oxygen conditions (GSXO) in the apolipoprotein E-deficient 8-week-old mice fed with high fat diet for 14 weeks. Supplementation with GSCC and GXO decreases circulating triglycerides, the expression of genes involved in lipogenesis, without change in cholesterol and glucose concentrations and HOMA-IR. Only GSXO supplementation ameliorates body weight gain, insulin level, and HDL/LDL ratio. GSXO supplementation does not modify cardiac parameters; while supplementation with GSCC decreases heart rate and improves cardiac output. Interestingly, GSCC and GSXO reduce systolic and diastolic blood pressure with a differential time course of action. These effects are associated with substantial decrease of atherosclerotic lesions. These data reinforce the knowledge about the vascular tropism of apple supplementation and underscore their ability to improve both cardiovascular and metabolic alterations in a mouse model of atherosclerosis.