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1.
Immunity ; 54(10): 2273-2287.e6, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644558

RESUMO

Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity.


Assuntos
Diferenciação Celular/imunologia , Hidroxicolesteróis/metabolismo , Imunoglobulina A/imunologia , Plasmócitos/imunologia , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Animais , Colesterol na Dieta/imunologia , Colesterol na Dieta/metabolismo , Hidroxicolesteróis/imunologia , Imunoglobulina A/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Plasmócitos/metabolismo
2.
Biomolecules ; 11(8)2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34439893

RESUMO

Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low-normal plasma vitamin E concentrations (7.19-15.68 µmol/L), while vitamin A concentrations were found to be normal or high (1.26-2.68 µmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2-0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial.


Assuntos
Suplementos Nutricionais , Síndrome de Smith-Lemli-Opitz/sangue , Síndrome de Smith-Lemli-Opitz/terapia , Vitamina E/uso terapêutico , Adolescente , Alelos , Antioxidantes/metabolismo , Comportamento , Criança , Pré-Escolar , Colesterol na Dieta/metabolismo , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Desidrocolesteróis/sangue , Feminino , Humanos , Lipídeos/química , Masculino , Estresse Oxidativo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Oxisteróis/metabolismo , Estudos Prospectivos , Esteróis/química , Espectrometria de Massas em Tandem , Vitamina A/metabolismo , Vitamina E/metabolismo , Adulto Jovem
3.
Int J Mol Sci ; 22(13)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34281217

RESUMO

BACKGROUND AND AIMS: Hypercholesterolemia is a major risk factor for atherosclerosis and cardiovascular diseases. Although resistant to hypercholesterolemia, the mouse is a prominent model in cardiovascular research. To assess the contribution of bile acids to this protective phenotype, we explored the impact of a 2-week-long dietary cholesterol overload on cholesterol and bile acid metabolism in mice. METHODS: Bile acid, oxysterol, and cholesterol metabolism and transport were assessed by quantitative real-time PCR, western blotting, GC-MS/MS, or enzymatic assays in the liver, the gut, the kidney, as well as in the feces, the blood, and the urine. RESULTS: Plasma triglycerides and cholesterol levels were unchanged in mice fed a cholesterol-rich diet that contained 100-fold more cholesterol than the standard diet. In the liver, oxysterol-mediated LXR activation stimulated the synthesis of bile acids and in particular increased the levels of hydrophilic muricholic acids, which in turn reduced FXR signaling, as assessed in vivo with Fxr reporter mice. Consequently, biliary and basolateral excretions of bile acids and cholesterol were increased, whereas portal uptake was reduced. Furthermore, we observed a reduction in intestinal and renal bile acid absorption. CONCLUSIONS: These coordinated events are mediated by increased muricholic acid levels which inhibit FXR signaling in favor of LXR and SREBP2 signaling to promote efficient fecal and urinary elimination of cholesterol and neo-synthesized bile acids. Therefore, our data suggest that enhancement of the hydrophilic bile acid pool following a cholesterol overload may contribute to the resistance to hypercholesterolemia in mice. This work paves the way for new therapeutic opportunities using hydrophilic bile acid supplementation to mitigate hypercholesterolemia.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol na Dieta/efeitos adversos , Ácidos Cólicos/uso terapêutico , Hipercolesterolemia/prevenção & controle , Animais , Colesterol na Dieta/metabolismo , Avaliação Pré-Clínica de Medicamentos , Hipercolesterolemia/etiologia , Masculino , Camundongos Endogâmicos C57BL , Receptores Citoplasmáticos e Nucleares/metabolismo
4.
Ticks Tick Borne Dis ; 12(6): 101790, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34325088

RESUMO

Cholesterol is a known precursor of arthropod molecules such as the hormone 20-hydroxyecdysone and the antimicrobial boophiline, a component of tick egg wax coat. Because the cholesterol biosynthetic pathway is absent in ticks, it is necessarily obtained from the blood meal, in a still poorly understood process. In contrast, dietary cholesterol absorption is better studied in insects, and many proteins are involved in its metabolism, including Niemann-Pick C (NPC) transporter and acyl-CoA:cholesterol acyltransferase (ACAT), as well as enzymes to convert between free cholesterol and esterified cholesterol. The present work addresses the hypothesis that tick viability can be impaired by interfering with cholesterol metabolism, proposing this route as a target for novel tick control methods. Two drugs, ezetimibe (NPC inhibitor) and avasimibe (ACAT inhibitor) were added to calf blood and used to artificially feed Rhipicephalus microplus females. Results show that, after ingesting avasimibe, tick reproductive ability and egg development are impaired. Also, eggs laid by females fed with avasimibe did not hatch and were susceptible to Pseudomonas aeruginosa adhesion and biofilm formation in their surfaces. The immunoprotective potential of ACAT against ticks was also accessed using two selected ACAT peptides. Antibodies against these peptides were used to artificially feed female ticks, but no deleterious effects were observed. Taken together, data presented here support the hypothesis that enzymes and other proteins involved in cholesterol metabolism are suitable as targets for tick control methods.


Assuntos
Acetamidas , Anticolesterolemiantes , Colesterol na Dieta/metabolismo , Ezetimiba , Rhipicephalus , Sulfonamidas , Controle de Ácaros e Carrapatos , Absorção Fisiológica , Animais , Indutores do Citocromo P-450 CYP3A , Embrião não Mamífero , Feminino , Larva/crescimento & desenvolvimento , Rhipicephalus/crescimento & desenvolvimento , Controle de Ácaros e Carrapatos/métodos
5.
Nutrients ; 13(2)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671529

RESUMO

The number of nutrigenetic studies dedicated to the identification of single nucleotide polymorphisms (SNPs) modulating blood lipid profiles in response to dietary interventions has increased considerably over the last decade. However, the robustness of the evidence-based science supporting the area remains to be evaluated. The objective of this review was to present recent findings concerning the effects of interactions between SNPs in genes involved in cholesterol metabolism and transport, and dietary intakes or interventions on circulating cholesterol concentrations, which are causally involved in cardiovascular diseases and established biomarkers of cardiovascular health. We identified recent studies (2014-2020) that reported significant SNP-diet interactions in 14 cholesterol-related genes (NPC1L1, ABCA1, ABCG5, ABCG8, APOA1, APOA2, APOA5, APOB, APOE, CETP, CYP7A1, DHCR7, LPL, and LIPC), and which replicated associations observed in previous studies. Some studies have also shown that combinations of SNPs could explain a higher proportion of variability in response to dietary interventions. Although some findings still need replication, including in larger and more diverse study populations, there is good evidence that some SNPs are consistently associated with differing circulating cholesterol concentrations in response to dietary interventions. These results could help clinicians provide patients with more personalized dietary recommendations, in order to lower their risk for cardiovascular disease.


Assuntos
Colesterol na Dieta/sangue , Colesterol/sangue , Metabolismo dos Lipídeos/genética , Polimorfismo de Nucleotídeo Único , Colesterol na Dieta/metabolismo , Regulação da Expressão Gênica , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo
6.
Toxicol Appl Pharmacol ; 415: 115430, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33524446

RESUMO

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.


Assuntos
Poluentes Atmosféricos/toxicidade , Aorta Torácica/efeitos dos fármacos , Colesterol na Dieta/toxicidade , Diabetes Mellitus Tipo 2/complicações , Dieta Aterogênica/efeitos adversos , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Ozônio/toxicidade , Doenças Vasculares/induzido quimicamente , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Colesterol na Dieta/metabolismo , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Exposição por Inalação , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/sangue , Lesão Pulmonar/patologia , Masculino , Necrose , Edema Pulmonar/sangue , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia , Ratos Wistar , Doenças Vasculares/sangue , Doenças Vasculares/fisiopatologia , Vasoconstrição/efeitos dos fármacos
7.
Toxicol Appl Pharmacol ; 415: 115427, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33524448

RESUMO

Epidemiological studies show that individuals with underlying diabetes and diet-associated ailments are more susceptible than healthy individuals to adverse health effects of air pollution. Exposure to air pollutants can induce metabolic stress and increase cardiometabolic disease risk. Using male Wistar and Wistar-derived Goto-Kakizaki (GK) rats, which exhibit a non-obese type-2 diabetes phenotype, we investigated whether two key metabolic stressors, type-2 diabetes and a high-cholesterol atherogenic diet, exacerbate ozone-induced metabolic effects. Rats were fed a normal control diet (ND) or high-cholesterol diet (HCD) for 12 weeks and then exposed to filtered air or 1.0-ppm ozone (6 h/day) for 1 or 2 days. Metabolic responses were analyzed at the end of each day and after an 18-h recovery period following the 2-day exposure. In GK rats, baseline hyperglycemia and glucose intolerance were exacerbated by HCD vs. ND and by ozone vs. air. HCD also resulted in higher insulin in ozone-exposed GK rats and circulating lipase, aspartate transaminase, and alanine transaminase in all groups (Wistar>GK). Histopathological effects induced by HCD in the liver, which included macrovesicular vacuolation and hepatocellular necrosis, were more severe in Wistar vs. GK rats. Liver gene expression in Wistar and GK rats fed ND showed numerous strain differences, including evidence of increased lipid metabolizing activity and ozone-induced alterations in glucose and lipid transporters, specifically in GK rats. Collectively, these findings indicate that peripheral metabolic alterations induced by diabetes and high-cholesterol diet can enhance susceptibility to the metabolic effects of inhaled pollutants.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Poluentes Atmosféricos/toxicidade , Colesterol na Dieta/toxicidade , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ozônio/toxicidade , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Composição Corporal/efeitos dos fármacos , Colesterol na Dieta/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Exposição por Inalação , Insulina/sangue , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos Wistar , Especificidade da Espécie
8.
Nat Metab ; 3(1): 59-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33462514

RESUMO

Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr-/- or Apoe-/- mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12α-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4α, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis.


Assuntos
Fator 3 Ativador da Transcrição/fisiologia , Aterosclerose/prevenção & controle , Ácidos e Sais Biliares/metabolismo , Hepatócitos/metabolismo , Lipoproteínas HDL/metabolismo , Animais , Apolipoproteínas E/genética , Colesterol na Dieta/metabolismo , Gorduras na Dieta/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Hidrocortisona/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/genética , Receptores Depuradores Classe B/metabolismo , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
9.
Food Funct ; 11(7): 6091-6103, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32568327

RESUMO

Ursolic acid (UA) is a triterpenoid acid widely abundant in fruits and vegetables such as apple, blueberry and cranberry. The present study was carried out to investigate the effect of UA supplementation in diet on blood cholesterol, intestinal cholesterol absorption and gut microbiota in hypercholesterolemic hamsters. A total of thirty-two hamsters were randomly assigned to four groups and given a non-cholesterol diet (NCD), a high-cholesterol diet containing 0.1% cholesterol (HCD), an HCD diet containing 0.2% UA (UAL), or an HCD diet containing 0.4% UA (UAH) for 6 weeks. Results showed that UA supplementation reduced plasma cholesterol by 15-16% and inhibited intestinal cholesterol absorption by 2.6-9.2%. The in vitro micellar cholesterol solubility experiment clearly demonstrated that UA could displace 40% cholesterol from micelles. In addition, UA decreased the ratio of Firmicutes to Bacteroidetes, whereas it enhanced the growth of short chain fatty acid (SCFA)-producing bacteria in the intestine. In conclusion, UA possessed a cholesterol-lowering activity and could favorably modulate the gut microbiota.


Assuntos
Bactérias/efeitos dos fármacos , Colesterol na Dieta/metabolismo , Suplementos Nutricionais , Microbioma Gastrointestinal/efeitos dos fármacos , Hipercolesterolemia/tratamento farmacológico , Absorção Intestinal/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Bacteroidetes/efeitos dos fármacos , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/sangue , Cricetinae , Dieta , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos Voláteis/metabolismo , Firmicutes/efeitos dos fármacos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Masculino , Mesocricetus , Micelas , Distribuição Aleatória , Solubilidade , Triterpenos/uso terapêutico
11.
Cell Biochem Funct ; 38(3): 309-318, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31926118

RESUMO

The aim is to test the hypothesis whether the cholesterol loaded lysosomes are capable of mediating lysosomal membrane permeabilization (LMP) during aging and to study the efficacy of epigallocatechin-3-gallate (EGCG) in preserving the lysosomal membrane stability. Aged rats were fed with high cholesterol diet (HCD) and treated with EGCG orally. Serum and tissue lipid status, cholesterol levels in lysosomal fraction, activities of lysosomal enzymes in lysosomal, and cytosolic fractions were measured. Transmission electron microscopic studies (TEM), oil red "O" (ORO) staining, and immunohistochemical analysis of oxidized low density lipoprotein (OxLDL) were carried out. Significant increase in serum, tissue lipid profile, and lysosomal cholesterol levels were observed in aged HCD-fed rats with a concomitant decrease in high density lipoprotein (HDL) levels. We also observed a significant increase in lipid accumulation in hepatocytes of aged HCD-fed rats by TEM, ORO, and immunohistochemical staining. Upon treatment with EGCG to aged HCD-fed animals, we found augmented levels of HDL with a concomitant decrease in lysosomal cholesterol levels and other lipoproteins. TEM studies and immunohistochemistry of OxLDL also showed a marked reduction in lipid deposition of hepatocytes. Thus, EGCG has preserved the lysosomal membrane stability in HCD stressed aged rats. SIGNIFICANCE OF THE STUDY: The research article is focused mainly on the effect of EGCG and its capability on mitigating the release of lysosomal enzymes in aged animals fed with HCD. The study signifies the cellular function of the organelle lysosome following administration of aged rats with HCD, which would make the readers to understand the action of EGCG and the interrelationship of both cholesterol and activity of lysosomes when cholesterol is loaded.


Assuntos
Catequina/análogos & derivados , Colesterol na Dieta/metabolismo , Fígado/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Envelhecimento , Animais , Antioxidantes/química , Catequina/farmacologia , Citosol/metabolismo , Suplementos Nutricionais , Hepatócitos/efeitos dos fármacos , Imuno-Histoquímica , Lipídeos/química , Lipoproteínas LDL/química , Lisossomos/enzimologia , Masculino , Microscopia Eletrônica de Transmissão , Estresse Oxidativo , Oxigênio/química , Ratos , Ratos Wistar
12.
J Atheroscler Thromb ; 27(5): 409-417, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484845

RESUMO

AIMS: The present study was conducted to establish a practical method for measuring non-cholesterol sterols and reference intervals of serum levels. METHODS: Healthy subjects (109 men and 151 women), four patients with sitosterolemia, and 10 heterozygous mutation carriers of ABCG5/ABCG8 genes were investigated. Then, three non-cholesterol sterols (sitosterol, campesterol, and lathosterol) of fasting serum samples were measured via a practical and highly sensitive gas chromatography (GC) method with 0.2 µg/mL as the lower limit of quantification. The coefficient of variation (CV) values for within-run reproducibility were 3.06%, 1.89%, and 1.77% for lathosterol, campesterol, and sitosterol, respectively. The CV values for between-run reproducibility were 2.81%, 2.06%, and 2.10% for lathosterol, campesterol, and sitosterol, respectively. RESULTS: The serum levels of sitosterol and campesterol were significantly higher in women than in men, whereas the serum levels of lathosterol were significantly higher in men than in women. Because of these gender difference, the determination of reference intervals of the three sterol values was performed by considering gender. The reference intervals of sitosterol, campesterol, and lathosterol were 0.99-3.88, 2.14-7.43, and 0.77-3.60 µg/mL in men and 1.03-4.45, 2.19-8.34, and 0.64-2.78 µg/mL in women, respectively. The serum levels of sitosterol and campesterol were higher in patients with sitosterolemia (94.3±47.3 and 66.3±36.6 µg/mL, respectively) than in healthy subjects. CONCLUSION: These results demonstrate a practical and highly sensitive GC method to measure non-cholesterol sterol levels and gender-segregated reference intervals of sitosterol, campesterol, and lathosterol in Japanese healthy subjects.


Assuntos
Colesterol na Dieta/metabolismo , Colesterol/análogos & derivados , Cromatografia Gasosa , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis/efeitos adversos , Sitosteroides/sangue , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Colesterol/sangue , Cromatografia Gasosa/métodos , Cromatografia Gasosa/normas , Feminino , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/genética , Hipercolesterolemia/terapia , Enteropatias/diagnóstico , Enteropatias/epidemiologia , Enteropatias/genética , Enteropatias/terapia , Japão/epidemiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/epidemiologia , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/terapia , Lipoproteínas/genética , Masculino , Pessoa de Meia-Idade , Fitosteróis/sangue , Fitosteróis/genética , Valores de Referência , Reprodutibilidade dos Testes , Fatores Sexuais
13.
Oxid Med Cell Longev ; 2019: 4521786, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885793

RESUMO

Lipid metabolic disorders due to poor eating habits are on the rise in both developed and developing countries, with a negative impact of the "Western diet" on sperm count and quality. Dietary lipid imbalance can involve cholesterol, fatty acids, or both, under different pathophysiological conditions grouped under the term dyslipidemia. The general feature of dyslipidemia is the development of systemic oxidative stress, a well-known deleterious factor for the quality of male gametes and associated with infertility. Sperm are particularly rich in polyunsaturated fatty acids (PUFA), an important characteristic associated with normal sperm physiology and reproductive outcomes, but also targets of choice for oxidative thrust. This review focuses on the effects of dietary cholesterol or different fatty acid overload on sperm composition and function in both animals and humans. The links between oxidative stress induced by dyslipidemia and sperm dysfunction are then discussed, including possible preventive or therapeutic strategies to preserve gamete quality, longevity when stored in cryobanking, and male fertility.


Assuntos
Colesterol na Dieta/metabolismo , Fertilidade/fisiologia , Lipídeos/fisiologia , Estresse Oxidativo/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Masculino
14.
Sci Rep ; 9(1): 12514, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467308

RESUMO

Precise molecular pathways involved in the progression of non-alcoholic steatohepatitis (NASH) remain to be elucidated. As Mallory-Denk bodies were occasionally observed in the enlarged hepatocytes in NASH model rat (SHRSP5/Dmcr) fed high-fat and high-cholesterol (HFC) diet, we aimed to clarify the roles of autophagy and endoplasmic reticulum (ER) stress in NASH progression. Male SHRSP5/Dmcr were randomly divided into 4 groups. Two groups were fed a control diet; the other two groups were fed a HFC diet for 2 and 8 weeks, respectively. The HFC diet increased the autophagy-related proteins levels and microtubule-associated protein 1 light chain 3-II/I ratio after 2 and 8 weeks, respectively. However, regarding ER stress-related proteins, the HFC diet decreased the levels of phosphorylated (p-) inositol-requiring kinase-1 (p-IRE-1) and p-protein kinase RNA-like ER kinase after 2 weeks. Additionally, the HFC diet increased anti-ubiquitin-positive cells and the level of the autophagy substrate p62, suggesting that the HFC diet induced dysfunction in ubiquitin-dependent protein degradation pathways. In conclusion, the HFC diet arrested the autophagy process in the liver; this was particularly associated with decreases in p-IRE-1 expression.


Assuntos
Autofagia , Colesterol na Dieta/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Endorribonucleases/metabolismo , Fígado/fisiopatologia , Complexos Multienzimáticos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , /metabolismo , Animais , Colesterol na Dieta/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Endorribonucleases/genética , Humanos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Complexos Multienzimáticos/genética , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Fosforilação , Ratos
15.
J Sci Food Agric ; 99(15): 6954-6961, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414497

RESUMO

BACKGROUND: Fructose and cholesterol-rich diets have been implicated in the upsurge of metabolic syndrome (MetS). Phytochemicals are being explored as alternatives for the prevention and management of MetS. Thirty-six 21-day-old, female Sprague Dawley rats fed a high-fructose, high-cholesterol diet post-weaning were used to investigate the prophylactic potential of quercetin. Group 1 was given standard rat chow (SRC); Group 2: SRC and quercetin (75 mg kg-1 daily); Group 3: SRC and fenofibrate (100 mg kg-1 daily); Group 4 was given a high cholesterol diet (HCD) (2% added dietary cholesterol in SRC), 20% fructose drinking solution (FS); Group 5 was given HCD, 20% FS and quercetin (75 mg kg-1 daily); Group 6: HCD, 20% FS and fenofibrate (100 mg kg-1 daily). Rats were fed ad libitum for 8 weeks, euthanized, and blood and liver samples were collected. RESULTS: The HCD and FS significantly increased (P < 0.05) absolute and relative liver masses and serum cholesterol. Fasting blood glucose, serum triglycerides, alanine transaminase, creatinine, and urea were not significantly different (P > 0.05) between groups. The HCD and FS significantly increased liver lipid yield compared to the SRC and rats receiving SRC with fenofibrate (P < 0.05). Quercetin or fenofibrate together with HCD and FS attenuated the diet-induced increase in liver lipids by approximately 50%, although this was not statistically significant. Liver macro- and micro-steatosis scores were significantly increased (P < 0.05) in rats receiving HCD and FS. Quercetin or fenofibrate administration together with HCD and FS significantly decreased (P < 0.05) liver macro-steatosis scores. CONCLUSION: The prophylactic effect of quercetin on fructose and cholesterol diet-induced liver lipid accumulation may be exploited in the fight against non-alcoholic fatty liver disease (NAFLD). © 2019 Society of Chemical Industry.


Assuntos
Colesterol na Dieta/efeitos adversos , Frutose/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Quercetina/administração & dosagem , Animais , Colesterol/sangue , Colesterol na Dieta/metabolismo , Feminino , Frutose/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue , Desmame
16.
World J Gastroenterol ; 25(20): 2450-2462, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31171889

RESUMO

BACKGROUND: Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM: To determine the effect of TMAO on the progression of NASH. METHODS: A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS: Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAO-treated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influx-related Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION: These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.


Assuntos
Fígado/efeitos dos fármacos , Metilaminas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Administração Oral , Animais , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
17.
Nutr Res ; 64: 64-71, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30802724

RESUMO

We hypothesized that schizandrin (SCH) A, a lignan found in the fruits of the Schisandra genus, would exert protective effects against high-fat and high-cholesterol (HFHC) diet-induced nonalcoholic fatty liver disease (NAFLD) via regulation of lipid metabolism and oxidative stress. To test our hypothesis, male C57BL/6J mice were fed an HFHC diet with or without SCH A for 15 weeks. There were no significant differences in food intake, body weight, fat mass, and plasma total cholesterol level between the 2 groups. However, supplementation of SCH A significantly decreased levels of plasma free fatty acid and triglyceride, whereas plasma high-density lipoprotein cholesterol level was increased in the SCH A-supplemented mice. Moreover, hepatic free fatty acid, triglyceride, and cholesterol content, as well as hepatic lipid droplet accumulation, were markedly lower in the SCH A group in contrast to the control group. Activity of hepatic enzymes involved in fatty acid and triglyceride synthesis was significantly decreased by SCH A supplementation, whereas SCH A markedly increased hepatic ß-oxidation and fatty acid oxidation-related gene expression as well as fecal excretion of free fatty acid and triglyceride. SCH A also significantly increased expression of genes involved in cholesterol homeostasis (biliary cholesterol excretion and cholesterol efflux to high-density lipoprotein) in the liver. Moreover, SCH A significantly decreased hepatic lipid peroxidation, which was accompanied by increased hepatic antioxidant enzymes activity. These results suggest that SCH A could alleviate HFHC diet-induced NAFLD by regulating hepatic lipid metabolism and oxidative stress as well as fecal lipid excretion.


Assuntos
Colesterol na Dieta/metabolismo , Ciclo-Octanos/uso terapêutico , Lignanas/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Compostos Policíclicos/uso terapêutico , Schisandra/química , Animais , Antioxidantes/metabolismo , Colesterol/sangue , Colesterol/metabolismo , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/sangue , HDL-Colesterol/sangue , Ciclo-Octanos/farmacologia , Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/metabolismo , Suplementos Nutricionais , Ácidos Graxos/metabolismo , Ácidos Graxos não Esterificados/sangue , Fezes/química , Lignanas/farmacologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Compostos Policíclicos/farmacologia , Triglicerídeos/sangue
18.
Nutrients ; 11(2)2019 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-30744113

RESUMO

Mechanisms to explain post-prandial increases in circulating glucocorticoids are not well understood and may involve increased adrenal secretion and/or altered steroid metabolism. We have compared salivary levels of cortisol and cortisone levels in healthy male and female volunteers fed either a low or cholesterol-rich midday meal. Urinary levels of steroids, bile acids and markers of lipid peroxidation were also measured. Males and females showed expected circadian changes in salivary steroids and postprandial peaks within 1h of feeding. After a high-cholesterol meal, postprandial cortisol increases were higher in males whereas post-prandial cortisone levels were higher in females. Urinary cortisol but not cortisone levels were higher on the day when males and females ate a high-cholesterol meal. Urinary bile acid excretion and anti-oxidant markers of lipid peroxidation, thiobarbituric acid reactive substances (TBARS), and total phenol content were not affected by dietary cholesterol but tended to be higher in males. Cross-tabulation of correlation coefficients indicated positive associations between urinary markers of peroxidation, bile acids, and cortisol:cortisone ratios. We conclude that dietary cholesterol (a substrate for steroidogenesis) does not have an acute effect on adrenal glucocorticoid synthesis and that gender but not a high-cholesterol meal may influence the interconversion of cortisol and cortisone. Longer term studies of the effects of dietary cholesterol are needed to analyze the associations between bile acids, steroid metabolism, and secretion and lipid peroxidation.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colesterol na Dieta/metabolismo , Glucocorticoides/análise , Período Pós-Prandial/fisiologia , Saliva/química , Adulto , Ácidos e Sais Biliares/urina , Colesterol na Dieta/administração & dosagem , Estudos Cross-Over , Dieta/estatística & dados numéricos , Feminino , Humanos , Masculino , Adulto Jovem
19.
Am J Physiol Gastrointest Liver Physiol ; 316(3): G350-G365, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629468

RESUMO

Difficulty in imaging the vertebrate intestine in vivo has hindered our ability to model nutrient and protein trafficking from both the lumenal and basolateral aspects of enterocytes. Our goal was to use live confocal imaging to increase understanding of intestinal trafficking of dietary cholesterol and apolipoprotein A-I (APOA-I), the main structural component of high-density lipoproteins. We developed a novel assay to visualize live dietary cholesterol trafficking in the zebrafish intestine by feeding TopFluor-cholesterol (TF-cholesterol), a fluorescent cholesterol analog, in a lipid-rich, chicken egg yolk feed. Quantitative microscopy of transgenic zebrafish expressing fluorescently tagged protein markers of early, recycling, and late endosomes/lysosomes provided the first evidence, to our knowledge, of cholesterol transport in the intestinal endosomal-lysosomal trafficking system. To study APOA-I dynamics, transgenic zebrafish expressing an APOA-I fluorescent fusion protein (APOA-I-mCherry) from tissue-specific promoters were created. These zebrafish demonstrated that APOA-I-mCherry derived from the intestine accumulated in the liver and vice versa. Additionally, intracellular APOA-I-mCherry localized to endosomes and lysosomes in the intestine and liver. Moreover, live imaging demonstrated that APOA-I-mCherry colocalized with dietary TF-cholesterol in enterocytes, and this colocalization increased with feeding time. This study provides a new set of tools for the study of cellular lipid biology and elucidates a key role for endosomal-lysosomal trafficking of intestinal cholesterol and APOA-I. NEW & NOTEWORTHY A fluorescent cholesterol analog was fed to live, translucent larval zebrafish to visualize intracellular cholesterol and apolipoprotein A-I (APOA-I) trafficking. With this model intestinal endosomal-lysosomal cholesterol trafficking was observed for the first time. A new APOA-I fusion protein (APOA-I-mCherry) expressed from tissue-specific promoters was secreted into the circulation and revealed that liver-derived APOA-I-mCherry accumulates in the intestine and vice versa. Intestinal, intracellular APOA-I-mCherry was observed in endosomes and lysosomes and colocalized with dietary cholesterol.


Assuntos
Apolipoproteína A-I/efeitos adversos , Colesterol na Dieta/metabolismo , Endossomos/metabolismo , Lisossomos/metabolismo , Animais , Transporte Biológico/fisiologia , Colesterol/metabolismo , Enterócitos/metabolismo , Intestinos/fisiologia , Lipoproteínas HDL/metabolismo , Transporte Proteico/fisiologia , Peixe-Zebra
20.
Lipids Health Dis ; 18(1): 3, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611265

RESUMO

BACKGROUND: The loss of muscle mass and concomitantly strength, poses a serious risk to the elderly and to astronauts. Dietary cholesterol (CL), in conjunction with resistance training (RT), has been strongly associated with improvements in lean mass. The purpose of this study was to examine the effects of two opposing environments on rat skeletal muscle: (1) hindlimb unloading and (2) CL and RT. METHODS: In protocol 1, 13 male Sprague-Dawley rats were unloaded for 28 days (HU; n = 6) or served as cage controls (CC; n = 7). In protocol 2, 42 rats were assigned to 1 of 6 groups: CC (n = 7), CC + CL (n = 4), RT controls (RTC; n = 7), RTC + CL (n = 8), RT (n = 8) and RT + CL (n = 8). RT/RTC consisted of squat-like exercise. RT had weights added progressively from 80 to 410 g over 5 weeks. CL was supplemented in the chow with either 180 ppm (controls) or 1800 ppm (CL). Lower limb muscles were harvested at the end of both protocols and analyzed by Western Blotting for sterol regulatory element-binding protein-2 (SREBP-2) and low-density lipoprotein-receptor (LDL-R) and protein synthesis. RESULTS: Gastrocnemius and plantaris masses and their body mass ratios were significantly lower in the HU rats than control rats. The RT rats gained significantly less body and lean mass than the RTC groups, but the plantar flexor muscles did not show any significant differences among groups. Moreover, RT groups had significantly higher plantaris mixed muscle fractional synthesis rate (FSR) than the RTC and CC animals, with the CL groups showing greater FSR than control rats. No significant differences among groups in SREBP-2 or LDL-R were observed in either protocol. CONCLUSIONS: These studies provide evidence for a relationship between skeletal muscle and cholesterol metabolism, but the exact nature of that association remains unclear.


Assuntos
Colesterol na Dieta/metabolismo , Elevação dos Membros Posteriores , Músculo Esquelético/efeitos dos fármacos , Condicionamento Físico Animal/fisiologia , Treinamento de Força/métodos , Animais , Colesterol na Dieta/administração & dosagem , Expressão Gênica , Masculino , Músculo Esquelético/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
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