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1.
Medicine (Baltimore) ; 99(35): e21739, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871893

RESUMO

RATIONALE: Anorexia nervosa (AN) is a serious eating disorder associated with a distorted body image. Hypercholesterolemia has been found in patients with AN but the mechanism of hyperlipidemia in AN remains little known. Ascites in patients with AN has been attributed to hypoalbuminemia and liver diseases, but massive ascites without the aforementioned etiologies has never been reported in AN. PATIENT CONCERNS: An 11-year-old girl was admitted for exclusion of organic underlying diseases due to severe body weight loss (18% within 3 weeks), poor appetite, and hypercholesterolemia (274 mg/dL). She complained of heartburn sensation, nausea, vomiting, constipation, and postprandial dull abdominal pain with fullness. DIAGNOSES: The patient's condition met with all 3 of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for diagnosing AN. On admission, her total cholesterol level was 337 mg/dL and hypocomplementemia (C3 55.5 mg/dL) was also found. Abdominal sonography and computed tomography scans showed massive ascites. However, neither proteinuria nor hypoalbuminemia was found. Upper gastroduodenal endoscopy showed chronic superficial gastritis and colonoscopy revealed negative findings. Ascites obtained by paracentesis demonstrated a transudate without bacterial infection, tuberculosis, or pancreatitis. Exploratory laparoscopy showed nonpurulent ascites. However, biopsies from the small intestine, mesentery, and liver showed chronic inflammation and fibrosis. INTERVENTIONS: The intensive nutritional therapy by increasing total energy intake stepwise with a combination of high-energy formula and her favorite foods. OUTCOMES: Her hypercholesterolemia, hypocomplementemia, and massive ascites resolved after her weight was restored. She developed binge eating with continuous weight gain after discharge. Her weight significantly increased to an obese level (body mass index [BMI] 25.9 kg/m) after loss to follow-up for 4 years until she returned to our emergency room due to suicide attempt. CONCLUSION: Diagnostic crossover between subtypes in anorexia nervosa might be a potential risk factor for illness severity and poor prognosis. AN can manifest as massive ascites with normal albumin concentrations that could possibly be due to chronic inflammation of the intestinal serosa, mesentery, and peritoneal surface of the liver.


Assuntos
Anorexia Nervosa/complicações , Anorexia Nervosa/diagnóstico , Ascite/etiologia , Hipercolesterolemia/etiologia , Adolescente , Anorexia Nervosa/sangue , Anorexia Nervosa/psicologia , Transtorno da Compulsão Alimentar/etiologia , Criança , Complemento C3/metabolismo , Feminino , Humanos , Perda de Peso
2.
Artigo em Inglês | MEDLINE | ID: mdl-32872631

RESUMO

(1) Background: Statin is the mainstay of treatment for the primary prevention of atherosclerotic cardiocerebrovascular diseases (CCVDs) in adults with hypercholesterolemia. This study aims to investigate the differences in effect on primary composite outcomes (CCVDs and CCVD-related deaths) among five statins in hypercholesterolemic individuals. (2) Methods: This retrospective study is based on the Korean National Health Insurance Service-National Health Screening Cohort. Participants, aged 40 to 69 years at baseline, were categorized into five statin-treated groups (pitavastatin, atorvastatin, rosuvastatin, simvastatin, and pravastatin) and two untreated groups (untreated hypercholesterolemia and no hypercholesterolemia). (3) Results: A total of 161,583 individuals was included. The median follow-up period was 8.2 years. Compared with the pitavastatin group, the hazard ratios (HRs; 95% confidence intervals (CIs)) for CCVDs and CCVD-related deaths of the atorvastatin, rosuvastatin, simvastatin, pravastatin, untreated hypercholesterolemia, and no-hypercholesterolemia groups were 0.969 (0.567-1.657), 0.988 (0.533-1.832), 0.862 (0.490-1.518), 0.906 (0.326-2.515), 2.665 (1.556-4.562), and 0.656 (0.388-1.110), respectively, in men and 1.124 (0.632-1.999), 1.119 (0.582-2.152), 1.324 (0.730-2.400), 1.023 (0.330-3.171), 2.650 (1.476-4.758), and 0.921 (0.522-1.625), respectively, in women, after being fully adjusted. (4) Conclusions: No significant differences among the five statins were observed, but there was an increased risk in untreated hypercholesterolemic individuals, for CCVDs and CCVDs-related deaths in individuals with hypercholesterolemia of either sex.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Transtornos Cerebrovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Adulto , Idoso , Atorvastatina/uso terapêutico , Doenças Cardiovasculares/mortalidade , Transtornos Cerebrovasculares/etiologia , Transtornos Cerebrovasculares/mortalidade , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Masculino , Pessoa de Meia-Idade , Pravastatina/uso terapêutico , Prevenção Primária , Pirróis , Quinolinas/uso terapêutico , Estudos Retrospectivos , Rosuvastatina Cálcica/uso terapêutico , Sinvastatina/uso terapêutico
3.
Nat Commun ; 11(1): 3612, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681035

RESUMO

Bile acid synthesis plays a key role in regulating whole body cholesterol homeostasis. Transcriptional factor EB (TFEB) is a nutrient and stress-sensing transcriptional factor that promotes lysosomal biogenesis. Here we report a role of TFEB in regulating hepatic bile acid synthesis. We show that TFEB induces cholesterol 7α-hydroxylase (CYP7A1) in human hepatocytes and mouse livers and prevents hepatic cholesterol accumulation and hypercholesterolemia in Western diet-fed mice. Furthermore, we find that cholesterol-induced lysosomal stress feed-forward activates TFEB via promoting TFEB nuclear translocation, while bile acid-induced fibroblast growth factor 19 (FGF19), acting via mTOR/ERK signaling and TFEB phosphorylation, feedback inhibits TFEB nuclear translocation in hepatocytes. Consistently, blocking intestinal bile acid uptake by an apical sodium-bile acid transporter (ASBT) inhibitor decreases ileal FGF15, enhances hepatic TFEB nuclear localization and improves cholesterol homeostasis in Western diet-fed mice. This study has identified a TFEB-mediated gut-liver signaling axis that regulates hepatic cholesterol and bile acid homeostasis.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Ácidos e Sais Biliares/metabolismo , Colesterol/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/antagonistas & inibidores , Linhagem Celular , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Células Hep G2 , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/prevenção & controle , Íleo/efeitos dos fármacos , Íleo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores
4.
Toxicol Appl Pharmacol ; 395: 114979, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234517

RESUMO

Epidemiology suggests that adverse environmental exposure during pregnancy may predispose children to hypercholesterolemia in adulthood. This study aimed to demonstrate hypercholesterolemia induced by prenatal dexamethasone exposure (PDE) in adult male offspring rats and explore the intrauterine programming mechanisms. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0, 0.1, 0.2, and 0.4 mg/kg∙d) from gestational days (GD) 9 to 21, and the serum and liver of the male offsprings were collected at GD21, postnatal week (PW) 12 and 28. Furthermore, the effects of dexamethasone on the expression of low-density lipoprotein receptor (LDLR) and its epigenetic mechanism was confirmed in the bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and continuous hepatocyte line. PDE could reduce the birth weight of male offsprings, increase the serum total cholesterol (TCH) level in adult rats, and decrease the liver low-density lipoprotein receptor (LDLR) expression. Serum TCH level and liver LDLR expression were decreased in PDE male fetuses in utero (GD21). Moreover, PDE increased the translocation of the glucocorticoid receptor (GR) in the fetal liver, the expression of DiGeorge syndrome critical region 8 gene (DGCR8), the pre- and post-natal expression of miR-148a. The results of PDE offspring in vivo and in vitro exhibited similar changes. These changes could be reversed by overexpressing LDLR, inhibiting miR-148a or GR. PDE caused hypercholesterolemia in male adult offspring rats, which was mediated via dexamethasone activated intrauterine hepatic GR, enhanced the expression of DGCR8 and miR-148a, thereby reducing the expression of LDLR, leading to impaired liver cholesterol reverse transport function, and finally causing hypercholesterolemia in adult rats.


Assuntos
Dexametasona/efeitos adversos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , MicroRNAs/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Receptores de LDL/fisiologia , Animais , Dexametasona/administração & dosagem , Epigênese Genética/efeitos dos fármacos , Feminino , Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Fígado/química , Fígado/embriologia , Fígado/metabolismo , Masculino , MicroRNAs/genética , Gravidez , Ratos , Ratos Wistar , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Glucocorticoides/fisiologia , Receptores de LDL/genética
5.
PLoS One ; 15(3): e0229669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163433

RESUMO

Exogenously hypercholesterolemic (ExHC) rats develop diet-induced hypercholesterolemia (DIHC) when fed with dietary cholesterol. Previously, we reported that, under the high-sucrose-diet-feeding condition, a loss-of-function mutation in Smek2 results in low activity of fatty acid synthase (FAS) followed by the shortage of hepatic triacylglycerol content in ExHC rats and the onset of DIHC. However, the relationship between the Smek2 mutation and FAS dysfunction is still unclear. Here, we focused on carbohydrate metabolism, which provides substrates for FAS, and analyzed carbohydrate and lipid metabolisms in ExHC rats to clarify how the deficit of Smek2 causes DIHC. Male ExHC and SD rats were fed high-sucrose or high-starch diets containing 1% cholesterol for 2 weeks. Serum cholesterol levels of the ExHC rats were higher, regardless of the dietary carbohydrate. Hepatic triacylglycerol levels were higher in only the SD rats fed the high-sucrose diet. Moreover, the ExHC rats exhibited a diabetes-like status and accumulation of hepatic glycogen and low hepatic mRNA levels of liver-type phosphofructokinase (Pfkl), which encodes a rate-limiting enzyme for glycolysis. These results suggest that the glucose utilization, particularly glycolysis, is impaired in the liver of ExHC rats. To evaluate how the diet with extremely low glucose affect to DIHC, ExHC.BN-Dihc2BN, a congenic strain that does not develop DIHC, and ExHC rats were fed a high-fructose diet containing 1% cholesterol for 2 weeks. The serum cholesterol and hepatic triacylglycerol levels were similar in the strains. Results of water-soluble metabolite analysis with primary hepatocytes, an increase in fructose-6-phosphate and decreases in succinate, malate and aspartate in ExHC rats, support impaired glycolysis in the ExHC rats. Thus, the Smek2 mutation causes abnormal hepatic glucose utilization via downregulation of Pfkl expression. This abnormal glucose metabolism disrupts hepatic fatty acid synthesis and causes DIHC in the ExHC rats.


Assuntos
Glucose/metabolismo , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Animais , Animais Congênicos , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Modelos Animais de Doenças , Regulação para Baixo , Ácido Graxo Sintase Tipo I/metabolismo , Glicólise/genética , Hipercolesterolemia/genética , Mutação com Perda de Função , Masculino , Fosfofrutoquinases/genética , Fosfofrutoquinases/metabolismo , Fosfoproteínas Fosfatases/deficiência , Fosfoproteínas Fosfatases/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley
6.
Life Sci ; 250: 117514, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145306

RESUMO

AIMS: Pigs are increasingly used as human metabolic disease models; however, there is insufficient research on breed-related genetic background differences. This study aimed to investigate the differential metabolic responses to high-fat and high-cholesterol (HFC) diet-induced non-alcoholic fatty liver disease (NAFLD) of two miniature pig breeds and explore the molecular mechanisms involved. MAIN METHODS: Male Wuzhishan (WZSP) and Tibetan pigs (TP) were randomly fed either a standard or an HFC diet for 24 weeks. Weight, serum lipids, bile acid, insulin resistance, liver function, liver histology, and hepatic lipid deposition were determined. RNA-Seq was used to detect the hepatic gene expression profiles. Western blot, immunohistochemistry, and qRT-PCR were used to detect the lipid and glucose metabolism-related gene expressions. KEY FINDINGS: The HFC diet caused obesity, hypertension, severe hypercholesterolemia, liver injury, increased hepatocellular steatosis and inflammation, and significantly increased serum insulin levels in both pig breeds. This diet led to higher serum and hepatic cholesterol level concentrations in WZSP and elevated fasting glucose levels in TP. Transcriptome analysis revealed that the genes controlling hepatic cholesterol metabolism and the inflammatory response were consistently regulated; lipid metabolism and insulin signaling related genes were uniquely regulated by the HFC diet in the WZSP and TP, respectively. SIGNIFICANCE: Our study demonstrated that the genetic background affects profoundly pigs' metabolic and hepatic responses to an HFC diet. These results deepened our understanding of the molecular mechanisms of HFC diet-induced NAFLD and provided a foundation for selecting the appropriate pig breeds for metabolic studies in the future.


Assuntos
Ração Animal , Colesterol na Dieta , Dieta Hiperlipídica , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transcriptoma , Animais , Glicemia/análise , Colesterol/metabolismo , Modelos Animais de Doenças , Biblioteca Gênica , Hipercolesterolemia/etiologia , Hiperlipidemias/etiologia , Hipertensão/etiologia , Inflamação/etiologia , Insulina/metabolismo , Fígado/metabolismo , Hepatopatias/etiologia , Masculino , Obesidade/etiologia , Fenótipo , Distribuição Aleatória , Especificidade da Espécie , Suínos , Porco Miniatura
7.
PLoS One ; 15(2): e0219412, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32106257

RESUMO

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. METHODS: Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. RESULTS: Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism-related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. CONCLUSIONS: Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.


Assuntos
Hipercolesterolemia/sangue , MicroRNAs/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Hipercolesterolemia/etiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/complicações , Regulação para Cima
8.
Arch Physiol Biochem ; 126(1): 23-30, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30032654

RESUMO

We study the effect of an enriched cholesterol-methionine diet administered to females on the cardiac tissue remodelling of the offspring during two successive pregnancies. Two groups are constituted, standard diet (SD) group fed a standard diet and CD group fed a combined diet (standard + cholesterol 1%-methionine 0.25%). The diet is administered during 80 days. The results show changes in serum and cardiac parameters of CD newborn, with the involvement of phospholipids (PLs) (phosphatidylethanolamine (PE) and phosphatidylcholine (PC), variations in malondialdehyde (MDA), conjugated diene (CD), and vitamin C [VIT-C] rates). Under the CD effect, serum matrix metalloproteinase (MMP)-2, pro-MMP-9, and MMP-9 activities change. As to cardiac MMP-2 activity, a rise is noticed in the second pregnancy. Histological analysis reveals constricted blood capillaries, collagen fibre deposits, and lipid accumulation in the CD newborn heart. Our study shows the amplified effect of the maternal cholesterol-methionine diet in the second pregnancy on newborn cardiac disorders (matrix remodelling, oxidative stress, and lipid accumulation).


Assuntos
Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hipercolesterolemia/metabolismo , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/sangue , Metionina/deficiência , Animais , Animais Recém-Nascidos , Ácido Ascórbico/metabolismo , Colesterol/administração & dosagem , Feminino , Glutationa/metabolismo , Hipercolesterolemia/etiologia , Peroxidação de Lipídeos , Malondialdeído/metabolismo , Metionina/administração & dosagem , Miocárdio/metabolismo , Estresse Oxidativo , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Gravidez , Coelhos
9.
Lipids Health Dis ; 18(1): 226, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870448

RESUMO

BACKGROUND: Endothelial lipase (EL) plays an important role in lipoprotein metabolism and atherosclerosis. To study the functional roles of EL, we recently generated transgenic (Tg) rabbits and reported that increased hepatic expression of EL in male Tg rabbits significantly reduced diet-induced hypercholesterolemia compared with non-Tg controls. This gender difference suggests that sex hormones may mediate EL functions thereby influencing lipoprotein metabolism. To examine this hypothesis, we compared the effects of orchiectomy and ovariectomy on plasma lipids and diet-induced atherosclerosis in both Tg and non-Tg rabbits. METHODS: Male rabbits were under orchiectomy whereas female rabbits were under ovariectomy. We compared plasma lipids, lipoproteins, and apolipoproteins of rabbits before and after surgery in each group fed either a chow diet or cholesterol-rich diet. RESULTS: On a chow diet, both male and female Tg rabbits showed lower plasma lipids than non-Tg counterparts and this lipid-lowering effect of EL was not affected by either orchiectomy in male or ovariectomy in female Tg rabbits. On a cholesterol diet; however, male Tg rabbits but not female Tg rabbits showed significant resistance to diet-induced hypercholesterolemia and atherosclerosis. The EL-mediated atheroprotective effect was eliminated after orchiectomy in male Tg rabbits. Female Tg rabbits showed similar levels of total cholesterol and lesion size of atherosclerosis compared with non-Tg rabbits and ovariectomy did not affect diet-induced hypercholesterolemia or atherosclerosis. CONCLUSION: These results suggest that increased EL protects against diet-induced hypercholesterolemia and atherosclerosis. The beneficial effect of EL was dependent upon the presence of androgenic hormones.


Assuntos
Aterosclerose/sangue , Hormônios Esteroides Gonadais/genética , Hipercolesterolemia/sangue , Lipase/genética , Animais , Animais Geneticamente Modificados/sangue , Animais Geneticamente Modificados/genética , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas/sangue , Aterosclerose/genética , Aterosclerose/patologia , Dieta/efeitos adversos , Células Endoteliais/enzimologia , Hormônios Esteroides Gonadais/metabolismo , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Lipase/sangue , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Lipoproteínas/sangue , Orquiectomia , Ovariectomia , Coelhos
10.
Int J Mol Sci ; 21(1)2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877743

RESUMO

The present study investigated and compared the effects of different molecular weights of chitosan (high molecular weight chitosan (HC) and low molecular weight chitosan (LC)) and its derivatives (chitosan oligosaccharide (CO)) on cholesterol regulation in high-fat (HF) diet-fed rats. A diet supplementation of 5% HC, 5% LC, or 5% CO for 8 weeks showed hypocholesterolemic potential in HF diet-fed rats. Unexpectedly, a 5% CO-supplemented diet exerted hepatic damage, producing increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-α). The supplementation of HC and LC, unlike CO, significantly decreased the hepatic total cholesterol (TC) levels and increased the fecal TC levels in HF diet-fed rats. The hepatic protein expression of the peroxisome proliferator-activated receptor-α (PPARα) in the HF diet-fed rats was markedly decreased, which could be significantly reversed by both HC and LC, but not CO, supplementation. Unlike the supplementation of CO, both HC and LC supplementation could effectively reverse the HF-inhibited/induced gene expressions of the low-density lipoprotein receptor (LDLR) and cholesterol 7α-hydroxylase (CYP7A1), respectively. The upregulated intestinal acyl-CoA cholesterol acyltransferase 2 (ACAT2) protein expression in HF diet-fed rats could be reversed by HC and LC, but not CO, supplementation. Taken together, a supplementation of 5% CO in HF diet-fed rats may exert liver damage via a higher hepatic cholesterol accumulation and a higher intestinal cholesterol uptake. Both HC and LC effectively ameliorated the hypercholesterolemia and regulated cholesterol homeostasis via the activation and inhibition of hepatic (AMPKα and PPARα) and intestinal (ACAT2) cholesterol-modulators, respectively, as well as the modulation of downstream signals (LDLR and CYP7A1).


Assuntos
Quitosana/farmacologia , Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Fígado/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/metabolismo , Quitosana/análogos & derivados , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta Hiperlipídica/efeitos adversos , Hipercolesterolemia/etiologia , Fígado/metabolismo , Masculino , PPAR alfa/metabolismo , Ratos , Ratos Sprague-Dawley , Esterol O-Aciltransferase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
11.
Acta Med Port ; 32(12): 760-766, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31851885

RESUMO

INTRODUCTION: Ketogenic diet is a low carbohydrate diet, which can be used as a treatment for refractory childhood epilepsy. The first aim of this study was to evaluate its efficacy, in patients receiving ketogenic diet for at least three months, on epilepsy control, behaviour and awareness. The secondary aims were to evaluate the variation in the number of antiepileptic drugs, reasons for discontinuing the diet and adverse effects. MATERIAL AND METHODS: Retrospective analysis of clinical records of patients who underwent ketogenic diet for refractory epilepsy, from October 2007 to January 2018, in a tertiary pediatric hospital. RESULTS: In the twenty-nine eligible patients, the mean age of initiation was 7.9 years-old (+/- 5.6). Of those, 18 had a ≥ 50% reduction of seizure activity, 19 a marked behaviour improvement and 18 improved awareness. The median number of antiepileptic drugs remained equal for the 15 patients who completed 18 months of treatment (three drugs). The main reason for discontinuing ketogenic diet was a familiar decision. The main adverse effects were hypercholesterolemia (n = 23) and hypertriglyceridemia (n = 21). DISCUSSION: Results were comparable to those of other cohorts, namely age of initiation, proportion of patients completing ketogenic diet, most frequent reasons for stopping and significant improvement of alertness and behavior. CONCLUSION: Beyond seizure control, patients experienced a marked improvement in behavior and awareness. It is necessary to develop strategies to increase the adherence of families to the diet.


Assuntos
Dieta Cetogênica , Epilepsia Resistente a Medicamentos/dietoterapia , Adolescente , Anticonvulsivantes/uso terapêutico , Conscientização , Comportamento , Criança , Pré-Escolar , Dieta Cetogênica/efeitos adversos , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Feminino , Humanos , Hipercolesterolemia/etiologia , Hipertrigliceridemia/etiologia , Lactente , Masculino , Portugal , Estudos Retrospectivos , Centros de Atenção Terciária , Resultado do Tratamento , Suspensão de Tratamento
12.
J Agric Food Chem ; 67(48): 13307-13317, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31679333

RESUMO

Epidemiological studies have demonstrated that hypercholesterolemia is associated with an elevated risk of atherosclerosis and cardiovascular diseases. In addition to the available cholesterol-lowering drugs, nutritionally balanced diets containing functional foods have attracted much interest as potential candidates to improve hypercholesterolemia. In the study, we demonstrated that dietary succinoglycan riclin effectively alleviated diet-induced hypercholesterolemia. Compared with the high-cholesterol-diet (HCD) group, the high-riclin group significantly decreased levels of the serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and hepatic cholesterol (34, 40, and 51%, respectively), consequently improving hepatic steatosis and reducing proinflammatory cytokine expressions. 1H nuclear magnetic resonance (NMR)-based lipidomics and metabolomics analyses revealed that the riclin group partially reversed metabolic profile changes induced by the HCD, approaching that of the normal diet (ND) group. Riclin has no direct effects on cholesterol metabolism-related gene expression among the three HCD model groups. Basically, riclin increased the solution viscosity and interfered in the process of bile acid-cholesterol emulsification, decreasing cholesterol digestion and promoting cholesterol and bile acid excretion in the feces. These results suggested potential therapeutic utility of succinoglycan riclin as a food additive for people suffering from hypercholesterolemia and related diseases.


Assuntos
Anticolesterolemiantes/metabolismo , Hipercolesterolemia/dietoterapia , Polissacarídeos Bacterianos/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , LDL-Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
13.
J Nutr Sci Vitaminol (Tokyo) ; 65(5): 421-429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31666479

RESUMO

Diosgenin (Dio) is a steroid sapogenin found in plants such as Dioscorea species, and is recognized as a phytochemical against various disorders as well as a natural precursor of steroidal drugs. The present study used rats fed high-cholesterol (Chol) diets supplemented with or without 0.5% Dio for 6 wk to investigate the effects of dietary Dio on lipid metabolism. Dio supplementation significantly increased serum high-density lipoprotein Chol concentrations and fecal Chol content, and significantly decreased fecal bile acid content compared rats fed a high-Chol diet alone, showing that dietary Dio may facilitate excretion of Chol rather than bile acids. A reduction in the liver triglyceride content and intra-abdominal visceral fat was observed in Dio-supplemented rats. Interestingly, dietary Dio also significantly increased the skeletal muscle-fiber diameter and area in the thigh muscles of the rats. Mouse myoblast-derived C2C12 cells were used to examine whether Dio directly affected skeletal muscle. Dio promoted fusion of myoblasts into multinucleated cells or myotubes. Furthermore, in myotube C2C12 cells, protein levels of phosphorylated AMP-activated protein kinase (AMPK) increased with Dio treatment in a dose-dependent manner. These results indicate that Dio may not only induce myoblast fusion and enhance skeletal muscle as an energy expenditure organ, but may also activate the catabolic pathway via AMPK in skeletal muscle cells. Thus, these effects of Dio on skeletal muscles may contribute to inhibition of visceral fat accumulation.


Assuntos
Suplementos Nutricionais , Diosgenina/administração & dosagem , Hipercolesterolemia/terapia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ácidos e Sais Biliares/análise , Colesterol/análise , HDL-Colesterol/sangue , Dieta Hiperlipídica , Fezes/química , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Hipertrofia , Gordura Intra-Abdominal/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Ratos , Coxa da Perna/patologia , Triglicerídeos/análise
14.
Am J Physiol Heart Circ Physiol ; 317(6): H1292-H1300, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584834

RESUMO

SUMOylation is a posttranslational modification of lysine residues. Modification of proteins by small ubiquitin-like modifiers (SUMO)1, -2, and -3 can achieve varied, and often unique, physiological and pathological effects. We looked for SUMO2-specific effects on vascular endothelial function. SUMO2 expression was upregulated in the aortic endothelium of hypercholesterolemic low-density lipoprotein receptor-deficient mice and was responsible for impairment of endothelium-dependent vasorelaxation in these mice. Moreover, overexpression of SUMO2 in aortas ex vivo, in cultured endothelial cells, and transgenically in the endothelium of mice increased vascular oxidative stress and impaired endothelium-dependent vasorelaxation. Conversely, inhibition of SUMO2 impaired physiological endothelium-dependent vasorelaxation in normocholesterolemic mice. These findings indicate that while endogenous SUMO2 is important in maintenance of normal endothelium-dependent vascular function, its upregulation impairs vascular homeostasis and contributes to hypercholesterolemia-induced endothelial dysfunction.NEW & NOTEWORTHY Sumoylation is known to impair vascular function; however, the role of specific SUMOs in the regulation of vascular function is not known. Using multiple complementary approaches, we show that hyper-SUMO2ylation impairs vascular endothelial function and increases vascular oxidative stress, whereas endogenous SUMO2 is essential for maintenance of normal physiological function of the vascular endothelium.


Assuntos
Endotélio Vascular/metabolismo , Hipercolesterolemia/metabolismo , Estresse Oxidativo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Vasodilatação , Animais , Dieta Hiperlipídica/efeitos adversos , Endotélio Vascular/fisiologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipercolesterolemia/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética
15.
J Agric Food Chem ; 67(38): 10614-10623, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31483658

RESUMO

Type 2 diabetes (T2D) is a pandemic disease chiefly characterized by hyperglycemia. In this study, the combination of serum lipidomic and metabolomic approach was employed to investigate the effect of arabinoxylan on type 2 diabetic rats and identify the critical biomarkers of T2D. Metabolomics analysis revealed that branched-chain amino acids, 12α-hydroxylated bile acids, ketone bodies, and several short- and long-chain acylcarnitines were significantly increased in T2D, whereas lysophosphatidylcholines (LPCs) were significantly decreased. Lipidomics analysis indicated T2D-related dyslipidemia was mainly associated with the increased levels of acetylcarnitine, free fatty acids (FFA), diacylglycerols, triacylglycerols, and cholesteryl esters and the decreased levels of some unsaturated phosphatidylcholines (less than 22 carbons). These variations indicated the disturbed amino acid and lipid metabolism in T2D, and the accumulation of incompletely oxidized lipid species might eventually contribute to impaired insulin action and glucose homeostasis. Arabinoxylan treatment decreased the concentrations of 12α-hydroxylated bile acids, carnitines, and FFAs and increased the levels of LPCs. The improved bile acid and lipid metabolism by arabinoxylan might be involved in the alleviation of hypercholesterolemia and hyperlipidemia in T2D.


Assuntos
Anticolesterolemiantes/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipolipemiantes/administração & dosagem , Xilanos/administração & dosagem , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Carnitina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hiperlipidemias/etiologia , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos , Lipídeos/química , Metabolômica , Ratos
16.
J Exp Clin Cancer Res ; 38(1): 404, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519191

RESUMO

BACKGROUND: Metabolic reprogramming is an important characteristic of tumors. In the progression of pituitary adenomas (PA), abnormal glucose metabolism has been confirmed by us before. However, whether cholesterol metabolism is involved in the process of PA remains unclear. This study aimed to investigate whether abnormal cholesterol metabolism could affect the progression of PA. METHODS: We analyzed the expression of sterol carrier protein 2 (SCP2) in 40 surgical PA samples. In vitro experiments and xenograft models were used to assess the effects of SCP2 and cholesterol on proliferation of PA. The incidence of hypercholesterolemia between 140 PA patients and 100 heathy controls were compared. RESULTS: We found an upregulation of SCP2 in PA samples, especially in tumors with high proliferation index. Forced expression of SCP2 promoted PA cell lines proliferation in vitro. Furthermore, SCP2 regulated cholesterol trafficking from cytoplasm to membrane in GH3 cells, and extracellularly treating GH3 cells and primary PA cells with methyl-ß-cyclodextrin/cholesterol complex to mimic membrane cholesterol concentration enhanced cell proliferation, which suggested a proliferative effect of cholesterol. Mechanistically, cholesterol induced activation of PKA/SUFU/GLI1 signaling via smoothened receptor, which was well-known as Hedgehog signaling, resulting in inhibiting apoptosis and promoting cell cycle. Accordingly, activation of Hedgehog signaling was also confirmed in primary PA cells and surgical PA samples. In vivo, SCP2 overexpression and high cholesterol diet could promote tumor growth. Intriguingly, the incidence of hypercholesterolemia was significantly higher in PA patients than healthy controls. CONCLUSIONS: Our data indicated that dysregulated cholesterol metabolism could promote PA growth by activating Hedgehog signaling, supporting a potential tumorigenic role of cholesterol metabolism in PA progression.


Assuntos
Proteínas de Transporte/metabolismo , Colesterol/metabolismo , Proteínas Hedgehog/metabolismo , Neoplasias Hipofisárias/metabolismo , Transdução de Sinais , Adulto , Idoso , Animais , Transporte Biológico , Biomarcadores , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias Hipofisárias/etiologia , Neoplasias Hipofisárias/patologia , Ratos
17.
World Neurosurg ; 132: e99-e108, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518751

RESUMO

BACKGROUND: High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated. METHODS: Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI. RESULTS: TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment. CONCLUSIONS: The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.


Assuntos
Anticolesterolemiantes/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Fármacos Neuroprotetores/uso terapêutico , Sinvastatina/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Colesterol/sangue , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/sangue
18.
Life Sci ; 233: 116702, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356905

RESUMO

AIMS: We previously demonstrated that iron overload induces endothelial dysfunction and oxidative stress, which could increase the risk for atherosclerosis. However, the iron-related harmfulness under a genetic predisposition to atherosclerosis is still unclear. Here, we have tested the hypothesis that chronic iron overload may change vascular reactivity associated with worsening of the atherosclerotic process in apolipoprotein E knockout (apoE(-/-)) mice. MAIN METHODS: Serum and aortas of wild-type (WT) and apoE(-/-) mice injected with iron-dextran (IO, 10 mg/mouse/day, ip) or saline 5 times a week for 4 weeks, were used. KEY FINDINGS: Iron overload increased serum levels of iron and biomarkers of liver injury and oxidative stress, and iron deposition in the aorta in both lines, but only apoE(-/-) IO mice had intensified hypercholesterolemia and atherosclerosis. By scanning electron microscopy, the small endothelial structural damage caused by iron in WT was worsened in the apoE(-/-) group. However, endothelial dysfunction was found only in the apoE(-/-) IO group, identified by impaired relaxation to acetylcholine and hyperreactivity to phenylephrine associated with reduced nitric oxide modulation. Moreover, tiron and indomethacin attenuated reactivity to phenylephrine with greater magnitude in aortas of the apoE(-/-) IO group. Confirming, there were changes in the antioxidant (superoxide dismutase and catalase) activity, increased expression of cyclooxygenase-2 in the aorta and elevated levels of thromboxane A2 and prostacyclin metabolites in the urine of apoE(-/-) IO. SIGNIFICANCE: Our results showed that chronic iron overload intensifies the atherosclerotic process and induces endothelial dysfunction in atherosclerotic mice, probably due to the oxidative stress and the imbalance between the relaxing and contractile factors synthesized by the damaged endothelium.


Assuntos
Apolipoproteínas E/fisiologia , Aterosclerose/patologia , Endotélio Vascular/patologia , Hipercolesterolemia/patologia , Sobrecarga de Ferro/complicações , Estresse Oxidativo , Acetilcolina/metabolismo , Animais , Aterosclerose/etiologia , Aterosclerose/metabolismo , Endotélio Vascular/metabolismo , Feminino , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Ferro/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Óxido Nítrico/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-31349672

RESUMO

Lead, mercury, and cadmium are common environmental pollutants in industrialized countries, but their combined impact on hypercholesterolemia (HC) is poorly understood. The aim of this study was to compare the performance of various machine learning (ML) models to predict the prevalence of HC associated with exposure to lead, mercury, and cadmium. A total of 10,089 participants of the Korea National Health and Nutrition Examination Surveys 2008-2013 were selected and their demographic characteristics, blood concentration of metals, and total cholesterol levels were collected for analysis. For prediction, five ML models, including logistic regression (LR), k-nearest neighbors, decision trees, random forests, and support vector machines (SVM) were constructed and their predictive performances were compared. Of the five ML models, the SVM model was the most accurate and the LR model had the highest area under receiver operating characteristic (ROC) curve of 0.718 (95% CI: 0.688-0.748). This study shows the potential of various ML methods to predict HC associated with exposure to metals using population-based survey data.


Assuntos
Cádmio/toxicidade , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/toxicidade , Hipercolesterolemia/etiologia , Chumbo/toxicidade , Aprendizado de Máquina , Mercúrio/toxicidade , Adulto , Árvores de Decisões , Feminino , Previsões , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , República da Coreia/epidemiologia , Máquina de Vetores de Suporte
20.
Lipids Health Dis ; 18(1): 148, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272450

RESUMO

BACKGROUND: The present research project was designed to evaluate the cholesterol lowering potential of different date varieties including one exotic (Ajwa) and three Pakistani varieties (Aseel, Khudravi, Hallawi). METHODS: The albino rats were divided into six groups on the basis of different diets which includes, control having basal diet, high cholesterol high sucrose diet, high cholesterol high sucrose diet plus Khudravi dates, high cholesterol high sucrose diet plus Hallawi dates, high cholesterol high sucrose diet plus Aseel dates, high cholesterol high sucrose diet plus Ajwa dates to evaluate maximum cholesterol lowering potential of each date variety. RESULTS: The results showed that Hallawi and Ajwa have lower crude fiber content as 2.02 ± 0.03% and 2.43 ± 0.04% however, lowest crude fat content (0.26 ± 0.01%) was also observed in ajwa. Mineral profile depicted that sodium (9.50-18.00 mg/100 g) was found to be in lesser amount among all varieties whereas, higher amount of potassium (465.00 to 887.20 mg/100 g) depicted that it is suitable for people having hypertension. Higher amount of reducing sugar was also observed in ajwa (79.45 ± 1.22%) followed by Hallawi (77.68 ± 1.42%). Total phenolic contents were found higher in Aseel (291.36 mg/100 g) whereas, minimum was observed in Khudravi (232.64 mg/100 g). Furthermore, date varieties were also examined rat modeling to evaluate their maximum cholesterol lowering efficiency. Ajwa and Hallawi were observed to suppress the cholesterol efficiently as 110 mg/dL and 103 mg/dL respectively. On the basis of chemical profiling and other parameters, two date varieties Ajwa and Hallawi showed almost similar results and found to have maximum serum cholesterol, LDL and triglyceride reduction potential with good kidney and liver functions. Functional date bar was also developed by using Hallawi variety andsubjected to sensory evaluation. CONCLUSION: In nutshell, Hallawi date variety was considered as better cholesterol lowering potential among other indigenous varieties and very close to Ajwa variety. So that Hallawi can be used to suppress the deadly effects of obesity and allied discrepancies particularly hypercholesterolemia.


Assuntos
Alimento Funcional , Hipercolesterolemia/prevenção & controle , Phoeniceae/química , Animais , Antioxidantes/análise , Colesterol/sangue , Modelos Animais de Doenças , Alimento Funcional/análise , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/etiologia , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Minerais/análise , Valor Nutritivo , Paquistão , Fenóis/análise , Ratos Sprague-Dawley , Paladar , Triglicerídeos/sangue
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