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1.
Artigo em Inglês | MEDLINE | ID: mdl-33949198

RESUMO

Phlebotomies are performed in hereditary hemochromatosis (HH) to maintain normal iron concentrations. Proton pump inhibitors (PPIs) can reduce the number of phlebotomies in HH patients. However, in patients without HH, the iron concentrations do not appear to be compromised when using PPIs. Therefore, we aim to explain the differences in iron absorption between patients with and without HH. METHODS: In ten p.C282Y homozygous HH patients with normalized iron stores and ten healthy control subjects (HCs), the iron parameters and hepcidin concentrations were determined before ingestion of a pharmacological dose of 50 mg iron (Fe3+) polymaltose, and hourly for four hours afterwards. This was repeated after seven days' treatment with pantoprazole 40 mg once daily. RESULTS: Serum iron concentrations and transferrin saturation percentages dropped significantly during PPI use in the HH patients, while no changes were observed in the HCs. Hepcidin concentrations were lower in the HH patients compared with the HCs both before and during PPI use. In both groups hepcidin levels did not significantly decrease during the treatment. CONCLUSIONS: Seven day PPI use significantly reduces iron absorption in HH patients but not in HCs. Changes in hepcidin concentrations could not explain these different PPI effects on iron absorption probably due to a small sample size.

2.
Gut ; 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632708

RESUMO

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

3.
Horm Metab Res ; 52(12): 869-876, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33260239

RESUMO

Brown adipose tissue (BAT) might be a beneficial mediator in the development and treatment of nonalcoholic steatohepatitis (NASH). We aim to evaluate the gene expression of BAT activity-related genes during the development and the dietary and surgical treatment of NASH. BAT was collected from male C57BL/6J mice that received a high fat-high sucrose diet (HF-HSD) or a normal chow diet (NCD) for 4 and 20 weeks (n=8-9 per dietary group and timepoint) and from mice that underwent dietary intervention (return to NCD) (n=8), roux-en-y gastric bypass (RYGB) (n=6), or sham procedure (n=6) after 12 weeks HF-HSD. Expression of BAT genes involved in lipid metabolism (Cd36 and Cpt1b; p<0.05) and energy expenditure (Ucp1 and Ucp3; p<0.05) were significantly increased after 4 weeks HF-HSD compared with NCD, whereas in the occurrence of NASH after 20 weeks HF-HSD no difference was observed. We observed no differences in gene expression regarding lipid metabolism or energy expenditure at 8 weeks after dietary intervention (no NASH) compared with HF-HSD mice (NASH), nor in mice that underwent RYGB compared with SHAM. However, dietary intervention and RYGB both decreased the BAT gene expression of inflammatory cytokines (Il1b, Tnf-α and MCP-1; p<0.05). Gene expression of the batokine neuregulin 4 was significantly decreased after 20 weeks HF-HSD (p<0.05) compared with NCD, but was restored by dietary intervention and RYGB (p<0.05). In conclusion, BAT is hallmarked by dynamic alterations in the gene expression profile during the development of NASH and can be modulated by dietary intervention and bariatric surgery.

5.
BMJ Case Rep ; 13(12)2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33370938

RESUMO

A 31-year-old woman with hepatocellular carcinoma suffered from recurrent oesophageal variceal bleeding due to portal hypertension, which was caused by severe compression of the portal vein by metastatic lymph nodes. Endoscopic band ligation and pharmacological treatment did not suffice to prevent recurrence of variceal bleeding. Eventually, after the fifth variceal bleeding within 6 months, the patient was admitted to the intensive care unit in a haemodynamic shock. A Sengstaken-Blakemore tube was inserted and all treatment options were discussed, but only percutaneous transhepatic recanalisation of the portal vein with stent placement to reduce portal vein pressure was thought to be feasible with any chance to relieve portal vein pressure. After successful portal vein stenting, our patient did not have any recurrent bleeding in the remaining year of her life. We suggest that percutaneous transhepatic portal vein stenting may be a feasible and adequate last line treatment for complications of portal hypertension.


Assuntos
Carcinoma Hepatocelular/complicações , Varizes Esofágicas e Gástricas/cirurgia , Hemorragia Gastrointestinal/cirurgia , Neoplasias Hepáticas/complicações , Prevenção Secundária/métodos , Choque Hemorrágico/cirurgia , Adulto , Varizes Esofágicas e Gástricas/diagnóstico , Varizes Esofágicas e Gástricas/etiologia , Esofagoscopia , Esôfago/irrigação sanguínea , Esôfago/diagnóstico por imagem , Estudos de Viabilidade , Feminino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Humanos , Veia Porta/cirurgia , Recidiva , Prevenção Secundária/instrumentação , Choque Hemorrágico/etiologia , Stents , Tomografia Computadorizada por Raios X , Resultado do Tratamento
6.
Alcohol Clin Exp Res ; 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33190239

RESUMO

BACKGROUND & AIMS: Alcohol-related liver disease (ALD) is the most frequent cause of cirrhosis and a major indication for liver transplantation (LTx). Several alcohol use biomarkers have been developed in recent years and are already in use in several centres. However, in patients with liver disease their diagnostic performance might be influenced by altered biomarker formation by hepatic damage, altered excretion by kidney dysfunction and diuretics use and altered deposition in hair and nails. We systematically reviewed studies on the diagnostic accuracy of biomarkers of alcohol use in patients with liver disease and performed a detailed study quality assessment. METHODS: A structured search in PubMed/Medline/Embase databases was performed for relevant studies, published until 28 April 2019. The risk of bias and applicability concerns were assessed according to the adapted quality assessment of diagnostic accuracy studies-2 (QUADAS-2) checklist. RESULTS: Twelve out of 6449 studies met inclusion criteria. Urinary ethyl glucuronide and urinary ethyl sulfate showed high sensitivity (70 - 89% and 73 - 82%, respectively) and specificity (93 - 99% and 86 - 89%, respectively) for assessing any amount of alcohol use in the past days. Serum carbohydrate deficient transferrin showed low sensitivity but higher specificity (40 - 79% and 57 - 99%, respectively) to detect excessive alcohol use in the past weeks. Whole blood phosphatidylethanol showed high sensitivity and specificity (73 - 100% and 90 - 96%, respectively) to detect any amount of alcohol use in the previous weeks. Scalp hair ethyl glucuronide showed high sensitivity (85 - 100%) and specificity (97 - 100%) for detecting chronic excessive alcohol use in the past three to six months. Main limitations of the current evidence are the lack of an absolute gold standard to assess alcohol use, heterogeneous study populations and the paucity of studies. CONCLUSIONS: Urinary and scalp hair ethyl glucuronide are currently the most validated alcohol use biomarkers in patients with liver disease with good diagnostic accuracies. Phosphatidylethanol is a highly promising alcohol use biomarker, but so far less validated in liver patients. Alcohol use biomarkers can complement each other regarding diagnostic time window. More validation studies on alcohol use biomarkers in patients with liver disease are needed.

7.
Hepatology ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33140868

RESUMO

A decrease or normalization of alkaline phosphatase (ALP) and bilirubin levels in patients treated for primary biliary cholangitis (PBC) predicts a better survival. Obeticholic acid (OCA) is the approved second-line therapy if ursodeoxycholic acid (UCDA) fails, but its use may worsen pruritus. Adding bezafibrate to UCDA improved biochemical markers of cholestatic liver injury and decreased pruritus severity. Because normalization of ALP and bilirubin was only achieved in a minority of patients in these studies, we explored whether bezafibrate (off-label drug) could improve the effect of OCA (licensed drug) on cholestasis.

8.
Gastroenterology ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031833

RESUMO

BACKGROUND AND AIMS: Pruritus may seriously impair quality of life in patients with cholestatic diseases such as primary or secondary sclerosing cholangitis (PSC, SSC) and primary biliary cholangitis (PBC). Pharmacologic strategies show limited efficacy and can provoke serious side effects. We hypothesized that bezafibrate, a broad peroxisome proliferator-activated receptor (PPAR) agonist, relieves cholestasis-associated itch by alleviating hepatobiliary injury. The aim of this investigator-initiated FITCH trial (Fibrates for cholestatic ITCH) was to assess effects of bezafibrate on pruritus in patients with PSC, PBC, and SSC. METHODS: Patients with moderate to severe pruritus (≥5 of 10 on visual analog scale [VAS]) due to PSC, PBC, or SSC were recruited for this double-blind, randomized, placebo-controlled trial between 2016 and 2019. Patients received once-daily bezafibrate (400 mg) or placebo for 21 days. The primary end point was ≥50% reduction of pruritus (VAS; intention-to-treat). RESULTS: Of 74 randomized patients, 70 completed the trial (95%; 44 PSC, 24 PBC, 2 SSC). For the primary end point, bezafibrate led in 45% (41% PSC, 55% PBC) and placebo in 11% to ≥50% reduction of severe or moderate pruritus (P = .003). For secondary end points, bezafibrate reduced morning (P = .01 vs placebo) and evening (P = .007) intensity of pruritus (VAS) and improved the validated 5D-Itch questionnaire (P = .002 vs placebo). Bezafibrate also reduced serum alkaline phosphatase (-35%, P = .03 vs placebo) correlating with improved pruritus (VAS, P = .01) suggesting reduced biliary damage. Serum bile acids and autotaxin activity remained unchanged. Serum creatinine levels tended to mildly increase (3% bezafibrate, 5% placebo, P = .14). CONCLUSIONS: Bezafibrate is superior to placebo in improving moderate to severe pruritus in patients with PSC and PBC. TRIAL REGISTRATION: Netherlands Trial Register, ID: NTR5436 (August 3, 2015), ClinicalTrials.gov ID: NCT02701166 (March 2, 2016).

9.
Liver Int ; 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33037768

RESUMO

BACKGROUND: The gut-liver axis is considered to play a critical role in the development and progression of nonalcoholic fatty liver disease (NAFLD). The integrity of the epithelial barrier is crucial to protect the liver against the invasion of microbial products from the gut, although its exact role in NAFLD onset and progression is not clear. METHODS: We performed a systematic review and meta-analysis of studies that addressed the intestinal permeability (IP) in association with NAFLD presence or severity as defined by the presence of nonalcoholic steatohepatitis (NASH) and the degree of steatosis, hepatic inflammation or fibrosis. A total of 14 studies were eligible for inclusion. RESULTS: Studies investigating IP in adult (n = 6) and paediatric (n = 8) NAFLD showed similar results. Thirteen of the included studies focussed on small IP, two studies on whole gut permeability and none on colonic permeability. In the pooled analysis, NAFLD patients showed an increased small intestinal permeability compared to healthy controls based on dual sugar tests (standardized mean difference 0.79, 95% CI 0.49-1.08) and serum zonulin levels (standardized mean difference 1.04 ng/mL, 95% CI 0.40-1.68). No clear difference in IP was observed between simple steatosis and NASH patients. Furthermore, whole gut and small intestinal permeability increased with the degree of hepatic steatosis in 4/4 studies, while no association with hepatic inflammation or fibrosis was observed. CONCLUSION: Based on the limited number of studies available, IP appears to be increased in NAFLD patients compared to healthy controls and is associated with the degree of hepatic steatosis.

10.
J Viral Hepat ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989861

RESUMO

BACKGROUND: Hepatitis B virus (HBV) immunity is recommended to optimize outcomes after solid organ transplantation (SOT). This study assessed the prevalence and predictors of HBV immunity at the time patients were placed on transplant waiting list over a period from 1997 to 2019 in a low HBV endemic region. METHODS: Data were obtained from the University Hospitals Leuven transplant database. Minors and patients with past/current HBV infection were excluded. From 1986, Belgian patients are covered by the universal infant vaccination; therefore, birth cohort was stratified in those born ≥1986 vs <1986. RESULTS: The study population consisted of 3297 SOT candidates. HBV immunity rate was superior in renal transplant candidates (55.3%), and this number was 21.5%, 15.4% and 16.8% for liver, cardiac and pulmonary transplant candidates, respectively, P < .001. Among liver transplant candidates, HBV immunity rate was 14.8% in decompensated cirrhotic patients and 27.9% in those without advanced cirrhosis (P < .001). The overall immunity rate increased from 19.3% in period 1997-2008 to 32.8% in 2009-2019, P < .001. In multivariable analyses, younger age (odds ratio (OR) 95% confidence interval (CI): 0.97-0.98, P < .001) and birth cohort ≥ 1986 (OR 95% CI: 1.18-2.66, P = .006) were associated with increased HBV immunity. CONCLUSION: An increase in HBV immunity was observed over a 20-year period related to the introduction of universal infant HBV vaccination. Nevertheless, this study highlights the low overall HBV immunity at the time of listing for organ transplantation and points out the need of an increased awareness and vaccination strategy at an early disease stage.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32828745

RESUMO

BACKGROUND AND AIM: Insulin resistance (IR) plays a central role in the complex pathophysiology of nonalcoholic fatty liver disease (NAFLD). IR is linked to fat infiltration in skeletal muscle (myosteatosis) and loss of skeletal muscle mass and function (sarcopenia). The clinical significance of myosteatosis in NAFLD is not well investigated. In this exploratory study we aimed to investigate the association between myosteatosis and NAFLD related hepatic and systemic variables in a well characterized NAFLD cohort. METHODS: We cross-sectionally studied forty-five NAFLD patients. The muscle fat fraction (MFF) was measured with chemical shift gradient echo MRI. In addition, the hepatic fat fraction (MRI), liver stiffness (FibroScan) and appendicular skeletal muscle mass (Dual-energy X-ray absorptiometry) were analyzed. RESULTS: The median hepatic fat fraction was 15.64% (IQR 12.05-25.13) and significant (F2-F3) liver fibrosis (liver stiffness ≥7kPa) was diagnosed in 18 NAFLD patients (40%). MFF was not correlated with hepatic fat fraction (r=-0.035, P=0.823) and did not differ between subjects with or without significant fibrosis (P=0.980). No patient was diagnosed with sarcopenia based on the skeletal muscle mass index. In a linear regression model, anthropometric parameters, including body mass index (BMI) (P=0.018) and total body fat percentage (P=0.005), were positively associated with MFF while no association with insulin resistance (HOMA-IR) was observed. CONCLUSION: Myosteatosis did not correlate with the degree of hepatic steatosis or fibrosis in this well characterized NAFLD cohort, but was positively correlated with total body fat percentage and BMI.

12.
Gastroenterology ; 159(2): 534-548.e11, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32376409

RESUMO

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

14.
Mol Psychiatry ; 24(1): 10-17, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29892052

RESUMO

Alcohol exposure during pregnancy affects the development of the fetus in various ways and may lead to Fetal Alcohol Spectrum Disorders (FASD). FASD is one of the leading preventable forms of neurodevelopmental disorders. In the light of prevention and early intervention, knowledge on how ethanol exposure induces fetal damage is urgently needed. Besides direct ethanol and acetaldehyde toxicity, alcohol increases oxidative stress, and subsequent general effects (e.g., epigenetic imprinting, gene expression, and metabolite levels). The current review provides an overview of the existing knowledge about specific downstream pathways for FASD that affects e.g., the SHH pathway, cholesterol homeostasis, neurotransmitter signaling, and effects on the cytoskeleton. Available human data vary greatly, while animal studies with controlled ethanol exposition are only to a certain limit transferable to humans. The main deficits in knowledge about FASD are the lack of pathophysiological understanding and dose-response relationships, together with the lack of reliable biomarkers for either FASD detection or estimation of susceptibility. In addition to single outcome experiments, omics data should be generated to overcome this problem. Therefore, for future studies we recommend holistic data driven analysis, which allows integrative analyses over multiple levels of genetic variation, transcriptomics and metabolomics data to investigate the whole image of FASD development and to provide insight in potential drug targets for intervention.


Assuntos
Transtornos do Espectro Alcoólico Fetal/genética , Transtornos do Espectro Alcoólico Fetal/metabolismo , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Animais , Modelos Animais de Doenças , Etanol/efeitos adversos , Feminino , Feto/metabolismo , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
16.
J Nucl Med ; 59(4): 682-690, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29348321

RESUMO

Animal studies suggest an important role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the pathophysiology of alcohol dependence, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGlu5 availability in alcohol-dependent subjects versus controls using 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (18F-FPEB) PET. Methods: Dynamic 90-min 18F-FPEB scans combined with arterial blood sampling were acquired for 16 recently abstinent alcohol-dependent subjects and 32 age-matched controls. Regional mGlu5 availability was quantified by the 18F-FPEB total distribution volume using both a voxel-by-voxel and a volume-of-interest analysis with partial-volume effect correction. Alcohol consumption within the last 3 mo was assessed by questionnaires and by hair ethyl glucuronide analysis. Craving was assessed using the Desire for Alcohol Questionnaire. Results: mGlu5 availability was lower in mainly limbic regions of alcohol-dependent subjects than in controls (P < 0.05, familywise error-corrected), ranging from 14% in the posterior cingulate cortex to 36% in the caudate nucleus. Lower mGlu5 availability was associated with higher hair ethyl glucuronide levels for most regions and was related to a lower level of craving specifically in the middle frontal gyrus, cingulate cortex, and inferolateral temporal lobe. Conclusion: These findings provide human in vivo evidence that limbic mGlu5 has a role in the pathophysiology of alcohol dependence, possibly involved in a compensatory mechanism helping to reduce craving during abstinence.


Assuntos
Alcoolismo/metabolismo , Sistema Límbico/metabolismo , Receptor de Glutamato Metabotrópico 5/metabolismo , Alcoolismo/diagnóstico por imagem , Alcoolismo/patologia , Atrofia/diagnóstico por imagem , Estudos de Casos e Controles , Feminino , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/patologia , Masculino , Pessoa de Meia-Idade , Nitrilos , Tomografia por Emissão de Pósitrons , Piridinas
18.
Lipids Health Dis ; 16(1): 46, 2017 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-28231800

RESUMO

BACKGROUND: Dietary intervention is the cornerstone of non-alcoholic steatohepatitis (NASH) treatment. However, histological evidence of its efficacy is limited and its impact on hepatic pathways involved in NASH is underreported. The efficacy of the angiotensin receptor type 1 blocker losartan is controversial because of varying results in a few animal and human studies. We evaluated the effect of dietary intervention versus losartan on NASH and associated systemic metabolic features in a representative mouse model. METHODS: Male C57BL/6 J mice with high fat-high sucrose diet (HF-HSD) induced NASH, obesity, insulin resistance and hypercholesterolemia were subjected to dietary intervention (switch from HF-HSD to normal chow diet (NCD)) (n = 9), continuation HF-HSD together with losartan (30 mg/kg/day) (n = 9) or continuation HF-HSD only (n = 9) for 8 weeks. 9 mice received NCD during the entire experiment (20 weeks). We assessed the systemic metabolic effects and performed a detailed hepatic histological and molecular profiling. A P-value of < 0.05, using the group with continuation of HF-HSD only as control, was considered as statistically significant. RESULTS: Dietary intervention normalized obesity, insulin resistance, and hypercholesterolemia (for all P < 0.001), and remarkably, completely reversed all histological features of pre-existent NASH (for all P < 0.001), including fibrosis measured by quantification of collagen proportional area (P < 0.01). At the hepatic molecular level, dietary intervention targeted fibrogenesis with a normalization of collagen type I alpha 1, transforming growth factor ß1, tissue inhibitor of metalloproteinase 1 mRNA levels (for all P < 0.01), lipid metabolism with a normalization of fatty acid translocase/CD36, fatty acid transport protein 5, fatty acid synthase mRNA levels (P < 0.05) and markers related to mitochondrial function with a normalization of hepatic ATP content (P < 0.05) together with sirtuin1 and uncoupling protein 2 mRNA levels (for both P < 0.001). Dietary intervention abolished p62 accumulation (P < 0.01), suggesting a restoration of autophagic flux. Losartan did not significantly affect obesity, insulin resistance, hypercholesterolemia or any histological NASH feature. CONCLUSIONS: Dietary intervention, and not losartan, completely restores the metabolic phenotype in a representative mouse model with pre-existent NASH, obesity, insulin resistance and hypercholesterolemia.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Losartan/farmacologia , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Obesidade/dietoterapia , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
20.
Curr Protoc Mouse Biol ; 6(2): 185-200, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27248434

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world. It is associated with obesity and type 2 diabetes and represents a spectrum of histological abnormalities ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which can further progress to fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and liver failure. To gain insight into the pathogenesis and evaluate treatment options, mouse models of NAFLD/NASH are of utmost importance. There is a high phenotypical variety in the available mouse models, however, models that truly display the full spectrum of histopathological and metabolic features associated with human NASH are rare. In this review, we summarize the most important NAFLD/NASH mouse models that have been developed over the years and briefly highlight the pros and cons. Also, we illustrate the preclinical research in which these models have been used. © 2016 by John Wiley & Sons, Inc.


Assuntos
Modelos Animais de Doenças , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Animais , Humanos
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