Indiana University-Purdue University Indianapolis (IUPUI) / Non-alcoholic fatty liver disease, or NAFLD, is characterized by excess fat deposition in the liver. Cellular senescence is a critical hallmark of NAFLD. Cholangiocytes in the liver plays a significant role in the progression of fatty liver by contributing to senescence. p16 is the main senescent protein expressed by cholangiocytes in primary sclerosing cholangitis (PSC). Thus, we aimed to downregulate p16 by vivo-morpholino and evaluate the disease phenotypes and signaling mechanisms in a murine model of NAFLD. We found that downregulation of p16 reduced i) steatosis), ii) inflammation, iii) fibrosis, and cholangiocyte proliferation in HFD mice compared to the HFD-fed, control vivo-morpholino injected mice. Moreover, the downregulation of p16 reduced insulin-like growth factor-1 (IGF-1) in cholangiocytes, previously identified by our laboratory as a principal SASP factor secreted from cholangiocytes during NAFLD. By ingenuity pathway analysis, we found that p16 might regulates IGF-1 expression via the E2F1/FOXO1axis. Further analyses indicate that p16 downregulation reduces E2F1 mRNA transcription, inhibiting FOXO1 and subsequent IGF-1 expression in cholangiocytes. The presence of mast cells in the liver has been implicated in multiple cholangiopathies. Our lab demonstrated that mast cell stabilization by cromolyn sodium treatment reduced histamine secretion, fibrosis, and biliary proliferation in Mdr2-/- mice, a model of PSC. Thus, we aimed to determine mast cell stabilization as a therapeutic approach to managing NAFLD and its more advanced form, NASH. We found that cromolyn sodium ameliorated i) serum histamine levels, ii) intrahepatic mast cells, iii) inflammation, iv) fibrosis, v) steatosis, and cholangiocyte proliferation in methionine choline deficient diet-fed mice compared to the saline controls. Overall, we report that amelioration of senescence is a critical factor in improving the disease phenotypes in NAFLD. Biliary senescence plays a crucial role in modulating the disease progression in NAFLD, and mast cell stabilization can be used as a therapeutic approach to reduce pathological hallmarks of fatty liver. / 2024-05-22

研究背景及實驗目的: 非酒精性脂肪性肝炎(NASH)使得肥胖和2 型糖尿病變得複雜，肝臟炎症的持續產生是其主要的發病機理。CXCL10 是一種促進炎症的細胞因數，其在肥胖和2 型糖尿病中的表達顯著升高。CXCL10 以及其受體CXCR3 是否在NASH 的發生發展中起作用尚不清楚。在本研究中，我們探索了CXCL10 以及其受體CXCR3 在脂肪性肝炎中的功能， 並評估了CXCL10 在NASH 中的臨床價值。 / 實驗方法：CXCL10 基因敲除鼠，CXCR3 敲除鼠以及野生型C57BL/6 小鼠給予蛋氨酸膽鹼缺乏食(MCD)4 周或者8 周。CXCL10 的信號通路以及下游靶點通過細胞因數分析，cDNA array, 蛋白DNA 結合實驗，自噬溶酶體系統分析進行檢測。為了闡明CXCL10 抑制對NASH 的預防治療作用，我們給MCD 餵養的小鼠注射抗CXCL10 抗體。用不同濃度的CXCL10 抗體以及CXCR3 抑制劑NIBR2130 幹預MCD 培養的肝細胞株AML-12。臨床研究中，我們收集了147個非酒精性脂肪肝患者以及73 個健康對照的血清，用酶聯免疫吸附試驗檢測血清中CXCL10 的水準。 / 結果：野生型小鼠給予MCD 餵養後，CXCL10 以及CXCR3 的表達升高，並出現脂肪性肝炎的表現。然而，MCD 飼養的CXCL10 以及CXCR3 基因敲除鼠中，脂肪性肝炎明顯減輕。CXCL10 通過促炎細胞因數的產生以及NK-κB 信號通路促進MCD 飼養的小鼠NASH 的發生。CXCL10 通過促進脂質合成的基因SREBP-1c, ChREBP 和 SCD-1 引起脂肪變性，並通過CYP2E1 以及 C/EBPβ 的上調引起氧化應激。值得注意的是，自噬的損傷在CXCL10 以及CXCR3 導致的脂肪性肝炎的進展中起重要作用。 MCD 飼養的野生型小鼠中p62 以及LC3-II 表達明顯高於CXCL10 以及CXCR3 基因敲除鼠。通過抗CXCL10 抗體中和CXCL10 可以減輕MCD 食引起的小鼠脂肪性肝炎以及MCD 培養液引起的AML-12 細胞損傷。高選擇性的CXCR3 抑制劑NIBR2130 也可以抑制MCD 引起的肝細胞損傷。我們進一步研究了CXCL10 的臨床應用價值，發現NASH 患者血清以及肝臟中CXCL10 的水準明顯升高。更重要的是，血液中CXCL10 的水準與肝小葉炎症程度有關，是NASH 的獨立危險因素。 / 結論：我們的研究首次發現CXCL10 以及其受體CXCR3 通過促進炎症，脂質聚集，氧化應激以及自噬缺乏在NASH 的發病中起重要作用。抑制CXCL10 或者CXCR3 為NASH 患者的治療提供了新的方法。CXCL10 可作為NASH 患者非侵入性診斷的標誌物。 / Background and aims: Non-alcoholic steatoheaptitis (NASH) complicates obesity and type 2 diabetes, while recruitment and perpetuation of liver inflammation is central to its pathogenesis. Expression of C-X-C motif chemokine 10 (CXCL10), a proinflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 and its receptor CXCR3 play a role in NASH is unknown. In this study, we investigated the functional significance of CXCL10 and its receptor CXCR3 in steatoheaptitis. Moreover, the clinical impact of CXCL10 in NASH was examined. / Methods: Gene-deleted CXCL10 (CXCL10-/-), CXCL10 receptor CXCR3 (CXCR3-/-) and C57BL/6 wildtype (WT) mice were fed methionine and choline-deficient (MCD) diet for 4 or 8 weeks. Cytokine profiling assay, cDNA array, protein-DNA binding activity assay and autophagosome-lysosome system analysis of CXCL10 signaling and downstream targets were performed. In other experiments, we injected neutralizing anti-CXCL10 monoclonal antibodies (mAb) into MCD diet-fed WT mice, while AML-12 cells were cultured in MCD medium in the presence of anti-CXCL10 mAb or CXCR3 inhibitor (NIBR2130) for 24 hours. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 controls. Circulating CXCL10 levels were determined by enzyme-linked immunosorbent assay. / Results: MCD-fed WT mice developed steatohepatitis with higher hepatic CXCL10 and CXCR3 expression. CXCL10-/- and CXCR3-/- mice were refractory to MCDinduced steatohepatitis. In WT mice with steatohepatitis, but not in CXCL10-/- mice, CXCL10 was associated with the induction of pro-inflammatory chemokines and cytokines, as well as activation of nuclear factor-κB (NF-κB) signaling. CXCL10 expression was linked to steatosis through lipogenic factors, including liver X receptors and its downstream targets (SREBP-1c, ChREBP and SCD-1), and also to oxidative stress (up-regulation of CYP2E1 and C/EBPβ). In particular, autophagy deficiency was involved in CXCL10- and CXCR3-induced steatohepatitis as indicated by p62 and LC3-I/II protein accumulation in MCD-fed WT mice than in CXCL10-/- and CXCR3-/- mice. Moreover, the impaired autophagic function was related to the reduction of lysosomal function in CXCL10- or CXCR3-induced NASH. Blockade of CXCL10 by anti-CXCL10 mAb protected against MCD-induced steatohepatitis in vivo and against MCD-mediated injury to AML-12 cells in vitro. The highly selective CXCR3 antagonist NIBR2130 also inhibited MCD-induced injury in AML-12 hepatocytes. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. / Conclusions: We demonstrate for the first time that CXCL10 and its receptor CXCR3 plays a pivotal role in the pathogenesis of NASH by promoting inflammation, fatty acid accumulation, oxidative stress and autophagy deficiency. Blockade of CXCL10 or CXCR3 is a potential novel approach for NASH intervention. CXCL10 is a noninvasive biomarker for NASH patients. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Zhang, Xiang. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 145-167). / Abstracts also in Chinese.

Immortalized normal hepatocytes AML-12 or primary hepatocytes were cultured in control, and the methionine and choline deficient (MCD) culture medium in the presence or absence of Phyllanthus urinaria for 24 hours. Hepatocyte triglyceride contents, release of alanine aminotransferase, lipoperoxides and reactive oxygen species production were determined in the cell culture study. Age-matched wild-type C57BL/6 and diabetes db/db mice were fed control or MCD diet for 10 days with or without Phyllanthus urinaria. The levels of Hepatic steatosis, necroinflammation, triglycerides and oxidative stress were investigated. Hepatic expression of inflammatory factors and lipid regulatory mediators were assayed. The results demonstrated that Phyllanthus urinaria reduced steatosis and alanine aminotransferase (ALT) levels in culture of hepatocytes in a dose-dependent manner. Phyllanthus urinaria protected the livers against MCD-induced hepatic fat accumulation and steatohepatitis in mice. This effect was associated with repressed levels of hepatic lipid peroxides, reduced expression of cytochrome P450 (CYP) 2e1, pro-inflammatory tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), dampened activation of inflammatory C-jun N-teuninal kinase (JNK) and nuclear factor kappaB (NF-kappaB), increased expression of lipolytic Cyp4a10 and suppressed transcriptional activity of lipogenic CCAAT/enhancer binding protein beta (C/EBPbeta). Hepatic acyl co-enzyme A oxidase (ACO) that regulated hepatic beta-oxidation of fatty acid and other lipid regulators were not affected by Phyllanthus urinaria. / Non-alcoholic steatohepatitis (NASH) results from excessive accumulation of hepatic fat (steatosis) and oxidative stress. Therefore, inhibition of fatty acid cytotoxicity and liver inflammtary change is an important goal in the treatment of NASH. Phyllanthus urinaria, a herbal medicine, has been reported to have potential anti-oxidant property. We tested the effects of Phyllanthus urinaria on nutritional steatohepatitis both in vitro and in vivo, and determined the mechanism of its action. / Our study indicated that Phyllanthus urinaria effectively prevented MCD-induced steatohepatitis. This effect were probably mediated through dampening oxidative stress, ameliorating inflammation and decreasing lipid accumulation. Phyllanthus urinaria deserves further evaluation for its potential therapeutic effect on NASH in humans. / Shen, Bo. / Adviser: Henry Ly Chan. / Source: Dissertation Abstracts International, Volume: 70-09, Section: B, page: . / Thesis submitted in: November 2008. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 128-142). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Submitted by Natalia Vieira (natalia.vieira@famerp.br) on 2016-05-20T17:39:42Z No. of bitstreams: 1 giovannazanellisilva_dissert.pdf: 2457622 bytes, checksum: 3faf263a6839bd66d93d3bcefc887385 (MD5) / Made available in DSpace on 2016-05-20T17:39:42Z (GMT). No. of bitstreams: 1 giovannazanellisilva_dissert.pdf: 2457622 bytes, checksum: 3faf263a6839bd66d93d3bcefc887385 (MD5) Previous issue date: 2015-11-27 / Introduction: Nonalcoholic Fatty Liver Disease (NAFLD) is characterized by an increase in intracellular content of triglycerides; its prevalence worldwidely is nearly 20-30% of the population. This disease has spectral nature that includes steatosis and nonalcoholic steatohepatitis (NASH) in the absence of significant alcohol consumption. Although NAFLD may remain as a stable disease for longer periods, this condition may progress to advanced stages of cirrhosis and liver cancer. Diabetes Mellitus Type 2, insulin resistance and obesity are important risk factors, among others, for development of NAFLD, and are directly related to sedentary lifestyle and inappropriate eating habits. Thus, alteration in lifestyle, changes in eating habits and regular physical activity play a fundamental role in treating this disease. Aim: To evaluate the effectiveness of hypocaloric diet for the treatment of NASH as well as adherence to treatment. Methods: This is a prospective longitudinal open cohort study, in which 26 NASH patients were divided into 2 group: 15 patients in the control group and 11 patients in the treatment group which were followed up for 6 months. Both groups were diagnosed by liver biopsy. The treatment group was a given lifestyle change program with supervised low-calorie diet (20-25 kcal / kg actual weight / day), monitored exercise, standard treatment of metabolic syndrome and drug maintenance treatment with metformin and N- acetylcysteine. The control group received general guidelines on diet and weight loss, encouragement to practice physical exercise, standard treatment of metabolic syndrome and maintenance of drug treatment with metformin. Criteria for inclusion: patients with at least one of the component of metabolic syndrome; BMI ≥ 25 and ≤ 40 kg /m² and sedentary for at least three months. Criteria for exclusion: other concomitant liver diseases, alcohol intake greater than or equal to 21 drinks / week, or 140 g / day for men and 14 drinks / week or 70g / day for women, medication known to be associated with NAFLD, untreated hypothyroidism or hyperthyroidism, previous bariatric surgery, or uncontrolled psychiatric disorder. Diagnostic criteria: the diagnosis of NASH was done by liver biopsy in patients with steatosis on ultrasound or MRI and at least one risk factor for advanced fibrosis into the period up to one year before entering the study. The lifestyle change program in the treatment group had a weight loss goal of 5% or more of their initial weight within six months. Evaluation criteria: a monthly basis applied the clinical evaluation protocol and on a quarterly basis the laboratorial, according to the following variables: weight, height, body mass index, waist circumference, hip circumference, aminotransferase levels, gamma GT, total cholesterol and fractions, triglycerides. Statistical analysis: the descriptive variables were expressed as frequency, mean or median, standard deviation and variation as applicable. The Student t test and Mann-Whitney test were used for comparative analysis. It was admitted confidence interval of 95% and a significance level of P <0.05. Results: Of the 15 patients enrolled with a diagnosis of NASH who were submitted to nutritional treatment, 12 patients completed the six month follow-up of the study. The average age was 51.42 years ± 8.50, being 08 (66%) women and 04 (33%) men. Of this total, only one patient refused to carry out physical activity. Two (17%) among the 12 participants who completed the six month follow-up reached the percentage of expected weight loss. The average percentage of adaptation to the proposed diet was 82.93% ± 13.51%. Conclusion: The lifestyle change program tested for six months associated with NASH treatment, was not effective for clinical and biochemical improvement even with satisfactory adherence by most patients. Our data point out to the potential role of more restrictive diets and intensive supervision in this context combined with multidisciplinary team for the treatment of NASH. This real-life study produced crucial information for readjustment of the multidisciplinary treatment protocol for patients followed up in the service. / Introducao: A doenca hepatica gordurosa nao alcoolica (DHGNA) e caracterizada pelo aumento do conteudo intracelular de triglicerideos, com prevalencia mundial de aproximadamente 20 a 30% da populacao. Esta doenca tem natureza espectral que engloba esteatose e esteatohepatite nao-alcoolica (NASH), na ausencia de consumo significante de alcool. Embora DHGNA possa permanecer como uma doenca estavel por longos periodos, esta condicao pode progredir para estagios avancados de cirrose e cancer de figado. O Diabetes Mellitus Tipo 2, resistencia a insulina e obesidade sao importantes fatores de risco, dentre outros, para desenvolvimento da DHGNA, e estao diretamente relacionadas ao estilo de vida sedentario e habitos alimentares inapropriados. Dessa forma, alteracao no estilo de vida, mudancas nos habitos alimentares e atividade fisica regular tem papel fundamental no tratamento desta doenca. Objetivo: Avaliar a eficacia da dieta hipocalorica durante o tratamento do NASH, assim como, a adesao ao tratamento instituido. Metodo e Casuistica: Trata-se de um estudo de coorte aberto prospectivo, longitudinal, no qual foram incluidos consecutivamente 26 pacientes, divididos em dois grupos: 15 pacientes no grupo tratamento e 11 pacientes no grupo controle acompanhados durante 6 meses. Ambos tinham diagnostico de NASH por biopsia. O grupo tratamento recebeu programa de mudanca no estilo de vida com dieta hipocalorica supervisionada (20 - 25 kcal/kg de peso atual/dia), exercicio fisico supervisionado, tratamento padrao dos componentes da sindrome metabolica e manutencao de tratamento medicamentoso com metformina e N-acetilcisteina. O grupo controle recebeu orientacoes gerais de dieta e perda de peso, estimulo a pratica de exercicio fisico, tratamento padrao dos componentes da sindrome metabolica e manutencao do tratamento medicamentoso com metformina. Criterios de inclusao: portadores de pelo menos uma caracteristica de sindrome metabolica, IMC . 25 e . 40kg/m2, e sedentarios por no minimo tres meses. Criterios de exclusao: outras doencas hepaticas concomitantes, ingestao alcoolica igual ou superior a 21 doses/semana ou 140g/dia para homens e 14 doses/semana ou 70g/dia para mulheres, medicacao conhecidamente relacionada com DHGNA, hipotireoidismo ou hipertireoidismo nao tratados, pos operatorio de cirurgia bariatrica, compulsao alimentar ou outro disturbio psiquiatrico nao controlado. Criterios diagnosticos: o diagnostico de NASH foi feito por biopsia de figado em pacientes portadores de esteatose ao ultrassom ou ressonancia magnetica e pelo menos um fator de risco para fibrose avancada, no periodo de ate 1 ano antes da entrada no estudo. Programa de mudanca no estilo de vida no grupo tratado teve como meta a reducao minima ou superior a 5% de seu peso inicial no periodo de seis meses. Criterios de avaliacao: aplicado mensalmente o protocolo de avaliacao clinica e trimestralmente o laboratorial, de acordo com as seguintes variaveis: peso, altura, indice de massa corporal, circunferencia abdominal, circunferencia do quadril, niveis de aminotransferases, gama GT, colesterol total e fracoes, triglicerideos. Analise estatistica: as variaveis descritivas foram expressas em frequencia, media ou mediana, desvio padrao e variacao conforme aplicaveis. Foram utilizados os testes t de Student e teste de Mann-Whitney para analises comparativas. Foi admitido intervalo de confianca de 95% e nivel de significancia para P<0,05. Resultados: Dos 15 pacientes incluidos com diagnostico de NASH que foram submetidos ao programa de mudanca no estilo de vida, 12 pacientes concluiram o acompanhamento de 6 meses do estudo. A idade média foi de 51,42 anos ± 8,50, sendo 08 (66%) pessoas do gênero feminino e 04(33%) do gênero masculino. Deste total, apenas um paciente negou a realização de atividade física. Dois (17%) participantes dentre os 12 que concluíram os seis meses de acompanhamento atingiram a porcentagem de perda de peso esperada. A média da porcentagem de adequação à dieta proposta dos participantes do estudo encontrada foi de 82,93% ± 13,51%. Conclusão: O programa de mudança no estilo de vida testado durante seis meses associado ao tratamento do NASH, não foi eficaz para a melhora clínica e bioquímica mesmo com adesão satisfatória pela maioria dos pacientes. Este estudo de vida real produziu informações de fundamental importância para readequação do protocolo de atendimento multidisciplinar dos pacientes em acompanhamento no serviço.

Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2018-01-08T16:01:25Z No. of bitstreams: 1 viniciusdelimafreitas_tese.pdf: 8494219 bytes, checksum: 35b61ce25b380b2ebf2433cf44ff18e5 (MD5) / Made available in DSpace on 2018-01-08T16:01:25Z (GMT). No. of bitstreams: 1 viniciusdelimafreitas_tese.pdf: 8494219 bytes, checksum: 35b61ce25b380b2ebf2433cf44ff18e5 (MD5) Previous issue date: 2017-05-05 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Introduction: The prevalence of hepatic steatosis and non-alcoholic fatty liver disease (NAFLD) in the Brazilian population is not known, and there are few studies about this disease in the country. Lifestyle modification, including physical activity and exercise are first line recommendation for the tratment of patients with NAFLD. Aim: To evaluate the efficacy of the Supervised physical activity and exercise program on-site and distance-supervised with duration of 12-month for patients with non-alcoholic steatohepatitis (NASH). Methods: This is a prospective, longitudinal, open cohort study including consecutive patients who had a histological diagnosis of NASH in the last 12 months and who were followed up at the outpatient NAFLD clinic. Exclusion criteria were: patients with concomitant liver diseases who could lead to steatosis; history or active significant alcohol intake such as equal or greater than 210g / week for men and 140g / week for women; drugs known to be related to NAFLD; untreated hypo or hyperthyroidism; pevious bariatric surgery; obesity equal or greater than grade III; binge eating or other uncontrolled psychiatric disorder. The patients were studied withing a pre-stated protocol study including clinical and laboratory evaluation, as well as the Baecke questionnaire and the six minute walk test (6MWT), before and after participation in the physical conditioning program. Descriptive statistics, Student's tes and the Mann-Whitney test, were performed for parametric and non-parametric variables as apropriated. The significance level adopted was p-value >0.05. Results: From the 15 included patients, three of them did not complete the multidisciplinary program during the 12-month study period. Thus, the total sample analyzed was 11 patients, that is, 73.33% of included patients. The 5% goal for body weight loss was not reached, however low density lipoprotein (LDL) presented significant reduction at the end of the study (p = 0.0130). The distance-supervised program was chosen by all patients and walking was the main physical activity (66.67%), followed by soccer. The 6-min walk distance (6MWD) was sgnificantly higher at trhee and six month when compared with basal distance at the entry of the study. Conclusion: The distancesupervised physical activity and exercise program had high adherence and was effective in improving the functional capacity for patitients with NASH. On the other hand, there was partial improvement for biochemical and antropometric variables. Aditionally, this is a distance-supervised life-style modification program with low cost and high potential cost-benefit for patients with DHGNA and NASH attended on the National Health System. / Introdução: A prevalência da Esteatose Hepática (EH) e da Doença Hepática Gordurosa Não Alcoólica (DHGNA) na população brasileira não é conhecida, e são poucos os estudos sobre esta doença no país. A mudança no estilo de vida representa a principal recomendação para o tratamento da DHGNA, assim, a atividade física e o exercício físico são ferramentas eficientes no combate à dislipidemia e acúmulo de gordura no fígado. Objetivo: Avaliar os efeitos do programa de condicionamento físico supervisionado in loco e supervisionado à distância com duração de 12 meses em pacientes com Esteatohepatite não alcoólica (NASH). Casuística e Método: Trata-se de um estudo de coorte aberto prospectivo, longitudinal, no qual foram estudados, pacientes em acompanhamento nos ambulatórios de DHGNA do Hospital de Base de São José do Rio Preto, que tiveram o diagnóstico histológico de NASH nos últimos 12 meses. Os critérios de exclusão apresentados foram: pacientes com outras doenças hepáticas concomitantes que possam cursar com esteatose; história prévia de ingestão alcoólica igual ou superior a 210g/semana para homens e 140g/semana para mulheres; medicação conhecidamente relacionada com a etiologia de DHGNA; hipotireoidismo ou hipertireoidismo não tratado; pós-operatório de cirurgia bariátrica; obesidade maior ou igual ao grau III; compulsão alimentar ou outro distúrbio psiquiátrico não controlado. Os pacientes foram analisados em protocolo de avaliação clínica e laboratorial, como o questionário de Baecke e o Teste de Caminhada de 6 minutos (TC6), antes e após a participação no programa de condicionamento físico em estudo. A estatística descritiva foi composta pelas variáveis paramétricas e não paramétricas (média, desvio padrão). As comparações entre os valores basais e, após a intervenção do programa de condicionamento físico foram efetuadas pelo teste t de Student (dados pareados) e teste não paramétrico de Mann-Whitney, com nível de significância (valores de p) inferior a 0,05. Resultados: Dos 15 pacientes incluídos no estudo, três pacientes não concluíram o programa multidisciplinar no período de 12 meses. Assim, a amostra total analisada foi de 11 pacientes, isto é, 73,33% dos incluídos no estudo. O programa supervisionado a distância foi escolhido por todos os pacientes avaliados tendo a caminhada como atividade física mais praticada (66,67%), seguido do futebol. A meta de perda de 5% do peso corporal não foi atingida ao final do estudo, e a lipoproteína plasmática de baixa densidade (LDL) apresentou redução significante (Tempo 4, p=0,0130) durante o estudo. A Distância Percorrida no Teste (DTC6) foi maior nos Tempos 1 e 2 quando comparado ao Tempo 0, com diferença significante (p < 0,05). Conclusão: O programa de condicionamento físico supervisionado à distância teve alta adesão e foi eficaz para a melhora da capacidade funcional de pacientes com NASH. A melhora foi parcial para os parâmetros bioquímicos e antropométricos. Adicionalmente, este programa de condicionamento físico, monitorado à distância, tem baixo custo e é de facil implantação no Sistema Único de Saúde, com alto potencial de custo-benefício para pacientes com DHGNA e NASH, que poderão ser maiores a longo prazo.

University of Macau / Institute of Chinese Medical Sciences

Nonalcoholic fatty liver disease (NAFLD) afflicts approximately a quarter of the world’s general population and more than half of the world’s obese population. The disease is characterized by a spectrum of liver pathologies, ranging from simple steatosis or the accumulation of fat within hepatic tissue to steatohepatitis comprised of inflammation and fibrosis, also known as NASH. Simple steatosis is relatively asymptomatic and is considered benign, but NASH poses great risk for advanced forms of liver disease, such as cirrhosis and hepatocellular cancer. Obstructive sleep apnea(OSA) is a respiratory disorder involving the recurrent collapse of the upper airway during sleep. Consequently, the patient experiences constant arousals due to constant blockage followed reopening of the airway. Aside from poor quality and disruption of sleep, chronic intermittent hypoxia (CIH) is also present during OSA. The presence of CIH leaves many vital organs deprived of adequate oxygen to carry out normal physiological function. In response to this hypoxic state, the body upregulates many transcription factors, many of which control inflammatory processes. In recent studies, chronic and recurrent hypoxia generated from OSA has been implicated in the onset and progression of NAFLD. The pathogenesis of NAFLD is believed to be associated with metabolic imbalances, mainly obesity and insulin resistance, both of which also overlap with OSA. These conditions are the main factors in predisposing a patient suffering from OSA to the effects of CIH. Multiple lines of evidence suggest that CIH may accelerate the development of NAFLD through 1) Lipolysis of hepatic adipose tissue and increased hepatic free fatty acids; 2) Upregulation of lipid biosynthetic through CIH; 3) Upregulation of hypoxia-inducible factor 1-alpha by CIH inducing liver inflammation and fibrosis. The primary focus of this thesis will attempt to determine a possible link between OSA and NAFLD. Through citation of prior scientific studies, it will formulate the theory of OSA as a predisposing factor in the heightened risk of NAFLD pathogenesis and development to more severe, terminal stages. Primarily, the review of literature will highlight the metabolic imbalances of obesity and insulin resistance and how each is related to OSA and NAFLD. Ultimately, deposition of fat and inflammation triggered through various chemical factors connected to OSA will depict both the generation and progression of NAFLD.

Made available in DSpace on 2014-06-11T19:22:13Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-17Bitstream added on 2014-06-13T19:27:11Z : No. of bitstreams: 1 lucchesi_an_me_botfm.pdf: 749829 bytes, checksum: 0aa5e082ee905bd7a05a8698d3112ee3 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O diabetes mellitus (DM) é tido como um problema de saúde pública mundial. No Brasil ele atinge mais de 14 milhões de pessoas, sendo acompanhado de altos índices de morbidade e mortalidade. Entretanto, os mecanismos primariamente responsáveis pela agressão dos tecidos e órgãos pelo DM ainda não são completamente conhecidos, o que explica a dificuldade em se estabelecer um tratamento eficaz para prevenir ou controlar a progressão das lesões diabéticas crônicas. O estresse oxidativo celular é tido como um dos mecanismos importantes na gênese do dano tecidual relacionado à hiperglicemia. Através deste mecanismo, o DM poderia aumentar a produção de espécies reativas do oxigênio (EROs) ao nível celular, que pela sua toxicidade, seria capaz de promover o desenvolvimento das lesões diabéticas crônicas. Evidências clínicas sugerem que o fígado de indivíduos diabéticos também poderia sofrer a ação das EROs, no longo prazo, levando a uma seqüência de eventos capaz de determinar a doença gordurosa do fígado de etiologia não-alcoólica (DGFNA), com progressão para esteato-hepatite e cirrose. Todavia, a presença de estresse oxidativo no tecido hepático de portadores de DM, ainda não está bem estabelecida na literatura, o que justifica a realização de novas investigações em modelos-animais de diabetes, no intuito de melhor esclarecer a real participação deste mecanismo na gênese e evolução das lesões hepáticas diabéticas crônicas. Neste estudo foram utilizados 60 ratos machos Lewis, distribuídos em 2 grupos experimentais, com 30 animais cada um, assim designados: GN - Grupo Controle: constituído de ratos normais, não-diabéticos; GD - Grupo Diabético: constituído por animais diabéticos induzidos pela aloxana, sem qualquer tratamento. Cada um dos grupos experimentais foi dividido em 3 subgrupos de ratos, com 10 animais cada um, para serem... / Diabetes mellitus (DM) is considered to be a public-health problem worldwide. In Brazil, it affects 14 million people, and it is accompanied by high morbidity and mortality rates. However, the mechanisms primarily responsible for tissue and organ aggression by DM are not yet fully known, which explains the difficulty in establishing effective treatment to prevent or control the progression of chronic diabetic lesions. Cellular oxidative stress is considered to be one of the important mechanisms in the genesis of hyperglycemia-related tissue damage. Through this mechanism, DM could increase the production of reactive oxygen species (ROS) in the cellular level, which, due to their toxicity, could promote the development of chronic diabetic lesions. Clinical evidence suggests that the liver of diabetic individuals could also suffer the action of ROS in the long term, thus leading to a sequence of events that can determine non-alcoholic fatty liver disease (NAFLD), with progression to steatohepatitis and cirrhosis. However, the presence of oxidative stress in the hepatic tissue of individuals with DM has not been yet well established in the literature, which justifies the performance of new investigations in diabetes animal models with the purpose to clarify the actual participation of such mechanisms in the genesis and development of chronic diabetic hepatic lesions. In this study, 60 males Lewis rats were used. They were distributed into 2 experimental groups, each containing 30 animals and designated as follows: GN – Control Group: consisting of non-diabetic control rats; GD – Diabetic Group: consisting of alloxan-induced diabetic rats without any treatment. Each experimental group was divided into 3 subgroups of rats with 10 animals each to be evaluated and sacrificed respectively at 4 experimental moments, namely: M1– animals from the 3 subgroups, at the initial moment... (Complete abstract click electronic access below)

Non-alcoholic fatty liver disease (NAFLD) is a worldwide health problem which includes steatosis (triglyceride accumulation alone), non-alcoholic steatohepatitis (NASH, with liver inflammation), fibrosis, cirrhosis and hepatocellular carcinoma. Liver fibrosis, which is a reversible response, is the final phase of most chronic liver disease and is characterized by accumulation of extracellular matrix (ECM) from activated hepatic stellate cells (HSCs). Glucocorticoids (GCs) regulate many aspects of metabolism involved in NAFLD. Also, GCs limit HSC activation in vitro. Tissue GC levels are regulated by 11β- hydroxysteroid dehydrogenase-1 (11β-HSD1) which converts inactive 11- dehydrocorticosterone (DHC) into active corticosterone. Previous studies demonstrate that 11β-HSD1 deficiency improves fatty liver in obesity models, but the role of 11β-HSD1 in mechanisms involved in the progression and/or resolution of hepatic injury is largely unknown. I hypothesized that 11β-HSD1 modulates fibrotic and inflammatory responses during hepatic injury and/or the resolution phase. First I sought to address if the levels of 11β-HSD1 during different models of liver injury are dysregulated. In mice, 11β-HSD1 was down-regulated in choline deficient diet (CDD) induced steatosis, methionine and choline deficient diet (MCDD) induced NASH, carbon tetrachloride (CCL4) induced liver fibrosis and thioacetamide (TAA) induced liver fibrosis. In CCL4 injured livers, the down regulation of 11β- HSD1 was observed around the scar area. To test if 11β-HSD1 plays a key role in modulating liver inflammation and fibrosis responses in NAFLD and liver fibrosis I used initially11β-HSD1 knockout (KO) mice. 11β-HSD1 KO showed higher HSC activation only in the High fat feeding model but not in CDD and MCDD models. In the CCL4 injury model, despite reduced hepatocellular injury, 11β-HSD1 KO mice showed enhanced collagen deposition during peak injury and increased fibrotic gene expression during the early resolution phase although unaltered inflammatory markers during both peak injury and resolution. To further dissect cell-specificity on the effect of 11β-HSD1, I repeated the CCL4-injury model using the hepatocyte-specific 11β-HSD1 KO (Alb-HSD1). Alb-HSD1 mice did not show increased susceptibility to fibrosis compared to control littermates suggesting that the 11β- HSD1 possibly modulates fibrotic response by affecting HSC function. To mechanistically address how GCs inhibit HSC activation in vitro I studied the effects of 11β-HSD1 on HSC in vitro. 11β-HSD1 expression was down-regulated during ‘spontaneous’ HSC activation, and 11β-HSD1 deficiency enhanced susceptibility to activation. The GC (11-DHC)’s inhibitory effect on HSC activation was reversed by 11β-HSD1 inhibition. Finally, to address the clinical relevance of 11β-HSD1 in hepatic injury and/or resolution a selective 11β-HSD1 inhibitor, UE2316, was used. UE2316 induced a pro-fibrotic phenotype in ob/ob mice and CCL4-treated C57BL/6 mice, but had no effect when administered only during injury resolution. In conclusion, 11β-HSD1 deficiency causes increased activation of HSCs following diet and chemical injury and promotes liver fibrosis. Effects of 11β-HSD1 inhibitors, which are a potential treatment for metabolic syndrome, are perhaps offset by adverse outcomes in liver.

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