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ABCD2 (D2) is a peroxisomal ATP binding cassette (ABC) transporter that is expressed in brain, adrenal and liver. D2 is transcriptionally regulated by key transcriptional factors that control lipid and glucose metabolism. Therefore, we examined its role in adipose tissue. These studies revealed that D2 is highly abundant in adipose tissue and upregulated during adipogenesis. However, D2 deficiency does not affect either adipogenesis or lipid accumulation. An examination of the lipid profile of adipose tissue revealed the accumulation of C20 and C22 fatty acids in D2 deficient (D2‐/‐) mice. When challenged with a diet enriched in erucic acid (C22:1, 10% kcal), this lipid accumulated in both liver and adipose tissue. Following 8 weeks of diet, D2‐/‐ mice showed increased adiposity, glucose intolerance, dyslipidemia and steatosis. Analysis of the hepatic lipid profile showed significant changes away from poly unsaturated fatty acids (PUFAs) and toward C18‐22 mono‐unsaturated fatty acids (MUFA). RT‐PCR of the mRNA from the adipose tissue and liver revealed significant changes in lipogenic (ACC, SCD1 & 2) and PUFA synthesis (Δ5 & 6‐desaturase) genes in D2‐/‐ mice. The molecular mechanisms by which D2 regulates lipid metabolism in adipose tissue remains unclear. To explore potential mechanisms, the subcellular localization of D2 in adipose tissue was determined. Our results demonstrated that D2 resides in a distinct subclass of peroxisomes that does not containing classical peroxisomal markers such as pex19 or PMP70, but are positive for pex14. In conclusion, our studies reveal a novel role of D2 and peroxisomes in the protection from disruptions of lipid metabolism induced by dietary erucic acid and that D2 resides in a unique compartment within adipocytes that plays a yet to be elucidated role in the regulation of lipid metabolism.

Coffee consumption has consistently been associated with a reduction in risk of type 2 diabetes mellitus (T2DM), although the mechanism for this association remains unknown. Sub-clinical inflammation, non-alcoholic fatty liver disease (NAFLD), and lipoprotein abnormalities characterize and predict T2DM. Limited evidence suggests that coffee may have a beneficial role in these disorders but further investigation is warranted. Our aim therefore was to investigate the associations of caffeinated and decaffeinated coffee with markers of inflammation, liver injury, and lipoproteins, in a non-diabetic cohort. No significant associations of caffeinated or decaffeinated coffee with inflammatory markers or lipoproteins were identified. Caffeinated coffee consumption however was inversely associated with alanine aminotransferase (β= -0.09, p= 0.0107) and aspartate aminotransferase (β= -0.05, p= 0.0161) in multivariate analysis. Decaffeinated coffee was not associated with liver enzymes. These analyses suggest that caffeinated coffee’s beneficial impact on NAFLD may be a potential mechanism for its inverse association with T2DM.

Coffee consumption has consistently been associated with a reduction in risk of type 2 diabetes mellitus (T2DM), although the mechanism for this association remains unknown. Sub-clinical inflammation, non-alcoholic fatty liver disease (NAFLD), and lipoprotein abnormalities characterize and predict T2DM. Limited evidence suggests that coffee may have a beneficial role in these disorders but further investigation is warranted. Our aim therefore was to investigate the associations of caffeinated and decaffeinated coffee with markers of inflammation, liver injury, and lipoproteins, in a non-diabetic cohort. No significant associations of caffeinated or decaffeinated coffee with inflammatory markers or lipoproteins were identified. Caffeinated coffee consumption however was inversely associated with alanine aminotransferase (β= -0.09, p= 0.0107) and aspartate aminotransferase (β= -0.05, p= 0.0161) in multivariate analysis. Decaffeinated coffee was not associated with liver enzymes. These analyses suggest that caffeinated coffee’s beneficial impact on NAFLD may be a potential mechanism for its inverse association with T2DM.

Introdução: Doentes Hepáticos mesmo após o Transplante de Fígado (TF) apresentam heranças fisiopatológicas que podem influenciar na diminuição da Capacidade Funcional (CF). Objetivo: Traçar o perfil dos pacientes pós TF em relação à CF, e definir quais os melhores exercícios físicos para compor futuro programa de condicionamento físico dos pacientes, tanto antes como depois do TF. Métodos: Estudo transversal com 52 pacientes submetidos ao TF entre os anos de 2002 e 2013. Foi realizado o Teste de Caminhada de 6 minutos (TC6). Resultados: 51,9% dos pacientes eram homens, sendo a média de idade da amostra 58 + 10,26 anos. Entre os participantes, 48,1% eram hipertensos, 42,3% obesos e 40,4% tinham diabetes tipo II. Tacrolimus é o medicamento mais utilizado em 84,6% dos pacientes. O DPTC6 média total foi de 497 + 90 metros, onde os homens andavam distância média mais alta que as mulheres (531 + 70 e 460 + 95 metros respectivamente). Sexo e Idade foram significativas (p=0,002 e p=0,011), evidenciando que a média do TC6 é maior em homens mais jovens do que em mulheres, independentemente do tempo transcorrido após o TF (p>0,05). Em relação a prática de exercícios físicos, apesar de não ser estatisticamente significativa, evidenciou-se que praticantes possuem melhores DPTC6. Conclusão: A DPTC6 por pacientes já submetidos ao Transplante de Fígado no Hospital de Clínicas de Porto Alegre, é indicativa de boa capacidade funcional, principalmente entre os pacientes mais jovens, os do sexo masculino e praticantes de exercícios físicos. / Introduction: The pathophysiological profile of patients with liver disease may impact functional capacity even after liver transplantation (LT). Objective: To describe functional capacity after LT in a group of Brazilian patients. Methods: This cross-sectional study included 52 patients submitted to LT between 2002 and 2013. Functional capacity was determined using the six-minute walk test (6MWT). Results: The mean age of the overall sample was 58 ± 10.26 years, and 51.9% were male. Hypertension was detected in 48.1%, obesity in 42.3%, and type 2 diabetes in 40.4%. Tacrolimus was the most used medicine (84.6% of patients). The mean distance traveled in the 6MWT was 497 + 90 m (531 ± 70 m for males vs. 460 ± 95 m for females). Gender and age were significantly associated with 6MWT results (p=0.002 and p=0.011), showing a higher mean 6MWT distance in younger men than in women, regardless of the time elapsed since LT (p<0.05). In relation to physical exercise, physically active individuals had more favorable 6MWT results; however, this association was not statistically significant. Conclusion: The present group of LT patients had good functional capacity as measured by the 6MWT, especially younger patients, male patients, and physically active patients.

Chronic liver diseases, which includes alcoholic liver disease (ALD), are consistently among the top 15 leading causes of death in the United States. ALD is characterized by progression from a normal liver to fatty liver disease (hepatic steatosis), which can lead to cirrhosis, alcoholic hepatitis, and liver failure. We have identified a novel role of phosphohistidine signaling, mediated through phosphohistidine phosphatase 1 (PHPT1), in the onset of hepatic steatosis. We have identified PHPT1 as a target of selective oxidation following acute ethanol exposure as well as being downregulated following chronic ethanol exposure. We mapped the oxidative modification site and developed a mass-spectrometry based phosphohistidine phosphatase assay to determine the impact of PHPT1 oxidative modification during acute ethanol exposure. To further understand the role of PHPT1 and phosphohistidine signaling during chronic ethanol exposure, we have developed PHPT1 overexpression and knockout mouse models. These mouse models were characterized using mass spectrometry-based proteomics. They were then utilized in a 10-day chronic ethanol plus binge model to determine the impact of PHPT1 expression on the onset of ethanol-induced hepatic steatosis. In addition, advanced mass spectrometry-based phenotypic characterization was performed on the treated liver tissues to determine the key regulators and canonical pathways influencing phosphohistidine signaling during chronic ethanol exposure. We have evidence to suggest that PHPT1 overexpression plays a protective role in the onset of hepatic steatosis, the PHPT1 heterozygous model is more susceptible to liver damage, and the complete knockout model is embryonically lethal. Additionally, we have identified novel pathways and regulators involved in phosphohistidine signaling during the development of ethanol-induced hepatic steatosis.

Objetivos: Quantificar a ingestão dietética de adultos portadores de hepatopatia crônica correlacionando-a ao estado nutricional, e comparar diferentes métodos de avaliação nutricional nesta população, especialmente métodos de avaliação funcional (dinamometria - FAM - e espessura do músculo adutor do polegar - MAP) e a avaliação global do Royal Free Hospital (RFH-GA). Materiais e métodos: Foram avaliados 97 pacientes ambulatoriais do Hospital de Clínicas de Porto Alegre, com diagnóstico de hepatopatia crônica (41 hepatite crônica – HCr - e 56 cirróticos - CIR) entre abril de 2009 e janeiro de 2010. Foi realizada avaliação nutricional através de inquérito alimentar (R24h), antropometria - Índice de massa corporal (IMC) e circunferência muscular do braço (CMB), avaliação subjetiva global (ASG), FAM, RFH-GA e MAP. Resultados: Pacientes do grupo HCr apresentaram maior ingestão calórica total (p=0,005) e maior ingestão proteica (p<0,0001) que os pacientes CIR. Houve relação entre RFH-GA (p<0,001) e FAM (p<0,05) e ingestão de calorias e proteínas. A prevalência de desnutrição no grupo HCr e no grupo CIR foi, de acordo com RFH-GA (51,2 vs 84% - p=0,002), FAM (61 vs 82,1% - p=0,02), ASG (14,6 vs 32,1% - p=0,048), MAP (7,3vs 14,3% - p=NS), CMB (4,9 vs 14,3% - p=NS) e IMC (2,4 vs 3,6% - p=NS). Houve concordância moderada entre FAM e RFH-GA (k=0,43). Conclusão: Pacientes portadores de hepatopatia crônica, mesmo não cirróticos, têm ingestão energética e proteica inadequadas. Desnutrição é frequente nos dois grupos, especialmente na cirrose. FAM e RFH-GA são os métodos que identificaram maior prevalência de desnutrição nesta população e apresentam concordância entre si. A ingestão insuficiente de calorias e proteinas foi associada ao diagnóstico de DPC pela RFH-GA e FAM. / Background/aims: Objectives: To quantify the dietary intake of adults with chronic liver disease and correlate the nutritional status. Compare different methods of nutritional assessment in this population, in special methods of functional evaluation (hand grip streght – HG and The thickness of the adductor pollices muscle - APM) and the Royal Free Hospital global assessment (RFH-GA). Methods: 97 patients at the Hospital de Clinicas de Porto Alegre, diagnosed with chronic liver disease (41 chronic hepatitis - CH - and 56 cirrhotic - CIR) between April 2009 and January 2010 was assessed. Nutritional assessment was carried out by dietary recall (24HR), anthropometry (body mass index - BMI - body and arm muscle circumference - AMC), subjective global assessment (SGA), HG, RFH-GA and APM. Results: CH group patients had higher total caloric intake (p = 0.005) and higher protein intake (p <0.0001) than patients CIR. There was a relationship between the RFH-GA (p <0.001) and HG (p <0.001) and intake of calories and proteins. The prevalence of malnutrition in the CH group and the CIR group was by RFH-GA (51.2 vs. 84% - p = 0.002), HG (61 vs 82.1% - p = 0.02), SGA (14.6 vs. 32.1% - p = 0.048), APM (7.3 vs 14.3% - p> 0.05), MAC (4.9 vs 14.3% - p> 0.05) and BMI (2.4 vs. 3.6% - p> 0.05). There was moderate agreement between HG and RFH-GA (k = 0.43). Conclusion: Patients HC and CIR have energy and protein intake inadequate. Malnutrition is common in both groups, especially in the second. RFH-GA and HG are the best methods to identify malnutrition in this population and usually correlate with each other. The insufficient intake of calories and protein contributed to the diagnosis of malnutrition by RFH-GA and HG.

A hepatopatia da fibrose cística (FC) é uma complicação grave sendo descrita como terceira causa de morte nestes pacientes. Sua prevalência é muito variável, desde 14,3% até 41% em crianças e adolescentes. A discrepância entre os diferentes estudos clínicos se deve à forma utilizada para o diagnóstico da hepatopatia (características clínicas, bioquímicas e/ou ultra-sonográficas), à idade dos pacientes selecionados, ao tipo de estudo empregado (transversal ou longitudinal) e também, à falta de um marcador específico e sensível de disfunção hepatobiliar. Em 1995, Williams et al, elaboraram um escore ultra-sonográfico que mostrou boa relação com as alterações laboratoriais hepáticas pretendendo, desta forma, graduar o nível da lesão hepática. O escore foi elaborado por meio da avaliação do padrão do parênquima hepático, do contorno do fígado e do grau de ecogenicidade periportal. Quanto aos marcadores não invasivos para diagnosticar a doença hepática, vários tem sido estudados, entre eles o ácido hialurônico (AH).O AH é o maior mucopolissacarídeo componente da matriz extracelular, é encontrado na maioria dos tecidos e fluidos corporais, particularmente abundante em tecido conectivo frouxo. É sintetizado na membrana citoplasmática de fibroblastos e de outras células, sendo que uma pequena parte é metabolizada neste local. Através dos vasos linfáticos chega à corrente sanguínea e é rapidamente eliminada pelo fígado, ao nível do sinusóide hepático. Neste estudo buscamos relacionar as alterações ultra-sonográficas com o nível sérico de AH e, desta forma, realizar o diagnóstico precoce da hepatopatia da FC. Foi realizado um estudo transversal em 57 pacientes com FC, todos caucasóides, que apresentavam uma média de idade de 10,2 + 4,9 anos. A avaliação constou de dados clínicos, laboratoriais e ultra-sonográficos. Os pacientes foram classificados de acordo com um escore ultra-sonográfico em:Grupo 1 (G1) – ausência de doença hepática: escore 3; - Grupo 2 (G2) – doença hepática moderada: escore 4 – 6; - Grupo 3 (G3) – doença hepática grave: escore 7 - 9. O nível sérico do ácido hialurônico foi medido através da técnica de ELISA (Enzyme Linked Immunoassay) e comparado com 23 controles saudáveis. Vinte e nove pacientes foram incluídos no G1, dezoito pacientes no G2 e dez pacientes no G3. Os pacientes do sexo masculino apresentaram escore ultra-sonográfico mais alterado (P= 0,018). O nível sérico da ALT e da AST foram consideravelmente mais elevados no G3 do que no G1. O nível sérico da GGT foi mais elevado no G3 do que no G1 e G2. A porcentagem do volume expiratório forçado no primeiro segundo (%VEF1) apresentou uma correlação positiva fraca com o escore Z P/I (r= 0,31/P= 0,031). O nível sérico de AH variou de 1,8 a 45 ng/mL (mediana= 13,9), apresentou uma mediana semelhante entre os grupos 1,2,3 e o grupo controle (P= 0,431), entre os grupos 1,2 e 3 (P= 0,24) e também, quando comparado cada grupo com o grupo controle (todos P> 0,1). Não houve correlação entre o nível sérico de AH e o escore ultra-sonográfico (P= 0,164). Desta forma, concluímos que o AH isoladamente não se mostrou um marcador da hepatopatia causada pela fibrose cística. / Cystic fibrosis (CF) liver disease (LD) is a serious complication, being described as the third cause of death in these patients. Its prevalence varies widely, from 14.3% to 41.0% in children and adolescents. The discrepancy shown by the various clinical studies is due to the method employed for the diagnosis of LD (clinical, biochemical and/or ultrasonographic characteristics), the age of selected patients, the type of study (crosssectional or longitudinal) and the absence of a specific and sensitive marker. In 1995, WILLIAMS et al, developed an ultrasonographic score that showed a good relation to liver biochemical alterations, in order to measure the liver involvement. The score was elaborated through an evaluation of three cardinal features of hepatic ultrasound in CF: coarseness of the parenchyma, nodularity of the liver edge and increased periportal echogenicity. Regarding non-invasive markers to diagnose the hepatic disease, several have been studied, among them the hyaluronic acid (HA). Hyaluronic acid is a major mucopolysaccharide in the extracellular matrix, found in most body tissues and fluids, particularly abundant in loose connective tissue. It is synthetized in the cytoplasmatic membrane of fibroblasts and other cells, with a small part being metabolized there. Through the lymph vessels, it reaches the bloodstream and is rapidly eliminated by the liver, at the hepatic sinusoid level. In this study, we attempted to correlate the ultrasound findings with HA serum level, and thus, obtain the early diagnosis of CFLD. A cross-sectional study was performed with 57 patients with CF, all white individuals presenting mean age of 10.2 + 4.9 years. The evaluation considered clinical, laboratorial and ultrasonographic data. The patients were classified according to an ultrasonographic score into: - Group 1 (G1) – absence of liver disease: score 3- Group 2 (G2) – moderate liver disease: score 4 – 6; - Group 3 (G3) – severe liver disease: score 7 - 9. HA serum level was measured by ELISA (Enzyme Linked Immunoassay) in the CF patients and 23 healthy controls. Twenty-nine patients were included in G1, 18 in G2 and 10 in G3. The male patients presented an ultrasonographic score with more alterations (P= 0,018). The serum levels of ALT and AST in G3 were considerably higher than in G1. The serum level of GGT in G3 was higher than in G1 and G2. The percent of forced expiratory volume in the first second (%FEV1) presented a small positive correlation with Z score W/A (r= 0.31/P= 0.031). HA serum level ranged from 1.8 to 45 ng/mL (mean = 13.9), and presented a similar mean value between Groups 1,2,3 and the control group (P= 0.431), among Groups 1,2 and 3 (P= 0.24), as well as when comparing each group to the control group (all P> 0.1). There was no correlation between HA serum level and ultrasonographic score (P= 0.164). Thus, we concluded that HA lonely cannot be considered as a marker of liver disease caused by cystic fibrosis.

A hepatopatia da fibrose cística (FC) é uma complicação grave sendo descrita como terceira causa de morte nestes pacientes. Sua prevalência é muito variável, desde 14,3% até 41% em crianças e adolescentes. A discrepância entre os diferentes estudos clínicos se deve à forma utilizada para o diagnóstico da hepatopatia (características clínicas, bioquímicas e/ou ultra-sonográficas), à idade dos pacientes selecionados, ao tipo de estudo empregado (transversal ou longitudinal) e também, à falta de um marcador específico e sensível de disfunção hepatobiliar. Em 1995, Williams et al, elaboraram um escore ultra-sonográfico que mostrou boa relação com as alterações laboratoriais hepáticas pretendendo, desta forma, graduar o nível da lesão hepática. O escore foi elaborado por meio da avaliação do padrão do parênquima hepático, do contorno do fígado e do grau de ecogenicidade periportal. Quanto aos marcadores não invasivos para diagnosticar a doença hepática, vários tem sido estudados, entre eles o ácido hialurônico (AH).O AH é o maior mucopolissacarídeo componente da matriz extracelular, é encontrado na maioria dos tecidos e fluidos corporais, particularmente abundante em tecido conectivo frouxo. É sintetizado na membrana citoplasmática de fibroblastos e de outras células, sendo que uma pequena parte é metabolizada neste local. Através dos vasos linfáticos chega à corrente sanguínea e é rapidamente eliminada pelo fígado, ao nível do sinusóide hepático. Neste estudo buscamos relacionar as alterações ultra-sonográficas com o nível sérico de AH e, desta forma, realizar o diagnóstico precoce da hepatopatia da FC. Foi realizado um estudo transversal em 57 pacientes com FC, todos caucasóides, que apresentavam uma média de idade de 10,2 + 4,9 anos. A avaliação constou de dados clínicos, laboratoriais e ultra-sonográficos. Os pacientes foram classificados de acordo com um escore ultra-sonográfico em:Grupo 1 (G1) – ausência de doença hepática: escore 3; - Grupo 2 (G2) – doença hepática moderada: escore 4 – 6; - Grupo 3 (G3) – doença hepática grave: escore 7 - 9. O nível sérico do ácido hialurônico foi medido através da técnica de ELISA (Enzyme Linked Immunoassay) e comparado com 23 controles saudáveis. Vinte e nove pacientes foram incluídos no G1, dezoito pacientes no G2 e dez pacientes no G3. Os pacientes do sexo masculino apresentaram escore ultra-sonográfico mais alterado (P= 0,018). O nível sérico da ALT e da AST foram consideravelmente mais elevados no G3 do que no G1. O nível sérico da GGT foi mais elevado no G3 do que no G1 e G2. A porcentagem do volume expiratório forçado no primeiro segundo (%VEF1) apresentou uma correlação positiva fraca com o escore Z P/I (r= 0,31/P= 0,031). O nível sérico de AH variou de 1,8 a 45 ng/mL (mediana= 13,9), apresentou uma mediana semelhante entre os grupos 1,2,3 e o grupo controle (P= 0,431), entre os grupos 1,2 e 3 (P= 0,24) e também, quando comparado cada grupo com o grupo controle (todos P> 0,1). Não houve correlação entre o nível sérico de AH e o escore ultra-sonográfico (P= 0,164). Desta forma, concluímos que o AH isoladamente não se mostrou um marcador da hepatopatia causada pela fibrose cística. / Cystic fibrosis (CF) liver disease (LD) is a serious complication, being described as the third cause of death in these patients. Its prevalence varies widely, from 14.3% to 41.0% in children and adolescents. The discrepancy shown by the various clinical studies is due to the method employed for the diagnosis of LD (clinical, biochemical and/or ultrasonographic characteristics), the age of selected patients, the type of study (crosssectional or longitudinal) and the absence of a specific and sensitive marker. In 1995, WILLIAMS et al, developed an ultrasonographic score that showed a good relation to liver biochemical alterations, in order to measure the liver involvement. The score was elaborated through an evaluation of three cardinal features of hepatic ultrasound in CF: coarseness of the parenchyma, nodularity of the liver edge and increased periportal echogenicity. Regarding non-invasive markers to diagnose the hepatic disease, several have been studied, among them the hyaluronic acid (HA). Hyaluronic acid is a major mucopolysaccharide in the extracellular matrix, found in most body tissues and fluids, particularly abundant in loose connective tissue. It is synthetized in the cytoplasmatic membrane of fibroblasts and other cells, with a small part being metabolized there. Through the lymph vessels, it reaches the bloodstream and is rapidly eliminated by the liver, at the hepatic sinusoid level. In this study, we attempted to correlate the ultrasound findings with HA serum level, and thus, obtain the early diagnosis of CFLD. A cross-sectional study was performed with 57 patients with CF, all white individuals presenting mean age of 10.2 + 4.9 years. The evaluation considered clinical, laboratorial and ultrasonographic data. The patients were classified according to an ultrasonographic score into: - Group 1 (G1) – absence of liver disease: score 3- Group 2 (G2) – moderate liver disease: score 4 – 6; - Group 3 (G3) – severe liver disease: score 7 - 9. HA serum level was measured by ELISA (Enzyme Linked Immunoassay) in the CF patients and 23 healthy controls. Twenty-nine patients were included in G1, 18 in G2 and 10 in G3. The male patients presented an ultrasonographic score with more alterations (P= 0,018). The serum levels of ALT and AST in G3 were considerably higher than in G1. The serum level of GGT in G3 was higher than in G1 and G2. The percent of forced expiratory volume in the first second (%FEV1) presented a small positive correlation with Z score W/A (r= 0.31/P= 0.031). HA serum level ranged from 1.8 to 45 ng/mL (mean = 13.9), and presented a similar mean value between Groups 1,2,3 and the control group (P= 0.431), among Groups 1,2 and 3 (P= 0.24), as well as when comparing each group to the control group (all P> 0.1). There was no correlation between HA serum level and ultrasonographic score (P= 0.164). Thus, we concluded that HA lonely cannot be considered as a marker of liver disease caused by cystic fibrosis.

Orientador: César Tadeu Spadella / Banca: José Guilherme Minossi / Banca: Silvio Fernando Guideti Marques / Resumo: 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... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: 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) / Mestre