O vÃrus da hepatite C (VHC) e a esteatose sÃo importantes causas de doenÃa hepÃtica crÃnica no mundo. Apesar de comum, a fisiopatologia da esteatose, e seu papel na progressÃo da fibrose em pacientes com VHC, permanece desconhecida. O objetivo deste trabalho foi quantificar esteatose macrovesicular e microvesicular e correlacionÃ-las com dados clÃnicos e histopatolÃgicos. O estudo analisou biÃpsias hepÃticas de pacientes portadores do VHC sem tratamento prÃvio. A fibrose e atividade necroinflamatÃria foram avaliadas segundo os escores de METAVIR e Ishak; as classificaÃÃes de Kleiner e Brunt foram utilizadas como suporte para o diagnÃstico de esteatohepatite realizado pelo patologista. Ademais, o nÃmero de hepatÃcitos com esteatose macrovesicular e esteatose microvesicular foram quantificados a partir do nÃmero total de hepatÃcitos. A fibrose e atividade necroinflamatÃria foram classificadas e semi-quantificadas. Foi encontrada associaÃÃo significante da fibrose avaliada pelo sistema de Ishak entre a esteatose macrogoticular e microgoticular (p= 0,017 e p= 0,0113, respectivamente). A atividade inflamatÃria global (classificaÃÃo Metavir ) apresentou correlaÃÃo linear com a piora da fibrose (< 0,001). A fibrose avaliada pelo sistema de Metavir se correlacionou com o IMC. A presenÃa de VHC associado à esteatohepatite apresentou correlaÃÃo significante com as mÃdias das AST/ALT, e com a fibrose de Ishak e Metavir, quando comparado aos dados dos pacientes com VHC, sem esteatohepatite (p = 0,006; p = 0,012; p = 0,0098 e p = 0,014, respectivamente). Em nosso trabalho, concluÃmos que a fibrose de Ishak esteve associado a esteatose macrogoticular e microgoticular. Igualmente, se demonstrou que a presenÃa da esteatohepatite esteve fortemente associado a fibrose. / The hepatitis C virus (HCV) and steatosis are important causes of chronic hepatic disease in the world. Although common, the pathofisiology of steatosis and its role in the progression of fibrosis in patients with HCV is uncertain. Our objective was to quantify the macrovacuolar and microvesicular steatosis and to correlate them with clinical and histophatologic data. The study included needle biopsy of the liver of patients with HCV without previous treatment. The fibrosis and necroinflammatory activity of hepatic damage by HCV were evaluated by METAVIR and Ishakâs scores; Kleinerâs and Bruntâs classification were used as a support for diagnosis of the steatohepatitis by the pathologist. Furthermore, the number of hepatocytes with the macrovacuolar and microvesicular steatosis was quantified in a total number of hepatocytes. Fibrosis and necroinflammatory activity were categorized and semi quantified. A significant association of the fibrosis was found and it was evaluated by the Ishak system between the macrogoticular and the microgoticular steatosis (p=0,017 e p= 0,0113, respectively). The global inflammatory activity (Metavir classification) has presented a linear correlation with the worsening of the fibrosis (< 0,001). The fibrosis which was evaluated by the Metavir system has been correlated with the BMI. The presence of HCV associated with the steatohepatitis has presented a significant correlation with the average of AST/ALT and with the Ishak and Metavir fibrosis, when compared to the data of the patients with HCV, without steatohepatitis (p= 0,006; p= 0,012; p= 0,0098 and p= 0,014, respectively) In our research we conclude that the Ishak fibrosis has been associated with the macrogoticular and microgoticular steatosis. Equally, it was demonstrated that the presence of the steatohepatitis was strongly associated to the fibrosis.

This study used the non-alcoholic steatohepatitis activity index (NAI), presence of fibrosis and Mallory-Denk bodies (MDBs), and quantification of glucose regulated protein 78 (GRP78) messenger ribonucleic acid (mRNA) as indicators of steatohepatitis development and recovery in the American mink (Neovison vison). Mink were fasted for 0, 1, 3, 5, or 7 days, and one group re-fed 28 days post 7-day fast. Liver NAI indicated that moderate fatty liver developed after 5 days of fasting. Liver recovery was achieved after the re-feeding period. There was no evidence of fibrosis or MDB formation. Upregulation of GRP78 was observed by day 7 of fasting indicating endoplasmic reticulum stress. This effect was greater in females. Results suggest that liver steatosis did not advance to steatohepatitis within a 7-day fast. However, should the length of fast be increased the mink may be at risk. Results also show that liver recovery from simple fatty liver is possible.

No description available.

Thesis (Ph.D.)--Indiana University, 2010. / Title from screen (viewed on July 21, 2010). Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Michael Sturek, Jeffrey A. Breall, Robert V. Considine, Alexander Obukhov, Johnathan D. Tune. Includes vitae. Includes bibliographical references (leaves 212-240).

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22664号 / 農博第2419号 / 新制||農||1080(附属図書館) / 学位論文||R2||N5295(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 佐藤 健司, 教授 澤山 茂樹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

The association between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been suggested by recent epidemiological studies although the results were inconsistent. This meta-analysis was conducted to summarize all available data. Methods A comprehensive literature review was conducted using MEDLINE and EMBASE database through May 2017 to identify all studies that reported the risk of AF among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. Results Of 1009 studies, 5 studies (two cross-sectional studies and three cohort studies) with 238,129 participants met the eligibility criteria and were included in the meta-analysis. The risk of AF in patients with NAFLD was significantly higher than subjects without NAFLD with the pooled risks ratio of 2.06 (95% confidence interval, 1.10–3.85). The statistical heterogeneity was high with an I2 of 78%, which was the major limitation of this meta-analysis. Conclusions A significantly increased risk of AF among patients with NAFLD was demonstrated in this study.

Indiana University-Purdue University Indianapolis (IUPUI) / CXXC finger protein 1 (CFP1) is an epigenetic regulator of H3K4 and cytosine methylation. Due to its role in establishing and maintaining methylation patterns, CFP1 determines whether DNA is found in its euchromatin or heterochromatin state and as such whether genes are transcriptionally active or inactive. In stem cells, deficiency of CFP1 results in inability to differentiate and in murine embryos it results in periimplantation death. Despite the demonstrated importance in developing tissue, the role of CFP1 in mature tissues, such as the liver, has yet to be elucidated. This study examined the role of CFP1 in maintaining liver homeostasis under conditions involving hepatocellular stress by examining liver regeneration, pregnancy-induced hepatomegaly, and non-alcoholic steatohepatitis (NASH) disease progression. The liver’s ability to recover was analyzed through liver:body mass ratios, blood serum analysis, liver histology, and qualitative observations. Deficiency of CFP1 in the livers of animals subjected to partial hepatectomies (PH) resulted in decreased liver regeneration capacity with liver mass restoration becoming significantly different starting at 48H post-PH and remaining so until 10D post-PH. This decreased regeneration appeared to be the result of reduced hepatocyte mitosis. Mouse dams lacking hepatic CFP1 mated with males expressing CFP1 displayed a proclivity for dystocia. Mice subjected to a fast food diet resulting in NASH while lacking hepatic CFP1 experienced decreased weight gain and hepatic lipid accumulation compared to their CFP1 expressing counterparts. Through these three studies, the critical role of CFP1 for the maintenance of liver homeostasis was demonstrated.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18682号 / 医博第3954号 / 新制||医||1007(附属図書館) / 31615 / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 野田 亮, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). NASH is characterized by steatosis, inflammation, cell death, and liver fibrosis and significantly increases the risk of cirrhosis and decompensated liver failure. There are currently no approved drugs on the market for treating NASH leaving a major unmet medical need for drug discovery research. The aim of this dissertation is to better understand the pathophysiology of NASH and elucidate disease driving molecular mechanisms that can be used for drug targeting. Analysis of human liver samples using state of the art mass spectrometry proteomics identified dysregulation of one-carbon metabolism in NASH. This dissertation details the molecular mechanisms for how these proteomic changes can drive NASH pathogenesis and be targeted for therapeutic purposes. Chapter 1 provides an extensive background on NASH prevalence and pathophysiology and the association of one-carbon metabolism and NASH. Chapter 2 presents the identification of reduced glycine N-methyltransferase, a key regulator of one-carbon metabolism, in human NASH patients. Using a diet-induced animal model of NASH and targeted proteomics and metabolomics it was found glycine N-methyltransferase reduction in NASH leads to an accumulation of S-adenosylmethionine, activation of polyamine metabolism, and production of oxidative stress. Oxidative stress is a key component to NASH pathogenesis and this work identifies a novel mechanism for how oxidative stress is produced during NASH. Chapter 3 covers the discovery of increased folate receptor gamma (FOLR3) specifically in the liver of NASH patients. Initially, FOLR3 was predicted to impact one-carbon metabolism through folate metabolism, but molecular characterization found FOLR3 drives liver fibrogenesis independent of one-carbon metabolism. Chapter 3 details the molecular mechanism for how FOLR3 drives liver fibrosis by enhancing transforming growth factor beta activation of hepatic stellate cells through its interaction with serine protease HTRA1. The effect of FOLR3 was then validated in an in vivo model of NASH showing FOLR3 treatment can induce severe liver fibrosis in mice comparable to human liver fibrosis. These findings provide a translational animal model that can be used for NASH drug development and introduce a novel drug target in FOLR3. Chapter 4 discusses the innovation and translational impact of these findings and Chapter 5 summarizes the main results of this dissertation. / Pharmaceutical Sciences

Indiana University-Purdue University Indianapolis (IUPUI) / Risk of coronary artery disease (CAD), the leading cause of death, greatly increases in metabolic syndrome. Metabolic syndrome (MetS; obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension) is increasing in prevalence with sedentary lifestyles and poor nutrition. Non-alcoholic steatohepatitis (NASH; i.e. MetS liver) is progressive and decreases life expectancy, with CAD as the leading cause of death. Pathogenic Ca2+ regulation transforms coronary artery smooth muscle from a healthy, quiescent state to a diseased, proliferative phenotype thus majorly contributing to the development of CAD. In particular, store-operated Ca2+ entry (SOCE) in vascular smooth muscle is associated with atherosclerosis. Genetic predisposition may render individuals more susceptible to Ca2+ dysregulation, CAD, NASH, and MetS. However, the metabolic and cellular mechanisms underlying these disease states are poorly understood. Accordingly, the goal of this dissertation was to investigate the role of dyslipidemia within MetS in the development of Ca2+ dysregulation, CAD, and NASH. The overarching hypothesis was that dyslipidemia within MetS would be necessary for induction of NASH and increased SOCE that would primarily mediate development of CAD. To test this hypothesis we utilized the Ossabaw miniature swine model of MetS. Swine were fed one of five diets for different lengths of time to induce varying severity of MetS. Lean swine were fed normal maintenance chow diet. F/MetS swine were fed high Fructose (20% kcal) diet that induced normolipidemic MetS. TMetS were fed excess high Trans-fat/cholesterol atherogenic diet that induced mildly dyslipidemic MetS and CAD. XMetS were TMetS swine with eXercise. DMetS (TMetS + high fructose) were moderately dyslipidemic and developed MetS and extensive CAD. sDMetS (Short-term DMetS) developed MetS with mild dyslipidemia, but no CAD. MMetS (Mixed-source-fat/cholesterol/fructose) were severely dyslipidemic, exhibited NASH, and developed severe CAD. Dyslipidemia in MetS predicted NASH severity (all groups < DMetS << MMetS), CAD severity (i.e. Lean, F/MetS, sDMetS < XMetS < TMetS < DMetS < MMetS), and was necessary for STIM1/TRPC1-mediated SOCE, which preceded CAD. Exercise ameliorated SOCE and CAD compared to TMetS. In conclusion, dyslipidemia elicits TRPC1/STIM1 SOCE that mediates CAD, is necessary for and predictive of NASH and CAD, and whose affects are attenuated by exercise.