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.

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

<p>Functioning as a “powerhouse”, the liver adapts to the metabolic needs of the body by maintaining a homeostatic balance. Prolactin receptor (PRLR) has been found to have a copious existence in the liver. Having established a well-defined role in both reproductive and endocrine systems, the role of this transmembrane protein in hepatocytes is yet to be elucidated. Due to its abundant nature, we hypothesized that PRLR is required for maintaining hepatic homeostasis and plays a role in liver diseases. To test this hypothesis, we defined two specific aims. The first was to explore whether PRLR loss-of-function affects liver structure and function in physiological conditions. The second was to determine whether PRLR is associated with liver pathology. We deleted the <i>Prlr</i> gene specifically in hepatocytes using a virus-based approach and evaluated liver function, transcriptome, and activities of downstream signaling molecules. Due to the absence of PRLR, we found that the urea cycle was disrupted, concomitant with excessive accumulation of urea in the blood; 133 genes exhibited differential expression, largely associated with hepatocyte structure, metabolism, and inflammation; and the activities of STAT3 and 5 were reduced. The results signify that PRLR indeed plays a homeostatic role in the liver. We also used <i>Prlr</i>^+/- mice to assess whether the loss of one allele of the <i>Prlr</i> gene alters maternal hepatic adaptations to pregnancy. As a result, in the pre-pregnancy state and during the first half of gestation, the expression of maternal hepatic PRLR protein was reduced approximately by half owing to <i>Prlr</i> insufficiency. However, during the second half of pregnancy, we observed compensatory upregulation of this molecule, leading to minimal interference in STAT 3 and 5 signaling and liver size. Contrary to a previous study in the breast and ovary, our results suggest that one allele of <i>Prlr</i> may be sufficient for the maternal liver to respond to this physiological stimulus (pregnancy). Furthermore, we examined the expression and activity of PRLR in fatty as well as cholestatic livers. Using a high fat diet, we induced non-alcoholic fatty liver disease (NAFLD). Strikingly and for the first time, we discovered that the short isoform of PRLR (PRLR-S) was completely inactivated in response to NAFLD, whereas the long isoform remained unchanged. This finding strongly suggests the involvement of PRLR-S in lipid metabolism. We also postulate that PRLR-L may be the major regulator of STAT signaling in the liver, consistent with other reports. Lastly, we induced extrahepatic cholestasis via bile duct ligation (BDL) in mice. As this liver disease progressed, the expression of both isoforms of PRLR generally declined and was surprisingly accompanied by increased STAT 3 and 5 activity. The data suggests that PRLR participates in this disease progression, with a disconnection between PRLR signaling and STAT proteins. Collectively, our preliminary studies suggest that PRLR signaling is required to maintain liver homeostasis and more prominently, is involved in liver diseases, especially NAFLD. These findings lay a foundation for our future studies.</p>

Indiana University-Purdue University Indianapolis (IUPUI) / Functioning as a “powerhouse”, the liver adapts to the metabolic needs of the body by maintaining a homeostatic balance. Prolactin receptor (PRLR) has been found to have a copious existence in the liver. Having established a well-defined role in both reproductive and endocrine systems, the role of this transmembrane protein in hepatocytes is yet to be elucidated. Due to its abundant nature, we hypothesized that PRLR is required for maintaining hepatic homeostasis and plays a role in liver diseases. To test this hypothesis, we defined two specific aims. The first was to explore whether PRLR loss-of-function affects liver structure and function in physiological conditions. The second was to determine whether PRLR is associated with liver pathology. We deleted the Prlr gene specifically in hepatocytes using a virus-based approach and evaluated liver function, transcriptome, and activities of downstream signaling molecules. Due to the absence of PRLR, we found that the urea cycle was disrupted, concomitant with excessive accumulation of urea in the blood; 133 genes exhibited differential expression, largely associated with hepatocyte structure, metabolism, and inflammation; and the activities of STAT3 and 5 were reduced. The results signify that PRLR indeed plays a homeostatic role in the liver. We also used Prlr+/- mice to assess whether the loss of one allele of the Prlr gene alters maternal hepatic adaptations to pregnancy. As a result, in the pre-pregnancy state and during the first half of gestation, the expression of maternal hepatic PRLR protein was reduced approximately by half owing to Prlr insufficiency. However, during the second half of pregnancy, we observed compensatory upregulation of this molecule, leading to minimal interference in STAT 3 and 5 signaling and liver size. Contrary to a previous study in the breast and ovary, our results suggest that one allele of Prlr may be sufficient for the maternal liver to respond to this physiological stimulus (pregnancy). Furthermore, we examined the expression and activity of PRLR in fatty as well as cholestatic livers. Using a high fat diet, we induced non-alcoholic fatty liver disease (NAFLD). Strikingly and for the first time, we discovered that the short isoform of PRLR (PRLR-S) was completely inactivated in response to NAFLD, whereas the long isoform remained unchanged. This finding strongly suggests the involvement of PRLR-S in lipid metabolism. We also postulate that PRLR-L may be the major regulator of STAT signaling in the liver, consistent with other reports. Lastly, we induced extrahepatic cholestasis via bile duct ligation (BDL) in mice. As this liver disease progressed, the expression of both isoforms of PRLR generally declined and was surprisingly accompanied by increased STAT 3 and 5 activity. The data suggests that PRLR participates in this disease progression, with a disconnection between PRLR signaling and STAT proteins. Collectively, our preliminary studies suggest that PRLR signaling is required to maintain liver homeostasis and more prominently, is involved in liver diseases, especially NAFLD. These findings lay a foundation for our future studies.

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La bronchopneumopathie chronique obstructive (BPCO) est une des maladies chroniques les plus fréquentes et constitue une des premières causes de mortalité dans le monde avec un impact sociétal majeur et des couts de santé considérables. La BPCO est aujourd’hui considérée comme une maladie multi-systémique dont le pronostic est lié en grande partie à ses comorbidités et à la survenue d’exacerbations. Les exacerbations qui vont ponctuer l’évolution de la BPCO précipitent le déclin de la fonction respiratoire et favorisent la décompensation des comorbidités et la survenue d’événements cardiovasculaires comme des infarctus du myocarde ou des accidents vasculaires cérébraux. La prise en charge moderne de la BPCO est basée sur la mise en place d’un soin intégré incluant la prise en charge des comorbidités et une meilleure détection et gestion des exacerbations.Dans ce travail de thèse nous abordons l’atteinte hépatique (stéatopathie hépatique non alcoolique - NAFLD) dans la BPCO comme une comorbidité sous-estimée (publication 1) alors qu’elle a probablement des implications pronostiques importantes (publication 2). La BPCO s'accompagne également de symptômes non respiratoires tel que des douleurs, dont les variations et localisations sont peu connues pendant et après l'exacerbation (publication 3). Le traitement de ces douleurs par des opiacés pourrait avoir un effet spécifiquement délétère dans cette population (publication 5). Les enjeux de réforme du système de santé avec une optimisation cout-efficacité incitent à développer et valider de nouvelles méthodes de prise en charge ambulatoire des exacerbations (publication 6).Dans une première partie de la thèse nous explorons les liens épidémiologiques entre BPCO et NAFLD. Nous explorerons également les conséquences d’une telle association sur le devenir cardiovasculaire des patients à moyen terme. Dans une deuxième partie, nous cherchons à définir les caractéristiques des douleurs avant et après exacerbation au cours de la BPCO, le lien entre douleur, anxiété et dépression chez ces patients et la sécurité d'emploi des morphiniques dans cette population fragile. Dans une dernière partie, nous aborderons la stratification du risque lié à une exacerbation de BPCO, et la possibilité d’une prise en charge ambulatoire extrahospitalière pour les exacerbations de sévérité modérée. / Chronic Obstructive Pulmonary Disease (COPD) is one of the most common chronic diseases and is one of the leading causes of death in the world with major societal impact and considerable health costs. COPD is now considered a multi-systemic disease whose prognosis is largely related to its comorbidities and the occurrence of exacerbations. The exacerbations that punctuate the evolution of COPD precipitate the decline of respiratory function and promote the decompensation of comorbidities and the occurrence of cardiovascular events such as myocardial infarction or cerebrovascular accidents. The modern management of COPD is based on the implementation of integrated care including the management of comorbidities and better detection and management of exacerbations.In this thesis we address liver injury (non-alcoholic fatty liver disease - NAFLD) in COPD as an underestimated comorbidity (publication 1), although it probably has important prognostic implications (publication 2). COPD is also associated with non-respiratory symptoms such as pain, the variations and locations of which are poorly known during and after exacerbation (publication 3). Treatment of this pain with opiates may have a specifically deleterious effect in this population (publication 5). The challenges of health system reform with cost-effectiveness optimization encourage the development and validation of new methods of outpatient management of exacerbations (publication 6).In a first part of the thesis we explore the epidemiological links between COPD and NAFLD. We will also explore the consequences of such an association on the cardiovascular outcome of patients in the medium term. In a second part, we seek to define the characteristics of pain before and after exacerbation during COPD, the link between pain, anxiety and depression in these patients and the safety of opioids in this fragile population. In the last part, we will discuss the stratification of the risk linked to an exacerbation of COPD, and the possibility of outpatient care for exacerbations of moderate severity.

Introduction: Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a headto- head comparison between both methods. Methods: Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34–66%, S3 $67%. Results: Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiveroperating characteristics curves were 0.93 vs. 0.88 for steatosis $S1 and 0.94 vs. 0.88 for $S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2–4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa. Conclusion: Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.

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.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis. To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes. Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.

BACKGROUND: Obesity is a global health problem that is associated with wide range of diseases, including atherosclerosis and Nonalcoholic fatty liver (NAFL) disease. Hepatic inflammation can cause cirrhosis, hepatic decompensation (liver failure) and cancer. Recent research now looks at the chronic systemic effects and inter-organ communication between atherosclerosis potentially promoting the development of NAFL. The resolution of inflammation is regulated naturally in the body by specialized pro-resolving mediators (SPMs). Immunoresolvents like ⍹6-derived Lipoxin A4 are suggested as a therapeutic strategy to overcome chronic inflammation and disease. In this study we investigated the therapeutic potential of Lipoxin A4 (LXA4) in cholesterol fed rabbit model of hypercholesterolemia, with atherosclerotic plaques and confined vascular endothelial injury and its effect on the progression of NAFL. OBJECTIVE: This is a continuation of studies pioneered in the Hamilton lab and an extension of the recent study by Taylor et. al in 201811 linking aortic plaque and liver disease. We will now investigate the therapeutic potential of Lipoxin A4 on lipid-rich atherosclerotic plaques in cholesterol fed rabbits and its effect on the progression of NAFL to NASH. METHODS: In vivo magnetic resonance imaging (MRI) measured aortic atherosclerotic inflammation (with plaque Gd-enhancement), plaque size (vessel wall area), and composition, within rabbits fed normal chow or a 1% cholesterol-enriched diet. Biomarkers in the blood were monitored in the rabbits, with follow-up by histology, which included Masson’s trichrome staining. Light Microscopy was used for liver imaging. Ex vivo MRI, T1W imaging was used to quantify VWA (vessel wall area), with Image J programming. RESULTS: Cholesterol-fed rabbits with and without aortic injury developed hypercholesterolemia, NAFL, and atherosclerotic plaques in the aorta. Elevated plasma gamma-glutamyl transferase (GGT; p =0.014) and the ratio of liver enzymes aspartate and alanine aminotransferases (AST/ALT; p = 0.033) confirmed the progression of steatosis to non-alcoholic steatohepatitis (NASH). Histological images showed less fibrosis in those rabbits fed 1% CHOL diet with injury treated with LipoxinA4, when compared to 1% CHOL diet and injury alone. The plasma biomarkers showed a decrease in cholesterol (79%) and triglycerides (49.9%) in those rabbits given LXA4 therapy. The LXA4 treated 1% CHOL diet with injury group showed a marked decrease in the aorta vessel wall area when compared to the 1% CHOL diet with injury, without treatment; as seen in ex vivo, MRI T1W imaging. CONCLUSION: Lipoxin implementation in cholesterol fed rabbits that have localized regions of highly inflamed aortic atherosclerotic plaques, may contribute to the attenuation on the progression of NAFL to NASH as seen in histology and plasma biomarkers including; cholesterol and triglycerides. Lipoxin as a therapeutic has an effect on treating atherosclerotic plaques and attenuating atherosclerosis progression.