Le syndrome métabolique est une association de plusieurs troubles métaboliques tels que l'obésité, la résistance à l'insuline, l'hypertension artérielle, des taux élevés de triglycérides, de cholestérol et de glucose sanguins. Ces anomalies métaboliques sont de réels facteurs de risques de diabète de type 2 et de maladies cardiovasculaires.L'apparition d'une résistance à l'insuline semble être l'un des éléments clés des pathologies métaboliques. Elle précède le développement du diabète de type 2 et est présente chez de nombreuses personnes obèses. Sa prévalence est difficile à apprécier et elle est probablement sous-estimée, d'une part car elle se situe en amont des signes cliniques qui conduisent le patient chez le médecin, et d'autre part car il n'existe pas de technique de mesure simple et robuste de l'IR utilisable en routine clinique. Le dépistage précoce de l'insulinorésistance et l’étude des mécanismes qui la sous-tendent sont donc essentiels en termes de santé publique.Le syndrome métabolique se caractérise également par des phénomènes hépatiques, les stéato-hépatopathies non alcooliques (ou NAFLD pour Non Alcoholic Fatty Liver Disease). Les NAFLD sont étroitement liées à l’obésité et à l’insulinorésistance, dont la prévalence n’a cessé d’augmenter ces dernières décennies, et représentent ainsi la première cause des maladies chroniques du foie. On admet qu’aujourd’hui, 25% de la population mondiale serait touchée par les NAFLD. Il est probable que cette prévalence soit sous-estimée compte tenu du manque d’outils diagnostiques, particulièrement pour les premiers stades asymptomatiques de la maladie.L'insulinorésistance et les stéatohépatopathies apparaissent donc comme deux composantes importantes du syndrome métabolique, présentant chacune une phase silencieuse. Ces travaux de thèse ont pour objectif le développement de techniques diagnostiques précoces, en imagerie nucléaire, à la fois pour une utilisation clinique mais aussi pour l'évaluation de nouvelles thérapeutiques en recherche préclinique. / Metabolic syndrome is an association of several metabolic dysregulations such as obesity, insulin resistance, high blood pressure, elevated blood triglycerides, cholesterol and glucose. These metabolic disorders are risk factors for type 2 diabetes and cardiovascular diseases.Insulin resistance (IR) is one of the key mechanisms in metabolic diseases development. IR forerun type 2 diabetes development and can be found in obese people. The IR prevalence is difficult to appreciate because of its lack of symptoms and the absence of simple and reliable tool to measure it. Early detection of IR is a real issue in terms of public health and could prevent many complications.Metabolic syndrome is also characterized by hepatic manifestations named Non-Alcoholic Fatty Liver Diseases (NAFLD). NAFLD are closely linked with obesity and insulin resistance. Sharing the same aetiologies, NAFLD has becoming the world first cause of chronic liver diseases. Nowadays it is estimated that almost 25% of the global population have NAFLD. This number could be underestimated because of a lack in diagnostic tools, especially for the early stages of the disease, which are totally asymptomatic.Insulin resistance and non-alcoholic liver diseases are both key components of the metabolic syndrome with a silent phase. The aim of this work is to develop early diagnostic techniques for these pathologies with nuclear imaging. These techniques could be useful both in daily clinical use and for the evaluation of new therapeutics in preclinical research.

Les atteintes hépatiques, asymptomatiques pour la plupart d’entre elles et pouvant évoluer vers des complications sévères telles que le carcinome hépatocellulaire (CHC) sont responsables de plus de 15 000 décès par an en France. Le manque de marqueurs cliniques et biologiques fiables pour déterminer le degré de sévérité de l’hépatopathie ainsi que pour reconnaître les stades précoces du CHC constitue actuellement un obstacle majeur à une prise en charge optimale de la maladie. Grâce aux approches de type métabolomique et aux techniques analytiques telles que la résonance magnétique nucléaire, il est désormais possible d’obtenir une véritable cartographie des métabolites d’un individu. L’objectif de ce travail a été d’explorer, par une approche RMN métabolomique, les changements métaboliques dans le foie et dans le sérum causés par différentes pathologies hépatiques afin de proposer de nouvelles pistes dans l’amélioration du diagnostic et de la prise en charge de ces maladies. Une attention particulière a également été donnée à l’étude de la validité des paramètres de qualité des modèles de discrimination réalisés lors des analyses statistiques des données multivariées. / Most liver diseases nowadays remain symptomless and tend to lead to hepatocellular carcinoma responsible for more than 15.000 patient deaths per year in France. Liver diseases are therefore a major concern for public health.Clinicians lack of non-invasive biomarkers allowing them to enhance identification of liver diseases stages in order to efficiently target the first HCC signs and accordingly improve clinical prognosis.Identification of new biomarkers set new challenges in translational research in order torefine the prognosis and adapt therapeutic procedures.Proton nuclear magnetic resonance spectroscopy-based metabolomics enable to identifyand quantify such metabolites by defining individual metabolic fingerprints.First part of this work was to explore the metabolic modifications of liver tissue to further establish diseases stages profiles.Second part was focused on the assessment of metabolic variations in HCC patients, by analyzing sequential serums taking, before and after a radiofrequency ablation curative treatment.Third and last part was centered on the validation of the quality parameters of the discriminant models used in multivariate statistical analysis.

No description available.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) is a spectrum of diseases that is rising in prevalence and is strongly associated with obesity, diabetes, and insulin resistance. There has been much research into potential therapeutics, as the current recommended treatment, thiazolidinediones (TZDs) present a host of negative side effects such as fluid retention and weight gain. CHS-131 is a selective PPAR-γ modulator with antidiabetic effects and less side effects compared to TZDs. The aim of this study was to investigate the effects of CHS-131 on metabolic parameters and liver pathology in a diet-induced obese (DIO) and biopsy-confirmed mouse model of non-alcoholic steatohepatitis. METHODS: Male C57BL/6JRj mice were fed an AMLN diet (40% fat with trans-fat, 20% fructose and 2% cholesterol) for 33 weeks prior to a liver biopsy procedure. Animals that were biopsy-confirmed to have steatosis and fibrosis were stratified into 3 treatment groups: 1) Low dose CHS-131 (10mg/kg), 2) High dose CHS-131 (30mg/kg), 3) Vehicle. Metabolic parameters, liver pathology including NAFLD activity score, metabolomics/lipidomics, markers of liver function and liver, subcutaneous and visceral adipose tissue gene expression was assessed. RESULTS: CHS-131 did not affect body weight, fat, lean or water mass, or food intake in DIO-NASH mice with fibrosis. CHS-131 improved fasting insulin levels and insulin sensitivity as assessed by intraperitoneal insulin tolerance test. CHS-131 improved total cholesterol, ALT, AST and increased adiponectin levels in plasma. CHS-131 improved NAS in liver histology and tended to reduce markers of hepatic fibrosis. Diet induced NASH mice treated with CHS-131 demonstrated a hepatic shift to diacyl- and triacyl-glycerol’s with shorter chains, increased expression of genes stimulating fatty acid oxidation and browning and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis and inflammation in adipose tissue. CONCLUSION: CHS-131 improves liver histology in a diet-induced obese and biopsy confirmed mouse model of NASH by affecting the hepatic lipidome, reducing insulin resistance and altering lipid metabolism and inflammation in adipose tissue. / 2022-06-04T00:00:00Z

Non-alcoholic fatty liver disease (NAFLD), described by the build-up of excess fat in the liver, is the most prevalent chronic liver condition globally. One of the essential metabolic functions of the liver is the production of ketone bodies, a process called, ketogenesis. Ketone bodies serve as alternative fat-derived sources of fuel for tissues under conditions of nutrient deficit (i.e., fasting). Interestingly, recent studies have found that ketogenesis is dysregulated in NAFLD patients. Similarly, we also found that high-fat diet-induced NAFLD mice exhibited diminished fasting-induced ketogenesis with reduced expression of liver Hmgcs2, the rate-limiting enzyme of ketogenesis. To understand the role of ketogenesis in NAFLD pathogenesis and treatment, we generated mouse models of ketogenic insufficiency and activation through Hmgcs2 loss- and gain-of-function, respectively. Notably, a change in dietary environment rescued the fatty liver phenotype of Hmgcs2 knockout mice and increased ketogenic function through HMGCS2 overexpression improved NAFLD-associated metabolic dysfunction and hepatosteatosis in adult mice. Furthermore, an untargeted metabolomics approach provided a comprehensive metabolic view underlying HMGCS2 overexpression-mediated NAFLD improvement, suggesting that hepatic ketogenesis impacts liver metabolism via regulation of other metabolic pathways. Together, our study adds new knowledge to the field of ketone body metabolism and suggests a viable therapeutic strategy involving ketogenesis activation in the prevention and treatment of NAFLD.

Insulin resistance is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). Intrahepatic triglyceride (IHTG), the primary feature of NAFLD, strongly predicts insulin resistance in the liver and peripheral (skeletal muscle and adipose) tissues. Hepatokines (e.g. fibroblast growth factor 21 (FGF21), leukocyte cell-derived chemotaxin 2 (LECT2), follistatin, selenoprotein P, and fetuin-A) are liver-derived proteins with capacity to exert endocrine effects and may potentially modulate the link between IHTG and peripheral insulin sensitivity/glycaemic control. Exercise is integral to the management of NAFLD and T2DM, with evidence suggesting that high-intensity exercise may provide the greatest benefits. Chapter 4 of this thesis demonstrates that, in individuals without chronic metabolic disease, plasma concentrations of FGF21 and LECT2 are higher, and follistatin lower, in individuals with overweight or obesity compared with normal weight individuals. Furthermore, FGF21 and follistatin are transiently elevated for up to 6 h after acute aerobic exercise (60 min at 60% V̇O2 peak). The response of follistatin to acute moderate-intensity exercise is also present in individuals with impaired glucose regulation (Chapter 5), but the response of FGF21 is abolished. A single bout of low-volume high-intensity interval training has no effect on FGF21, follistatin or fetuin-A in individuals with dysglycaemia (Chapter 5). Chapter 6 demonstrates that six weeks of sprint interval training (SIT) is feasible for men with NAFLD and reduces IHTG despite no change in body weight. Peripheral insulin sensitivity tends to increase after SIT but hepatic insulin sensitivity and circulating hepatokines remain unchanged. Through meta-analyses, Chapter 7 confirms that exercise training reduces IHTG, even in the absence of weight loss. However, the magnitude of this effect is greater when weight loss occurs and benefits increase proportionally. Exercise training improves basal hepatic insulin sensitivity, but evidence in this area is currently limited (Chapter 7). Collectively, the studies in this thesis demonstrate that some hepatokines may be sensitive to acute and chronic changes in energy metabolism. However, further evidence is required before definitive statements can be made. Exercise training, including SIT, has the potential to reduce IHTG in men with NAFLD, even in the absence of weight loss. However, the greatest benefits on IHTG will likely be elicited when exercise training is performed in combination with dietary energy restriction to elicit sustained reduction in body weight.

Esteatosis de origen dietético: ¿La inflamación y la Oxidación actúan de forma coordinada? La respuesta metabólica hepática frente a dietas ricas en grasa y colesterol difiere en los ratones con diferentes trastornos metabólicos y carga genética (ApoE-/- y LDLr-/-). Unos responden desarrollando esteatohepatitis y aumentando la expresión de genes relacionados con la inflamación y la oxidación mientras que en otros disminuye la expresión de genes que protegen el desarrollo de esteatosis y obesidad. En humanos, también se aprecian diferencias respecto al desarrollo de esteatosis o esteatohepatitis lo que sugiere que los datos encontrados pueden resultar útiles. Hemos probado la hipótesis de que las moléculas encargadas de la protección frente a la oxidación (principalmente paraoxonasas) actúan de forma coordinada con las quimiocinas responsables del reclutamiento de los macrófagos (proteínas que atraen los monocitos). Presentamos datos que indican que ambas moléculas se expresan constitutivamente en casi todos los tejidos de ratón C57BL/6J. La sorprendente ubicuidad de ambas moléculas y la expresión aparentemente conjunta en las mismas células sugieren que, al menos en el hígado, las respuestas frente a la oxidación y la inflamación pueden estar coordinadas para determinar el curso futuro de las lesiones producidas por el exceso de nutrientes. / Diet-induced hepatic steatosis: Do inflammation and oxidation act coordinately?The metabolic response to high-fat, high-cholesterol diet may differ in mice with different genetic and metabolic background (ApoE-/- and LDLr-/-). Some develop steatohepatitis and increased expression of genes related to both inflammation and oxidation; in others, the expression of genes protective for the development of obesity and steatosis is decreased. Similar differences have been found in humans and consequently obtained data should be considered in translational research. We tested the hypothesis that molecules preventing oxidation (mainly paraoxonases) may coordinately act with responsible effectors for macrophage recruitment (especially monocyte chemoattractant proteins). We present here data indicating that both molecules are constitutively expressed in most tissues from C57BL/6J mice. Surprisingly this ubiquity and the apparent co-expression suggest, at least in liver, that antioxidand and pro-inflammatory responses may jointly determine the course of lesions induced by nutrient excess.

Arsenic is common metalloid that is found globally. Its ubiquitous nature means that large portions of the global population are exposed through a variety of pathways. Arsenic is a known human carcinogen and its role in the development of cardiovascular and metabolic disease has become more completely characterized in the past decades. However, the examination of arsenic exposure during embryonic development at relatively low level exposures is an emergent area where lots of questions remain unanswered. As arsenic is difficult and costly to remove from water, the investigation of exposures in vulnerable populations at relevant concentrations is necessary to justify remediation efforts. This dissertation work examines fetal arsenic metabolism contributing to the understanding of tissue specific arsenic effects during embryonic development. Following that, the focus shifts to fetal and early life exposure to arsenite at 100 parts per billion in drinking water (10 times higher than the EPA mandated limit in municipal water but common in well water globally) and how it contributes to the severity and incidence of diet-induced non-alcoholic fatty liver disease (NAFLD). NAFLD is the most prevalent chronic liver disease in the United States and it contributes to increased cardiovascular morbidity and mortality. NAFLD also results in alterations in hepatic drug metabolism and disposition which contributes to adverse drug reactions. We demonstrate similar effects in arsenic potentiated NAFLD in addition to changes in transporter expression with arsenic exposure alone independent of triglyceride accumulation associated with NAFLD. Taken together, this work highlights deleterious health effects of low level arsenic exposure during development and demonstrates the need for further investigation of developmental arsenic effects.

Increased sugar consumption is considered to be a contributor to the worldwide epidemics of obesity and diabetes and the consequent cardio metabolic risks. These include a significant increase for Type II diabetes and associated multiple comorbidities such as non-alcoholic fatty liver disease (NAFLD). The accumulation of excess triglycerides characterizes NAFL with a prevalence of up to 53% in morbidly obese populations. While in itself benign, fatty liver can progress to non-alcoholic steatohepatitis (NASH), which is characterized by apoptosis, inflammation and fibrosis in 10-20% of individuals. Progression to NASH increases the risk of further deterioration to cirrhosis and hepatocellular carcinoma (HCC). However, progression is unpredictable in any given individual and no risk factors predisposing to progression have been identified. Variation in a limited number of genes, such as patatin-like phospholipase (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), have been linked to an increased susceptibility to NAFLD. Recently, fibroblast growth factor 21 (FGF21) was reported to be a potential predictor for NAFLD as it significantly increases in patients with obesity and NAFL. Multiple lines of evidence indicate that FGF21 plays an important role in liver metabolism in mice and humans, playing a key role in carbohydrate and lipid metabolism. FGF21 was originally identified as an endocrine member of the fibroblast growth factor family as it can be released into the circulation. FGF21 was initially assigned a purely metabolic role as infusions led to weight loss and increased glucose clearance through induced expression of the GLUT1 transporter. However, FGF21 biology is now understood to be extremely complex, as it is expressed in many metabolically active tissues including, liver, white (WAT) and brown adipose tissue (BAT), muscle and pancreas. Functions of FGF21 are distinct in all these tissues. In the previous studies from our lab, we have seen fructose consumption, but not glucose, leads to an increase in serum FGF21 levels both in humans and mice. In general, sugar is typically consumed by humans in the form of sucrose or high fructose corn syrup (HFCS), both of which consist of nearly equal amounts of the simple sugars, glucose and fructose. Although attention has been focused on sucrose and fructose in many studies, no direct comparison was found to study fructose, glucose and sucrose. The current study aims to expand on the role of FGF21 in mediating the effects of chronic consumption of these refined sugars in mice. Wildtype (WT) and FGF21 knockout (KO) mice were fed with one of these diets for 20 weeks and in general, mice eating diets with high refined sugars gained less weight than mice eating chow, although calorie consumption was the same. In terms of body composition, sucrose fed FGF21 KO mice had less fat mass compared to chow fed animals. Dextrose fed and fructose fed mice had comparable fat mass reduction in WT and KO mice. Interestingly, glucose tolerance tests (GTT) showed increased glucose sensitivity in dextrose fed WT and KO mice after four weeks, however glucose tolerance decayed after 12 weeks on the diet. At 16 weeks fructose fed KO mice had significant increased glucose sensitivity compared to controls. Insulin tolerance tests showed similar results between all cohorts and a larger sample size would be needed to elicit any differences. Pyruvate tolerance tests (PTT) showed significantly increased hepatic gluconeogenesis in fructose fed KO mice compared to controls but not in dextrose or sucrose fed mice. Energy expenditure was measured by indirect calorimetry. No significance changes were observed in dextrose fed mice compared to chow controls in terms of VO2 or heat production. Both WT and KO dextrose fed mice had a higher RER, consistent with utilization of carbohydrates over fat for baseline energy expenditure. Sucrose fed mice showed marked increases in VO2 over an averaged 24-hour period and similarly fructose fed mice FGF21 KO mice had increased energy expenditure. Significant increases in RER were observed in both WT and KO sucrose fed mice controls and a similar trend was observed in WT and KO fructose fed mice. Overall, we see differential metabolic effects of all the high carbohydrate diets on the mice. Chronic consumption of dextrose only affected glucose sensitivity. Whereas chronic consumption of sucrose influences glucose and insulin sensitivity and energy expenditure suggesting internal metabolic changes while fructose consumption additionally showed increased hepatic gluconeogenesis without the marked increase in insulin sensitivity. However, detailed tissue analysis is required to determine specific physiological and molecular changes between refined sugar cohorts and the role of FGF21 in this context.

PURPOSE: The Nrf2/Keap1/ARE pathway is a major regulator of cytoprotective responses to oxidants. Gluatredoxin-1 (Glrx-1), a small thiol transferase removes glutathione (GSH) adducts from proteins and participates in redox signaling. Glrx-/- mice exhibit increased protein GSH adducts (PSSG) and non-alcoholic fatty liver disease (NAFLD). Unexpectedly, our Glrx-/- mice showed increased hepatic glutathione (GSH) levels. The Nrf2/Keap1/ARE pathway, as an important regulator of glutathione synthesis, could be regulated by Glrx-1 activity. METHODS: To determine the role of Nrf2 in vivo, we treated Glrx-/- mice with high fat high sucrose (HFHS) diet to induce metabolic and oxidative stress. Livers were harvested at 10 months of age after 8 months on HFHS diet. Gene expression of Nrf2 and its down-signaling targets were determined using RT-qPCR and protein expression was accessed via WB. To determine the role of Nrf2 in Glrx-deficiency in vitro, Glrx siRNA was transfected in HEK293A and HepG2 cells and exposed to high palmitate high glucose (HPHG) to mimic metabolic stress and hydrogen peroxide to mimic oxidative stress. RESULTS: Glrx-/- deficiency increased Nrf2 activity and gene expression, and decreased Keap1 activity and gene expression. Glrx silencing in liver promoted Nrf2 activity and translocation to the nucleus, and downstream targets of Nrf2 were upregulated. CONCLUSION: Our findings indicate that the Nrf2/Keap1/ARE pathway is regulated by Glrx in vitro and in vivo.