Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed

Cannabinoid CB2 Receptor Potentiates Obesity-Associated Inflammation, Insulin Resistance and Hepatic Steatosis

BACKGROUND: Obesity-associated inflammation is of critical importance in the development of insulin resistance and non-alcoholic fatty liver disease. Since the cannabinoid receptor CB2 regulates innate immunity, the aim of the present study was to investigate its role in obesity-induced inflammation, insulin resistance and fatty liver. METHODOLOGY: Murine obesity models included genetically leptin-deficient ob/ob mice and wild type (WT) mice fed a high fat diet (HFD), that were compared to their lean counterparts. Animals were treated with pharmacological modulators of CB2 receptors. Experiments were also performed in mice knock-out for CB2 receptors (Cnr2 -/-). PRINCIPAL FINDINGS: In both HFD-fed WT mice and ob/ob mice, Cnr2 expression underwent a marked induction in the stromal vascular fraction of epididymal adipose tissue that correlated with increased fat inflammation. Treatment with the CB2 agonist JWH-133 potentiated adipose tissue inflammation in HFD-fed WT mice. Moreover, cultured fat pads isolated from ob/ob mice displayed increased Tnf and Ccl2 expression upon exposure to JWH-133. In keeping, genetic or pharmacological inactivation of CB2 receptors decreased adipose tissue macrophage infiltration associated with obesity, and reduced inductions of Tnf and Ccl2 expressions. In the liver of obese mice, Cnr2 mRNA was only weakly induced, and CB2 receptors moderately contributed to liver inflammation. HFD-induced insulin resistance increased in response to JWH-133 and reduced in Cnr2 -/- mice. Finally, HFD-induced hepatic steatosis was enhanced in WT mice treated with JWH-133 and blunted in Cnr2 -/- mice. CONCLUSION/SIGNIFICANCE: These data unravel a previously unrecognized contribution of CB2 receptors to obesity-associated inflammation, insulin resistance and non-alcoholic fatty liver disease, and suggest that CB2 receptor antagonists may open a new therapeutic approach for the management of obesity-associated metabolic disorder

Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans

Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues to identify molecules associated with ASH progression, and focused on mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets

Rodent models of fatty liver diseases

Fatty liver diseases including alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are leading causes of chronic liver diseases worldwide. ALD and NAFLD encompass a broad spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and superimposed hepatocellular carcinoma. Despite considerable advances in our understanding of the pathogenesis of fatty liver diseases over the past 40 years, effective diagnostic, prognostic, and therapeutic tools are still lacking. The use of animal models is crucial to investigate the cellular and molecular mechanisms underlying the development and progression of fatty liver diseases and develop novel therapeutic strategies. Although no animal model to date can faithfully replicate all the clinical and histological features of ALD or NAFLD, existing models can mimic specific aspects of human diseases. This review provides an overview of the most commonly used and recently developed rodent models of ALD and NAFLD and discusses their major strengths and shortcomings. Keywords: Alcoholic liver disease (ALD), Non-alcoholic fatty liver disease (NAFLD), Animal models, Fatty liver, Inflammation and injury, Fibrosi

Rôle de l'inflammation dans le développement de la stéatohépatite non alcoolique chez les patients obèses (interrelations entre le foie et le tissu adipeux)

L obésité s accompagne de complications hépatiques allant de la stéatose à la stéatohépatite non alcoolique (NASH) jusqu à la fibrose, la cirrhose et l hépatocarcinome. Les mécanismes physiopathologiques impliqués dans le développement de la NASH restent peu connus. Au cours de l obésité, les cytokines proinflammatoires produites par les adipocytes et les macrophages infiltrant le tissu adipeux pourraient jouer un rôle central dans le développement de ces complications hépatiques. Par une technique de PCR quantitative à grande échelle, nous avons identifié des gènes de l inflammation et de l immunité dont l expression est altérée dans le foie des patients obèses morbides avec une NASH. Nos résultats suggèrent une polarisation de la réponse immunitaire vers un phénotype Th1 dans le foie de ces patients. De plus, nous avons identifié la famille des sémaphorines immunes comme un nouvel acteur potentiel de la NASH. Récemment, le tissu adipeux a été identifié comme une nouvelle source d ostéopontine . Cette cytokine proinflammatoire joue un rôle important dans différents modèles murins de maladies du foie. Nous avons mis en évidence une association entre l expression de l ostéopontine et l inflammation du tissu adipeux et les atteintes hépatiques chez les patients obèses morbides. Nos résultats suggèrent que l ostéopontine pourrait favoriser l infiltration des macrophages dans le tissu adipeux et que l augmentation de son expression dans le foie au cours de la stéatose pourrait participer à l évolution des complications hépatiques. Ces travaux ont permis d identifier de nouveaux acteurs impliqués dans la pathogénèse des complications hépatiques de l obésité chez l homme.NICE-BU Sciences (060882101) / SudocSudocFranceF

Serum and peritoneal exudate concentrations after high doses of β-lactams in critically ill patients with severe intra-abdominal infections: an observational prospective study

International audienceBackground: Critically ill patients with severe intra-abdominal infections (IAIs) requiring surgery may undergo several pharmacokinetic (PK) alterations that can lead to b-lactam underdosage.Objectives: To measure serum and peritoneal exudate concentrations of b-lactams after high doses and optimal administration schemes.Methods: This observational prospective study included critically ill patients with suspicion of IAI who required surgery and a b-lactam antibiotic as empirical therapy. Serum and peritoneal exudate concentrations were measured during surgery and after a 24h steady-state period. The PK/pharmacodynamic (PD) target was to obtain serum b-lactam concentrations of 100% fT>4%MIC based on a worst-case scenario (based on the EUCAST highest epidemiological cut-off values) before bacterial documentation (a priori) and redefined following determination of the MIC for the isolated bacteria (a posteriori). Registered with ClinicalTrials.gov (NCT03310606).Results: Forty-eight patients were included with a median (IQR) age of 64 (53–74) years and a SAPS II of 40 (32–65). The main diagnosis was secondary nosocomial peritonitis. Piperacillin/tazobactam was the most administered b-lactam antibiotic (75%). The serum/peritoneal piperacillin/tazobactam ratio was 0.88 (0.64–0.97) after a 24h steady-state period. Prior to bacterial documentation, 16 patients (33.3%) achieved the a priori PK/PD target. The identification of microorganisms was available for 34 patients (71%). Based on the MIC for isolated bacteria, 78% of the patients achieved the serum PK/PD target.Conclusions: In severe IAIs, high doses of b-lactams ensured 100% fT>4%MIC in the serum for 78% of critically ill patients with severe IAIs within the first 24h. In order to define optimal b-lactam dosing, the PK/PD target should take into account the tissue penetration and local ecology

Hepatic expression patterns of inflammatory and immune response genes associated with obesity and NASH in morbidly obese patients.

BACKGROUND: Obesity modulates inflammation and activation of immune pathways which can lead to liver complications. We aimed at identifying expression patterns of inflammatory and immune response genes specifically associated with obesity and NASH in the liver of morbidly obese patients. METHODOLOGY/PRINCIPAL FINDINGS: Expression of 222 genes was evaluated by quantitative RT-PCR in the liver of morbidly obese patients with histologically normal liver (n = 6), or with severe steatosis without (n = 6) or with NASH (n = 6), and in lean controls (n = 5). Hepatic expression of 58 out of 222 inflammatory and immune response genes was upregulated in NASH patients. The most notable changes occurred in genes encoding chemokines and chemokine receptors involved in leukocyte recruitment, CD and cytokines involved in the T cell activation towards a Th1 phenotype, and immune semaphorins. This regulation seems to be specific for the liver since visceral adipose tissue expression and serum levels of MCP1, IP10, TNFα and IL6 were not modified. Importantly, 47 other genes were already upregulated in histologically normal liver (e.g. CRP, Toll-like receptor (TLR) pathway). Interestingly, serum palmitate, known to activate the TLR pathway, was increased with steatosis. CONCLUSION/SIGNIFICANCE: The liver of obese patients without histological abnormalities already displayed a low-grade inflammation and could be more responsive to activators of the TLR pathway. NASH was then characterized by a specific gene signature. These findings help to identify new potential actors of the pathogenesis of NAFLD