Dataset Information

Alcoholic Liver Disease: A Mouse Model Reveals Protection by Lactobacillus fermentum.

ABSTRACT: Alcoholism is one of the most devastating diseases with high incidence, but knowledge of its pathology and treatment is still plagued with gaps mostly because of the inherent limitations of research with patients. We developed an animal model for studying liver histopathology, Hsp (heat-shock protein)-chaperones involvement, and response to treatment.The system was standardized using mice to which ethanol was orally administered alone or in combination with Lactobacillus fermentum following a precise schedule over time and applying, at predetermined intervals, a battery of techniques (histology, immunohistochemistry, western blotting, real-time PCR, immunoprecipitation, 3-nitrotyrosine labeling) to assess liver pathology (e.g., steatosis, fibrosis), and Hsp60 and iNOS (inducible form of nitric oxide synthase) gene expression and protein levels, and post-translational modifications.Typical ethanol-induced liver pathology occurred and the effect of the probiotic could be reliably monitored. Steatosis score, iNOS levels, and nitrated proteins (e.g., Hsp60) decreased after probiotic intake.We describe a mouse model useful for studying liver disease induced by chronic ethanol intake and for testing pertinent therapeutic agents, e.g., probiotics. We tested L. fermentum, which reduced considerably ethanol-induced tissue damage and deleterious post-translational modifications of the chaperone Hsp60. The model is available to test other agents and probiotics with therapeutic potential in alcoholic liver disease.

SUBMITTER: Barone R

PROVIDER: S-EPMC4737872 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Alcoholic Liver Disease: A Mouse Model Reveals Protection by Lactobacillus fermentum.

Barone Rosario R Rappa Francesca F Macaluso Filippo F Caruso Bavisotto Celeste C Sangiorgi Claudia C Di Paola Gaia G Tomasello Giovanni G Di Felice Valentina V Marcianò Vito V Farina Felicia F Zummo Giovanni G Conway de Macario Everly E Macario Alberto J L AJ Cocchi Massimo M Cappello Francesco F Marino Gammazza Antonella A

Clinical and translational gastroenterology 20160121

<h4>Objectives</h4>Alcoholism is one of the most devastating diseases with high incidence, but knowledge of its pathology and treatment is still plagued with gaps mostly because of the inherent limitations of research with patients. We developed an animal model for studying liver histopathology, Hsp (heat-shock protein)-chaperones involvement, and response to treatment.<h4>Methods</h4>The system was standardized using mice to which ethanol was orally administered alone or in combination with Lac ...[more]

PMID: 26795070

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Project description:Background & aimsThe accumulation of neutral lipids within hepatocytes underlies non-alcoholic fatty liver disease (NAFLD), which affects a quarter of the world's population and is associated with hepatitis, cirrhosis, and hepatocellular carcinoma. Despite insights gained from both human and animal studies, our understanding of NAFLD pathogenesis remains limited. To better study the molecular changes driving the condition we aimed to generate a humanised NAFLD mouse model.MethodsWe generated TIRF (transgene-free Il2rg -/-/Rag2 -/-/Fah -/-) mice, populated their livers with human hepatocytes, and fed them a Western-type diet for 12 weeks.ResultsWithin the same chimeric liver, human hepatocytes developed pronounced steatosis whereas murine hepatocytes remained normal. Unbiased metabolomics and lipidomics revealed signatures of clinical NAFLD. Transcriptomic analyses showed that molecular responses diverged sharply between murine and human hepatocytes, demonstrating stark species differences in liver function. Regulatory network analysis indicated close agreement between our model and clinical NAFLD with respect to transcriptional control of cholesterol biosynthesis.ConclusionsThese NAFLD xenograft mice reveal an unexpected degree of evolutionary divergence in food metabolism and offer a physiologically relevant, experimentally tractable model for studying the pathogenic changes invoked by steatosis.Lay summaryFatty liver disease is an emerging health problem, and as there are no good experimental animal models, our understanding of the condition is poor. We here describe a novel humanised mouse system and compare it with clinical data. The results reveal that the human cells in the mouse liver develop fatty liver disease upon a Western-style fatty diet, whereas the mouse cells appear normal. The molecular signature (expression profiles) of the human cells are distinct from the mouse cells and metabolic analysis of the humanised livers mimic the ones observed in humans with fatty liver. This novel humanised mouse system can be used to study human fatty liver disease.

Project description:BackgroundSeveral clinical studies have suggested a strong correlation between cholecystectomy and the incidence of non-alcoholic fatty liver disease (NAFLD) although the exact correlation and causal relationship are unclear. This study aimed to investigate whether cholecystectomy increases the incidence of NAFLD or aggravates pre-existing NAFLD.MethodsStandard diet-fed and high-fat (HF) diet-fed mice were subjected to sham operation and cholecystectomy. In study 1, 20 standard diet-fed C57BL/6N mice were sacrificed at months 1, 2, and 4 post-surgery. Meanwhile, in study 2, 25 HF diet-induced NAFLD C57BL/6N mice were biopsied at months 2 and 3 post-surgery and sacrificed at month 6 post-surgery. The hepatic fatty acid and bile acid metabolic pathways and the hepatic bile composition were evaluated.ResultsThe bodyweight and biochemical parameters (hepatic enzyme, triglyceride, and cholesterol levels) were not significantly different between the standard diet-fed sham and cholecystectomy groups. The NAFLD activity score and the levels of hepatocyte apoptosis markers (Krt18 expression and DNA fragmentation) and de novo lipid synthesis genes were not significantly different between the standard diet-fed sham and cholecystectomy groups. Cholecystectomy did not exacerbate hepatic steatosis, inflammation, and ballooning in the HF diet-fed mice. Hepatic bile acid composition was not markedly different in the sham and cholecystectomy groups fed on standard or HF diet. Cholecystectomy significantly downregulated Cyp7a1 and Cyp27a1 mRNA levels at months 1 and 4 post-surgery but did not affect the degree of steatosis and triglyceride levels. Analysis of bile acid metabolism revealed that taurine-conjugated bile acids were significantly downregulated in the standard diet-fed and high-fat diet-fed mice, but the histological and biochemical parameters were not markedly different.ConclusionsCholecystectomy did not increase the incidence of NAFLD in standard diet-fed mice. Additionally, NAFLD incidence was not significantly different between the HF diet-fed sham and cholecystectomy groups. Furthermore, the histological parameters were not markedly different between the sham and cholecystectomy groups fed on standard or HF diet. These findings suggest that cholecystectomy does not induce NAFLD.

Dataset Information

Alcoholic Liver Disease: A Mouse Model Reveals Protection by Lactobacillus fermentum.

Publications

Alcoholic Liver Disease: A Mouse Model Reveals Protection by Lactobacillus fermentum.

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