Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet
| Autor: | Anthony M. Diomino, David A. Brenner, Hyeok Choon Kwon, Gibraan Rahman, Sara Brin Rosenthal, Tatiana Kisseleva, Linshan Shang, Souradipta Ganguly, Ruoyu Wang, Debanjan Dhar, Rob Knight, Pejman Soorosh, Mojgan Hosseini, Yanhan Wang, Bernd Schnabl, German R. Aleman Muench |
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| Rok vydání: | 2021 |
| Předmět: |
Cirrhosis
medicine.medical_treatment Cell Cycle Proteins RC799-869 Gastroenterology Mice 0302 clinical medicine Fibrosis Aetiology Original Research Cancer Liver Disease Liver Neoplasms ILC innate lymphoid cell Diseases of the digestive system. Gastroenterology Immunohistochemistry HSC hepatic stellate cell DSI distal small intestine Editorial FACS fluorescence-activated cell sorter 030211 gastroenterology & hepatology FITC fluorescein isothiocyanate NASH nonalcoholic steatohepatitis Western IHC immunohistochemistry medicine.medical_specialty Carcinoma Hepatocellular Knockout CVD cardiovascular disease Hyperphagia digestive system 03 medical and health sciences Humans RPCA robust principal component analysis Dyslipidemias Animal nutritional and metabolic diseases Hepatocellular PE Phycoerythrin Hepatocellular Carcinoma Gene signature medicine.disease WT wild-type digestive system diseases IL interleukin LBP lipopolysaccharide binding protein 030104 developmental biology NAFLD nonalcoholic fatty liver disease MIP2 Macrophage Inflammatory Protein 2 Digestive Diseases Biomarkers Liver Inflammation Liver Cirrhosis 0301 basic medicine Chemokine CXCL2 C-X-C motif chemokine ligand 2 Adipose tissue Nonalcoholic Steatohepatitis Gut Inflammation Oral and gastrointestinal Hepatitis Risk Factors Non-alcoholic Fatty Liver Disease 2.1 Biological and endogenous factors Mice Knockout TNF tumor necrosis factor WD Western diet biology rRNA ribosomal RNA Cytokine Hepatocellular carcinoma LPS lipopolysaccharide Disease Susceptibility medicine.symptom eWAT white adipose tissue (epididymal fat) NASH Regression Biotechnology Liver Cancer APC Allophycocyanin Chronic Liver Disease and Cirrhosis PBS phosphate-buffered saline Inflammation CD-HFD choline-deficient high-fat diet SI small intestine Rare Diseases FBS fetal bovine serum ALT alanine aminotransferase Internal medicine medicine Animals IFN interferon Obesity Nutrition Hepatology business.industry Gene Expression Profiling CKD chronic kidney disease Carcinoma qRT-PCR quantitative reverse-transcription polymerase chain reaction Diet Disease Models Animal Good Health and Well Being Diet Western Disease Models biology.protein Insulin Resistance HCC hepatocellular carcinoma business |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 12, Iss 3, Pp 891-920 (2021) Cellular and molecular gastroenterology and hepatology, vol 12, iss 3 |
| ISSN: | 2352-345X |
| DOI: | 10.1016/j.jcmgh.2021.05.010 |
| Popis: | Background & Aims How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH–HCC progression, as well as regression. Methods Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. Results Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. Conclusions The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure. Supplemental Graphical Summary |
| Databáze: | OpenAIRE |
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