Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling
Autor: | Kerstin Stemmer, Rachel Sheridan, Shiva Kumar Shanmukhappa, Matthew J. Lawson, Rebekah Karns, Maria E. Moreno-Fernandez, Daniel A. Giles, C. Ronald Kahn, Monica Cappelletti, Samir Softic, Simon Graspeuntner, Senad Divanovic, Simon P. Hogan, Kris A. Steinbrecher, Christian Sina, Calvin C. Chan, Yoichiro Iwakura, Annika Sünderhauf, Traci E. Stankiewicz, David Wu, Damien Reynaud, Christopher L. Karp, Jared Klarquist, Jan Rupp, David B. Haslam, Bruce J. Aronow, Rajib Mukherjee |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine Pathology Cirrhosis Disease Chronic liver disease Machine Learning Pathogenesis Mice Non-alcoholic Fatty Liver Disease Nonalcoholic fatty liver disease Medicine Intestinal Mucosa Mice Knockout Receptors Interleukin-17 Reverse Transcriptase Polymerase Chain Reaction Temperature General Medicine Flow Cytometry Housing Animal 3. Good health Cold Temperature Jejunum Disease Progression Female medicine.medical_specialty Diet High-Fat Permeability General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine 03 medical and health sciences Sex Factors Immune system Stress Physiological Gram-Negative Bacteria Animals Humans Obesity Microbiome Inflammation business.industry Gene Expression Profiling nutritional and metabolic diseases Hematopoietic Stem Cells medicine.disease Gastrointestinal Microbiome Toll-Like Receptor 4 Disease Models Animal 030104 developmental biology Immunology Corticosterone business |
Zdroj: | Nat. Med. 23, 829-838 (2017) |
ISSN: | 1546-170X 1078-8956 |
Popis: | Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis. |
Databáze: | OpenAIRE |
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