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
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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