TY - JOUR
T1 - Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling
AU - Giles, Daniel A.
AU - Moreno-Fernandez, Maria E.
AU - Stankiewicz, Traci E.
AU - Graspeuntner, Simon
AU - Cappelletti, Monica
AU - Wu, David
AU - Mukherjee, Rajib
AU - Chan, Calvin C.
AU - Lawson, Matthew J.
AU - Klarquist, Jared
AU - Sünderhauf, Annika
AU - Softic, Samir
AU - Kahn, C. Ronald
AU - Stemmer, Kerstin
AU - Iwakura, Yoichiro
AU - Aronow, Bruce J.
AU - Karns, Rebekah
AU - Steinbrecher, Kris A.
AU - Karp, Christopher L.
AU - Sheridan, Rachel
AU - Shanmukhappa, Shiva K.
AU - Reynaud, Damien
AU - Haslam, David B.
AU - Sina, Christian
AU - Rupp, Jan
AU - Hogan, Simon P.
AU - Divanovic, Senad
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85027021543&partnerID=8YFLogxK
U2 - 10.1038/nm.4346
DO - 10.1038/nm.4346
M3 - Journal articles
C2 - 28604704
AN - SCOPUS:85027021543
SN - 1078-8956
VL - 23
SP - 829
EP - 838
JO - Nature Medicine
JF - Nature Medicine
IS - 7
ER -