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Article: Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice

TitleToll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice
Authors
Issue Date2012
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2012, v. 61 n. 7, p. 1058-1067 How to Cite?
AbstractBackground: Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. Objective: Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. Methods: ApoE -/-/TLR4 mut mice and ApoE -/-/TLR4 wild-type mice (ApoE -/-/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE -/-) strain with TLR4-mutant (TLR4 mut) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity. Results: ApoE -/-/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE -/-/TLR4 mutmice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE -/-/TLR4- WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE -/-/TLR4 mut mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice. Conclusions: These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.
Persistent Identifierhttp://hdl.handle.net/10722/145898
ISSN
2015 Impact Factor: 14.921
2015 SCImago Journal Rankings: 6.474
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council of Hong KongHKU5/CRF/08
HKU4/CRF10
University of Hong Kong
National Basic Research Program of China2011CB504004
Funding Information:

This work is supported by Collaborative Research Fund (HKU5/CRF/08 and HKU4/CRF10) from the Research Grant Council of Hong Kong, Seeding fund for basic research from the University of Hong Kong (to AX), and the National Basic Research Program of China (2011CB504004).

References
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DC FieldValueLanguage
dc.contributor.authorYe, Den_HK
dc.contributor.authorLi, FYLen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorLi, Hen_HK
dc.contributor.authorJia, Wen_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorLo, CMen_HK
dc.contributor.authorLi, Xen_HK
dc.contributor.authorXu, Aen_HK
dc.date.accessioned2012-03-27T09:01:22Z-
dc.date.available2012-03-27T09:01:22Z-
dc.date.issued2012en_HK
dc.identifier.citationGut, 2012, v. 61 n. 7, p. 1058-1067en_HK
dc.identifier.issn0017-5749en_HK
dc.identifier.urihttp://hdl.handle.net/10722/145898-
dc.description.abstractBackground: Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. Objective: Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. Methods: ApoE -/-/TLR4 mut mice and ApoE -/-/TLR4 wild-type mice (ApoE -/-/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE -/-) strain with TLR4-mutant (TLR4 mut) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity. Results: ApoE -/-/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE -/-/TLR4 mutmice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE -/-/TLR4- WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE -/-/TLR4 mut mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice. Conclusions: These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.en_HK
dc.languageengen_US
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/en_HK
dc.relation.ispartofGuten_HK
dc.rightsGut. Copyright © BMJ Publishing Group.-
dc.titleToll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in miceen_HK
dc.typeArticleen_HK
dc.identifier.emailMan, K: kwanman@hkucc.hku.hken_HK
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hken_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityLo, CM=rp00412en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1136/gutjnl-2011-300269en_HK
dc.identifier.pmid22253482-
dc.identifier.scopuseid_2-s2.0-84861547908en_HK
dc.identifier.hkuros198907en_US
dc.identifier.hkuros213337-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84861547908&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume61en_HK
dc.identifier.issue7en_HK
dc.identifier.spage1058en_HK
dc.identifier.epage1067en_HK
dc.identifier.isiWOS:000304443200016-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridYe, D=55232626600en_HK
dc.identifier.scopusauthoridLi, FYL=55232963900en_HK
dc.identifier.scopusauthoridLam, KSL=55192819200en_HK
dc.identifier.scopusauthoridLi, H=24066677600en_HK
dc.identifier.scopusauthoridJia, W=45961153100en_HK
dc.identifier.scopusauthoridWang, Y=37008681000en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridLo, CM=7401771672en_HK
dc.identifier.scopusauthoridLi, X=35224906000en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK

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