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Article: TRIF-dependent Toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis

TitleTRIF-dependent Toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis
Authors
Issue Date2017
PublisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://stke.sciencemag.org/
Citation
Science Signaling, 2017, v. 10 n. 491, p. eaal3336 How to Cite?
AbstractNonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-β (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells. The aggravated steatosis in Trif-/- mice was due to the increased hepatocyte transcription of the gene encoding stearoyl-coenzyme A (CoA) desaturase 1 (SCD1), the rate-limiting enzyme for lipogenesis. Activation of the TRIF pathway by polyinosinic:polycytidylic acid [poly(I:C)] suppressed the increase in SCD1 abundance induced by palmitic acid or an HFD and subsequently prevented lipid accumulation in hepatocytes. Interferon regulatory factor 3 (IRF3), a transcriptional regulator downstream of TRIF, acted as a transcriptional suppressor by directly binding to the Scd1 promoter. These results suggest an unconventional metabolic function for TLR/TRIF signaling that should be taken into consideration when seeking to pharmacologically inhibit this pathway.
Persistent Identifierhttp://hdl.handle.net/10722/242802
ISSN
2023 Impact Factor: 6.7
2023 SCImago Journal Rankings: 2.341
ISI Accession Number ID
Grants

 

DC FieldValueLanguage
dc.contributor.authorChen, J-
dc.contributor.authorLi, J-
dc.contributor.authorYiu, JHC-
dc.contributor.authorLam, JKW-
dc.contributor.authorWong, CM-
dc.contributor.authorDorweiler, B-
dc.contributor.authorXu, A-
dc.contributor.authorWoo, WHC-
dc.date.accessioned2017-08-25T02:45:31Z-
dc.date.available2017-08-25T02:45:31Z-
dc.date.issued2017-
dc.identifier.citationScience Signaling, 2017, v. 10 n. 491, p. eaal3336-
dc.identifier.issn1945-0877-
dc.identifier.urihttp://hdl.handle.net/10722/242802-
dc.description.abstractNonalcoholic fatty liver disease (NAFLD) includes a spectrum of diseases that ranges in severity from hepatic steatosis to steatohepatitis, the latter of which is a major predisposing factor for liver cirrhosis and cancer. Toll-like receptor (TLR) signaling, which is critical for innate immunity, is generally believed to aggravate disease progression by inducing inflammation. Unexpectedly, we found that deficiency in TIR domain-containing adaptor-inducing interferon-β (TRIF), a cytosolic adaptor that transduces some TLR signals, worsened hepatic steatosis induced by a high-fat diet (HFD) and that such exacerbation was independent of myeloid cells. The aggravated steatosis in Trif-/- mice was due to the increased hepatocyte transcription of the gene encoding stearoyl-coenzyme A (CoA) desaturase 1 (SCD1), the rate-limiting enzyme for lipogenesis. Activation of the TRIF pathway by polyinosinic:polycytidylic acid [poly(I:C)] suppressed the increase in SCD1 abundance induced by palmitic acid or an HFD and subsequently prevented lipid accumulation in hepatocytes. Interferon regulatory factor 3 (IRF3), a transcriptional regulator downstream of TRIF, acted as a transcriptional suppressor by directly binding to the Scd1 promoter. These results suggest an unconventional metabolic function for TLR/TRIF signaling that should be taken into consideration when seeking to pharmacologically inhibit this pathway.-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science. The Journal's web site is located at http://stke.sciencemag.org/-
dc.relation.ispartofScience Signaling-
dc.rightsScience Signaling. Copyright © American Association for the Advancement of Science.-
dc.rightsThis is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in [Science Journal Title] on [Volume number and date], DOI: [insert DOI number].-
dc.titleTRIF-dependent Toll-like receptor signaling suppresses Scd1 transcription in hepatocytes and prevents diet-induced hepatic steatosis-
dc.typeArticle-
dc.identifier.emailLam, JKW: jkwlam@hku.hk-
dc.identifier.emailXu, A: amxu@hkucc.hku.hk-
dc.identifier.emailWoo, WHC: cwhwoo@hku.hk-
dc.identifier.authorityLam, JKW=rp01346-
dc.identifier.authorityXu, A=rp00485-
dc.identifier.authorityWoo, WHC=rp01860-
dc.identifier.doi10.1126/scisignal.aal3336-
dc.identifier.pmid28790196-
dc.identifier.scopuseid_2-s2.0-85027410384-
dc.identifier.hkuros274251-
dc.identifier.volume10-
dc.identifier.issue491-
dc.identifier.spageeaal3336-
dc.identifier.epageeaal3336-
dc.identifier.isiWOS:000407114900002-
dc.publisher.placeUnited States-
dc.relation.projectA Multi-disciplinary Approach to Investigate Vascular Dysfunction in Obesity and Diabetes: From Molecular Mechanism to Therapeutic Intervention-
dc.identifier.issnl1945-0877-

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