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

Jing Chen, Jin Li, Jensen H.C. Yiu, Jenny K.W. Lam, Chi Ming Wong, Bernhard Dorweiler, Aimin Xu, Connie W. Woo

Research output: Journal article publicationJournal articleAcademic researchpeer-review

8 Citations (Scopus)


Nonalcoholic 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-b (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.
Original languageEnglish
Article numberaal3336
JournalScience Signaling
Issue number491
Publication statusPublished - 8 Aug 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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