Research ArticleMetabolism

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

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Sci. Signal.  08 Aug 2017:
Vol. 10, Issue 491, eaal3336
DOI: 10.1126/scisignal.aal3336

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TRIF against fatty liver

Viral detection by TLR pathways triggers inflammatory responses, which generally aggravate metabolic diseases. However, Chen et al. found that the TLR signaling adaptor TRIF in hepatocytes, rather than myeloid cells, limited diet-induced hepatic steatosis in mice. TRIF activation downstream of TLR3 led to the transcriptional suppression of Scd1, which encodes a key lipogenic enzyme. Viral RNA and mimetics activate TLR3, and application of RNA generated by adipose tissue prevented the increase in SCD1 abundance and the enhanced triglyceride accumulation that normally occurs in hepatocytes exposed to palmitic acid, a saturated fatty acid that is enriched in high-fat diets. The authors note that the hepatitis C virus co-opts host lipogenesis to ensure its replication and that TRIF-mediated suppression of Scd1 transcription may therefore serve to limit viral infection of hepatocytes.

Abstract

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-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.

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