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  1. Philip J Smith
  1. Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals Foundation Trust, Liverpool, UK
  1. Correspondence to Dr Philip J Smith, Department of Gastroenterology, Royal Liverpool Hospital, Liverpool University Hospitals Foundation Trust, Liverpool, L7 8XP, UK; Philip.Smith{at}liverpoolft.nhs.uk

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Basic science

MYC activation in liver non-parenchymal cells drives hepatic damage in acute liver failure

Kolodziejczyk A, Federici S, Zmora N et al. Acute liver failure is regulated by MYC- and microbiome-dependent programs. Nat Med 2020; doi: 10.1038/s41591-020-1102-2

Acute liver failure (ALF) remains a devastating condition with a high mortality and limited treatment options short of liver transplantation. It is therefore imperative that we develop a deeper understanding of the cellular and molecular mechanisms regulating ALF, with the hope of identifying novel therapeutic targets. In this study, Kolodziejczyk et al have employed a cutting-edge single-cell RNA-sequencing approach to study transcriptional changes in mouse non-parenchymal liver cells following ALF induced by either acetaminophen (APAP) or thioacetamide (TAA). As anticipated, they showed significant alterations in the phenotype of hepatic stellate cells, endothelial cells and macrophages following ALF. Strikingly, however, comparative analyses demonstrated a conserved injury response signature of 77 genes across these different cell lineages, which was enriched for binding sites of the transcriptional regulator MYC. Inhibition of MYC attenuated liver injury in mouse ALF and prevented the development of these activated non-parenchymal cell populations. Furthermore, this MYC activation signature was reduced in germ-free mice, following antimicrobial treatment and in response to inhibition of toll-like receptor signalling in the liver. Overall, these data suggest that a combination of liver cell death and translocation of gut microbial products results in hepatic MYC upregulation, which propagates liver non-parenchymal cell activation, tissue damage and inflammation in ALF. Hepatic MYC protein levels were also increased in patients with ALF, suggesting that targeting MYC may represent a potential treatment for patients. However, more detailed characterisation of non-parenchymal cell phenotypes in human ALF is required, before the true translational relevance of these findings can be fully understood.

Human-Gut-DNA virome variations across geography, ethnicity and urbanisation

Zuo T, Sun Y, Wan Y et al. Human-Gut-DNA virome variations across geography, ethnicity, and urbanization. Cell Host Microbe 2020; 28 (5): 741–751.e4. doi: 10.1016/j.chom.2020.08.005 …

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Footnotes

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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