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. 2021 Aug 3;33(8):1685-1700.e9.
doi: 10.1016/j.cmet.2021.06.005. Epub 2021 Jul 7.

Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Anne Loft  1 , Ana Jimena Alfaro  2 , Søren Fisker Schmidt  3 , Felix Boel Pedersen  4 , Mike Krogh Terkelsen  4 , Michele Puglia  5 , Kan Kau Chow  2 , Annette Feuchtinger  6 , Maria Troullinaki  2 , Adriano Maida  2 , Gretchen Wolff  2 , Minako Sakurai  2 , Riccardo Berutti  7 , Bilgen Ekim Üstünel  2 , Peter Nawroth  8 , Kim Ravnskjaer  4 , Mauricio Berriel Diaz  2 , Blagoy Blagoev  4 , Stephan Herzig  9
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Free article

Liver-fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication

Anne Loft et al. Cell Metab. .
Free article

Abstract

Liver fibrosis is a strong predictor of long-term mortality in individuals with metabolic-associated fatty liver disease; yet, the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely understood. Using cell-type-resolved genomics, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a network of fibrosis-activated transcription factors, as exemplified by the transcription factor Elf-3 (ELF3) and zinc finger protein GLIS2 (GLIS2). Indeed, ELF3- and GLIS2-controlled fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell gene programs. Thus, interconnected transcription factor networks not only promoted hepatocyte dysfunction but also directed the intra-hepatic crosstalk necessary for NASH and fibrosis progression, implying that molecular "hub-centered" targeting strategies are superior to existing mono-target approaches as currently used in NASH therapy.

Keywords: Cell type-specific profiling; ELF3; GLIS2; genomic reprogramming; hepatocytes; liver fibrosis; metabolic-associated fatty liver disease; nonalcoholic steatohepatitis; transcription factor networks.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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