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

• Published in: Cell metabolism 2021-08, Vol.33 (8), p.1685-1700.e9
• Main Authors: Loft, Anne, Alfaro, Ana Jimena, Schmidt, Søren Fisker, Pedersen, Felix Boel, Terkelsen, Mike Krogh, Puglia, Michele, Chow, Kan Kau, Feuchtinger, Annette, Troullinaki, Maria, Maida, Adriano, Wolff, Gretchen, Sakurai, Minako, Berutti, Riccardo, Ekim Üstünel, Bilgen, Nawroth, Peter, Ravnskjaer, Kim, Diaz, Mauricio Berriel, Blagoev, Blagoy, Herzig, Stephan
• Format: Article
• Language: English
• Subjects: Cell type-specific profiling; Communication; ELF3; Gene Regulatory Networks; genomic reprogramming; GLIS2; hepatocytes; Hepatocytes - metabolism; Humans; Liver - metabolism; Liver Cirrhosis - metabolism; liver fibrosis; metabolic-associated fatty liver disease; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic steatohepatitis; transcription factor networks
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2021.06.005

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. [Display omitted] •Advanced NASH is accompanied by partial loss of hepatocyte identity•NASH-induced hepatokines associate with fibrosis-linked genes in hepatic stellate cells•A cooperative transcription factor network drives hepatocyte genomic reprogramming in NASH•Fibrosis-activated ELF3 and GLIS2 promote intra-hepatic crosstalk and liver fibrosis The mechanisms that drive the advanced stages of metabolic-associated fatty liver disease (MALFD) are still largely unknown. Using a cell type-resolved genomics approach, Loft et al. identified a fibrosis-activated hepatocyte transcription factor network that contributes to the loss of hepatocyte identity and dictates intra-hepatic cross-talk during the progression of MALFD.