| First Author | Xiong J | Year | 2020 |
| Journal | Hepatology | Volume | 71 |
| Issue | 4 | Pages | 1228-1246 |
| PubMed ID | 31469911 | Mgi Jnum | J:329508 |
| Mgi Id | MGI:6714445 | Doi | 10.1002/hep.30921 |
| Citation | Xiong J, et al. (2020) hnRNPU/TrkB Defines a Chromatin Accessibility Checkpoint for Liver Injury and Nonalcoholic Steatohepatitis Pathogenesis. Hepatology 71(4):1228-1246 |
| abstractText | BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation, and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress-induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive. APPROACH AND RESULTS: Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA-seq and chromatin immunoprecipitation-seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte-specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated molecular signature of NASH, and sensitized mice to diet-induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB (TRKB-T1) that promotes inflammatory signaling in hepatocytes and stress-induced cell death. Brain-derived neurotrophic factor treatment reduced membrane TRKB-T1 protein and protected mice from diet-induced NASH. CONCLUSIONS: These findings illustrate a mechanism through which disruptions of chromatin architecture drive the emergence of disease-specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis. |
