| First Author | Dashek RJ | Year | 2024 |
| Journal | Cell Mol Gastroenterol Hepatol | Volume | 18 |
| Issue | 3 | Pages | 101365 |
| PubMed ID | 38797477 | Mgi Jnum | J:373862 |
| Mgi Id | MGI:8253142 | Doi | 10.1016/j.jcmgh.2024.101365 |
| Citation | Dashek RJ, et al. (2024) Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-associated Steatohepatitis Development. Cell Mol Gastroenterol Hepatol 18(3):101365 |
| abstractText | BACKGROUND & AIMS: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild-type mice. Hepatocyte-specific RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlights its potential as a novel therapeutic in MASH. |
