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TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis.
- Source :
-
Cell metabolism [Cell Metab] 2024 May 07; Vol. 36 (5), pp. 1030-1043.e7. Date of Electronic Publication: 2024 Apr 25. - Publication Year :
- 2024
-
Abstract
- The mechanisms of hepatic stellate cell (HSC) activation and the development of liver fibrosis are not fully understood. Here, we show that deletion of a nuclear seven transmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primary human HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activation of the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternative splicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicing factor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusion of the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSC activation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisense oligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1 alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation and the progression of MASH-related fibrosis.<br />Competing Interests: Declaration of interests R.I. and J.M.O. are co-inventors on a provisional patent for the use of ASO 56 as an inhibitor of liver fibrosis.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Alternative Splicing
Mice, Inbred C57BL
Nuclear Proteins metabolism
Nuclear Proteins genetics
Hepatic Stellate Cells metabolism
Male
Fatty Liver metabolism
Fatty Liver pathology
Fatty Liver genetics
Mice, Knockout
TEA Domain Transcription Factors metabolism
Liver Cirrhosis metabolism
Liver Cirrhosis pathology
Liver Cirrhosis genetics
Transcription Factors metabolism
Transcription Factors genetics
DNA-Binding Proteins metabolism
DNA-Binding Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 36
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 38670107
- Full Text :
- https://doi.org/10.1016/j.cmet.2024.04.003