美国加州大学Jerrold M. Olefsky研究团队近日取得一项新成果。经过不懈努力，他们的最新研究表明TM7SF3通过调控TEAD1剪接来阻止MASH诱导的肝纤维化。2024年4月25日，国际学术期刊《细胞-代谢》发表了这一成果。

研究人员发现核七跨膜蛋白TM7SF3的缺失会加速肝脏器官组织、原代人肝星状细胞（HSC）以及代谢功能障碍相关性脂肪肝炎（MASH）小鼠体内HSC的活化，导致纤维化程序激活和HSC增殖。因此，TM7SF3基因敲除可通过抑制剪接因子异质核糖核蛋白U（hnRNPU）来促进Hippo通路转录因子TEAD1的替代剪接。这将导致抑制性外显子5失活，从而产生更活跃的TEAD1并导致HSC活化。

此外，用特异性反义寡聚体（ASO）抑制TEAD1的替代剪接可使体外HSC失活，并减轻MASH饮食诱导的肝纤维化。总之，通过抑制TEAD1的替代剪接，TM7SF3在减轻造HSC活化和MASH相关肝纤维化进展过程中发挥了关键作用。

据了解，HSC活化和肝纤维化进展的机制尚不完全清楚。

附：英文原文

Title: TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis

Author: Roi Isaac, Gautam Bandyopadhyay, Theresa V. Rohm, Sion Kang, Jinyue Wang, Narayan Pokhrel, Sadatsugu Sakane, Rizaldy Zapata, Avraham M. Libster, Yaron Vinik, Asres Berhan, Tatiana Kisseleva, Zea Borok, Yehiel Zick, Francesca Telese, Nicholas J.G. Webster, Jerrold M. Olefsky

Issue&Volume: 2024-04-25

Abstract: The mechanisms of hepatic stellate cell (HSC) activation and the development of liverfibrosis are not fully understood. Here, we show that deletion of a nuclear seventransmembrane protein, TM7SF3, accelerates HSC activation in liver organoids, primaryhuman HSCs, and in vivo in metabolic-dysfunction-associated steatohepatitis (MASH) mice, leading to activationof the fibrogenic program and HSC proliferation. Thus, TM7SF3 knockdown promotes alternativesplicing of the Hippo pathway transcription factor, TEAD1, by inhibiting the splicingfactor heterogeneous nuclear ribonucleoprotein U (hnRNPU). This results in the exclusionof the inhibitory exon 5, generating a more active form of TEAD1 and triggering HSCactivation. Furthermore, inhibiting TEAD1 alternative splicing with a specific antisenseoligomer (ASO) deactivates HSCs in vitro and reduces MASH diet-induced liver fibrosis. In conclusion, by inhibiting TEAD1alternative splicing, TM7SF3 plays a pivotal role in mitigating HSC activation andthe progression of MASH-related fibrosis.

DOI: 10.1016/j.cmet.2024.04.003

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00123-2