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TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis
Cell Metabolism ( IF 27.7 ) Pub Date : 2024-04-25 , DOI: 10.1016/j.cmet.2024.04.003 Roi Isaac 1 , Gautam Bandyopadhyay 1 , Theresa V Rohm 1 , Sion Kang 1 , Jinyue Wang 1 , Narayan Pokhrel 2 , Sadatsugu Sakane 3 , Rizaldy Zapata 1 , Avraham M Libster 2 , Yaron Vinik 4 , Asres Berhan 5 , Tatiana Kisseleva 6 , Zea Borok 5 , Yehiel Zick 4 , Francesca Telese 2 , Nicholas J G Webster 7 , Jerrold M Olefsky 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2024-04-25 , DOI: 10.1016/j.cmet.2024.04.003 Roi Isaac 1 , Gautam Bandyopadhyay 1 , Theresa V Rohm 1 , Sion Kang 1 , Jinyue Wang 1 , Narayan Pokhrel 2 , Sadatsugu Sakane 3 , Rizaldy Zapata 1 , Avraham M Libster 2 , Yaron Vinik 4 , Asres Berhan 5 , Tatiana Kisseleva 6 , Zea Borok 5 , Yehiel Zick 4 , Francesca Telese 2 , Nicholas J G Webster 7 , Jerrold M Olefsky 1
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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 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 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.
中文翻译：
TM7SF3控制TEAD1剪接预防MASH诱导的肝纤维化
肝星状细胞（HSC）激活和肝纤维化发展的机制尚不完全清楚。在这里，我们发现核七跨膜蛋白 TM7SF3 的缺失会加速肝类器官、原代人类 HSC 和代谢功能障碍相关脂肪性肝炎 (MASH) 小鼠中 HSC 的激活，从而导致纤维化程序的激活和 HSC 增殖。因此，TM7SF3 敲除通过抑制剪接因子异质核糖核蛋白 U (hnRNPU) 来促进 Hippo 途径转录因子 TEAD1 的选择性剪接。这导致抑制性外显子 5 被排除，产生更活跃的 TEAD1 形式并触发 HSC 激活。此外，用特定的反义寡聚物 (ASO) 抑制 TEAD1 选择性剪接可使 HSC 失活并减少 MASH 饮食诱导的肝纤维化。总之，通过抑制 TEAD1 选择性剪接，TM7SF3 在减轻 HSC 激活和 MASH 相关纤维化进展方面发挥着关键作用。
更新日期：2024-04-25
中文翻译：
TM7SF3控制TEAD1剪接预防MASH诱导的肝纤维化
肝星状细胞（HSC）激活和肝纤维化发展的机制尚不完全清楚。在这里，我们发现核七跨膜蛋白 TM7SF3 的缺失会加速肝类器官、原代人类 HSC 和代谢功能障碍相关脂肪性肝炎 (MASH) 小鼠中 HSC 的激活，从而导致纤维化程序的激活和 HSC 增殖。因此，TM7SF3 敲除通过抑制剪接因子异质核糖核蛋白 U (hnRNPU) 来促进 Hippo 途径转录因子 TEAD1 的选择性剪接。这导致抑制性外显子 5 被排除，产生更活跃的 TEAD1 形式并触发 HSC 激活。此外，用特定的反义寡聚物 (ASO) 抑制 TEAD1 选择性剪接可使 HSC 失活并减少 MASH 饮食诱导的肝纤维化。总之，通过抑制 TEAD1 选择性剪接，TM7SF3 在减轻 HSC 激活和 MASH 相关纤维化进展方面发挥着关键作用。
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