Howard Donninger, Katherine Hobbing, Gavin E. Arteel, Geoffrey J. Clark
{"title":"NORE1A loss promotes MASLD/MASH","authors":"Howard Donninger, Katherine Hobbing, Gavin E. Arteel, Geoffrey J. Clark","doi":"10.1007/s11248-024-00407-8","DOIUrl":null,"url":null,"abstract":"<p>NORE1A (RASSF5) is a tumor suppressor that is frequently down-regulated in liver tumors. It is an upstream component of the HIPPO pathway, a key regulator of liver development and metabolism. HIPPO disruption can lead to the development of MASLD/MASH. While studying the phenotype of NORE1A knockout mice, we noticed that they exhibit no overt liver tumor phenotype, but have a strong propensity to develop fatty livers characteristic of MASLD/MASH. Additionally, knockdown of NORE1A in liver cells upregulates sterol regulator element binding protein 1 (SREBP1), whose deregulation is central to the development MASLD. Examination of primary human MASLD samples showed an inverse correlation between the expression of NORE1A protein and TAZ, a downstream effector of the HIPPO pathway. Thus, loss of NORE1A expression may contribute to the development of MASLD/MASH in humans and NORE1A knockout mice may provide a new MASLD/MASH model that more accurately mimics the human disease.</p>","PeriodicalId":2,"journal":{"name":"ACS Applied Bio Materials","volume":null,"pages":null},"PeriodicalIF":4.6000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Bio Materials","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1007/s11248-024-00407-8","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
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Abstract
NORE1A (RASSF5) is a tumor suppressor that is frequently down-regulated in liver tumors. It is an upstream component of the HIPPO pathway, a key regulator of liver development and metabolism. HIPPO disruption can lead to the development of MASLD/MASH. While studying the phenotype of NORE1A knockout mice, we noticed that they exhibit no overt liver tumor phenotype, but have a strong propensity to develop fatty livers characteristic of MASLD/MASH. Additionally, knockdown of NORE1A in liver cells upregulates sterol regulator element binding protein 1 (SREBP1), whose deregulation is central to the development MASLD. Examination of primary human MASLD samples showed an inverse correlation between the expression of NORE1A protein and TAZ, a downstream effector of the HIPPO pathway. Thus, loss of NORE1A expression may contribute to the development of MASLD/MASH in humans and NORE1A knockout mice may provide a new MASLD/MASH model that more accurately mimics the human disease.
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