NORE1A loss promotes MASLD/MASH

IF 2.7 3区 生物学 Q2 BIOCHEMICAL RESEARCH METHODS Transgenic Research Pub Date : 2024-09-09 DOI:10.1007/s11248-024-00407-8
Howard Donninger, Katherine Hobbing, Gavin E. Arteel, Geoffrey J. Clark
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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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NORE1A 缺失会促进 MASLD/MASH
NORE1A(RASSF5)是一种肿瘤抑制因子,在肝脏肿瘤中经常下调。它是 HIPPO 通路的上游成分,而 HIPPO 是肝脏发育和新陈代谢的关键调节因子。HIPPO中断可导致MASLD/MASH的发生。在研究 NORE1A 基因敲除小鼠的表型时,我们注意到它们没有表现出明显的肝肿瘤表型,但却有强烈的倾向发展成 MASLD/MASH 特征的脂肪肝。此外,敲除肝细胞中的 NORE1A 会上调固醇调节因子结合蛋白 1(SREBP1),而固醇调节因子结合蛋白 1 的失调是导致 MASLD 的核心原因。对原发性人类 MASLD 样本的研究表明,NORE1A 蛋白的表达与 HIPPO 通路的下游效应因子 TAZ 之间存在反相关性。因此,NORE1A的表达缺失可能会导致人类MASLD/MASH的发生,而NORE1A基因敲除小鼠可能会提供一种新的MASLD/MASH模型,更准确地模拟人类疾病。
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来源期刊
Transgenic Research
Transgenic Research 生物-生化研究方法
CiteScore
5.40
自引率
0.00%
发文量
38
审稿时长
4-8 weeks
期刊介绍: Transgenic Research focusses on transgenic and genome edited higher organisms. Manuscripts emphasizing biotechnological applications are strongly encouraged. Intellectual property, ethical issues, societal impact and regulatory aspects also fall within the scope of the journal. Transgenic Research aims to bridge the gap between fundamental and applied science in molecular biology and biotechnology for the plant and animal academic and associated industry communities. Transgenic Research publishes -Original Papers -Reviews: Should critically summarize the current state-of-the-art of the subject in a dispassionate way. Authors are requested to contact a Board Member before submission. Reviews should not be descriptive; rather they should present the most up-to-date information on the subject in a dispassionate and critical way. Perspective Reviews which can address new or controversial aspects are encouraged. -Brief Communications: Should report significant developments in methodology and experimental transgenic higher organisms
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