Zhuang Chunbo, Cui Fangfang, Chen Jin, He Dezhi, Sun Ting, Wang Pei
Department of Clinical Laboratory, Key Clinical Laboratory of Henan Province, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Department of Gastroenterology, Kaifeng People's Hospital, Kaifeng, Henan 475000, PR China.
Biochim Biophys Acta Mol Basis Dis. 2025 Jun;1871(5):167815. doi: 10.1016/j.bbadis.2025.167815. Epub 2025 Mar 26.
Excessive hepatic lipid accumulation is the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms still not fully understood. In this study, we identified RNA binding motif protein 39 (Rbm39) as a key modulator of hepatic lipid homeostasis during MASLD progression. To establish in vivo MASLD model, mice were fed either a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet. We employed adeno-associated virus to manipulate Rbm39 expression levels to assess its role in MASLD. Transcriptome analysis was conducted to pinpoint the genes targeted by Rbm39. Western blot, RT-PCR, dual-luciferase reporter gene assays, and alternative splicing analysis were utilized to delve into the molecular mechanisms. Our results showed that Rbm39 expression was notably decreased in the livers of MASLD mice. Knockdown of hepatic Rbm39 aggravated HFD-induced hepatic steatosis and GAN diet-induced MASH, along with a notable decrease in serum lipid levels. Conversely, overexpression of Rbm39 attenuated MASLD development and progression. RNA sequencing data analysis indicated that Rbm39 regulated the expression of apolipoprotein B (Apob) and fatty acid-binding protein 4 (Fabp4), both of which are crucial for lipid transport. Mechanistically, Rbm39 enhanced the transcription of Apob by upregulating hepatocyte nuclear factor 4α (Hnf4α), while it suppressed Fabp4 transcription by regulating alternative splicing of hypoxia inducible factor-1α (Hif-1α). These findings highlight the pivotal role of Rbm39 in maintaining hepatic lipid homeostasis and suggest its potential as a therapeutic target for MASLD.
肝脏脂质过度积累是代谢功能障碍相关脂肪性肝病（MASLD）的标志，但其潜在机制仍未完全明确。在本研究中，我们确定RNA结合基序蛋白39（Rbm39）是MASLD进展过程中肝脏脂质稳态的关键调节因子。为建立体内MASLD模型，给小鼠喂食高脂饮食（HFD）或古布拉 - 胰淀素NASH（GAN）饮食。我们使用腺相关病毒来操纵Rbm39表达水平，以评估其在MASLD中的作用。进行转录组分析以确定Rbm39靶向的基因。利用蛋白质免疫印迹、逆转录 - 聚合酶链反应、双荧光素酶报告基因测定和可变剪接分析来深入研究分子机制。我们的结果表明，MASLD小鼠肝脏中Rbm39表达显著降低。敲低肝脏中的Rbm39会加重HFD诱导的肝脏脂肪变性和GAN饮食诱导的MASH，同时血清脂质水平显著降低。相反，Rbm39的过表达减弱了MASLD的发展和进程。RNA测序数据分析表明，Rbm39调节载脂蛋白B（Apob）和脂肪酸结合蛋白4（Fabp4）的表达，这两者对脂质转运都至关重要。机制上，Rbm39通过上调肝细胞核因子4α（Hnf4α）增强Apob的转录，而通过调节缺氧诱导因子 - 1α（Hif - 1α）的可变剪接抑制Fabp4转录。这些发现突出了Rbm39在维持肝脏脂质稳态中的关键作用，并表明其作为MASLD治疗靶点的潜力。
