Ansari Abulaish, Yadav Pradeep Kumar, Zhou Liye, Prakash Binu, Ijaz Laraib, Christiano Amanda, Ahmad Sameer, Rimbert Antoine, Hussain M Mahmood
Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, Mineola, New York, USA.
Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York, USA.
JCI Insight. 2025 Jan 9;10(1):e182260. doi: 10.1172/jci.insight.182260.
High apolipoprotein B-containing (apoB-containing) low-density lipoproteins (LDLs) and low apoA1-containing high-density lipoproteins (HDLs) are associated with atherosclerotic cardiovascular diseases. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both significantly decreases apoB and increases apoA1 expression by inducing mRNA degradation of 2 different transcription factors, Znf101 and Casz1. We found that Znf101 enhances apoB expression, while Casz1 represses apoA1 expression. The hepatic knockdown of Casz1 in mice increased plasma apoA1, HDL, and cholesterol efflux capacity. The hepatic knockdown of Zfp961, an ortholog of Znf101, reduced lipogenesis and production of triglyceride-rich lipoproteins and atherosclerosis, without causing hepatic lipid accumulation. This study identifies hepatic Znf101/Zfp961 and Casz1 as potential therapeutic targets to alter plasma lipoproteins and reduce atherosclerosis without causing liver steatosis.
富含载脂蛋白B（apoB）的低密度脂蛋白（LDL）和含载脂蛋白A1（apoA1）较少的高密度脂蛋白（HDL）与动脉粥样硬化性心血管疾病相关。为了寻找一种能够同时且相互调控LDL和HDL水平的分子调节剂，我们利用人肝癌Huh-7细胞筛选了一个微小RNA（miR）文库。我们鉴定出miR-541-3p，它通过诱导两种不同转录因子Znf101和Casz1的mRNA降解，显著降低apoB并增加apoA1的表达。我们发现Znf101增强apoB表达，而Casz1抑制apoA1表达。小鼠肝脏中Casz1的敲低增加了血浆apoA1、HDL和胆固醇流出能力。Znf101的直系同源物Zfp961在肝脏中的敲低减少了脂肪生成以及富含甘油三酯脂蛋白的产生和动脉粥样硬化，且不会导致肝脏脂质蓄积。本研究确定肝脏中的Znf101/Zfp961和Casz1是改变血浆脂蛋白并减少动脉粥样硬化而不引起肝脂肪变性的潜在治疗靶点。
