2025-12-15 カリフォルニア大学リバーサイド校(UCR)
<関連情報>
- https://news.ucr.edu/articles/2025/12/15/scientists-identify-small-rna-molecule-regulates-cholesterol-and-heart-disease
- https://www.nature.com/articles/s41467-025-67387-z
コレステロール応答性肝臓tRNA由来小RNAはコレステロール恒常性と動脈硬化の発症を制御する A cholesterol-responsive hepatic tRNA-derived small RNA regulates cholesterol homeostasis and atherosclerosis development
Xiuchun Li,Rebecca Hernandez,Xudong Zhang,Sijie Tang,Xiaohong Yuan,Jing Wu,Kathy Pham,Hukam C. Rawal,Erica C. Heinrich,Shenglong Zhang,Qi Chen,Tong Zhou & Changcheng Zhou
Nature Communications Published:15 December 2025
DOI:https://doi.org/10.1038/s41467-025-67387-z
Abstract
Transfer RNA-derived small RNAs (tsRNAs) have emerged as crucial players in diverse biological processes. Yet, their involvement in lipid metabolism and cardiovascular disease remains elusive. Using an advanced PANDORA-seq method, we identify tsRNA-Glu-CTC as the most abundant tsRNA in mouse liver. Intriguingly, tsRNA-Glu-CTC is cholesterol responsive. Overexpression of tsRNA-Glu-CTC elicits hypercholesterolemia and hepatic steatosis, whereas its knockdown protects against diet-induced hypercholesterolemia and atherosclerosis in mice. Mechanistically, tsRNA-Glu-CTC regulates key hepatic lipogenic genes including Srebp2, a master regulator of lipid metabolism. tsRNA-Glu-CTC interacts with SREBP2 to regulate its own transcription through an E-box motif. We further identify site-specific RNA modifications of endogenous tsRNA-Glu-CTC by a mass spectrometry-based MLC-seq and demonstrate the modified tsRNA-Glu-CTC as a more potent regulator of cholesterol homeostasis compared to its unmodified synthetic counterpart. Collectively, our study reveals an important role of a liver-enriched tsRNA in lipid metabolism and cardiovascular health, opening new therapeutic avenues for cardiometabolic disease.
