A cholesterol-responsive hepatic tRNA-derived small RNA regulates cholesterol homeostasis and atherosclerosis development
Xiuchun Li, Rebecca Hernandez, Xudong Zhang, Sijie Tang, Xiaohong Yuan, Kaichun Wu, Kathy Pham, Hukam C. Rawal, Erica C. Heinrich, Shenglong Zhang, Qi Chen, Tong Zhou, Changcheng Zhou
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.