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<p>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 <i>Srebp2</i>, 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.</p>

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A cholesterol-responsive hepatic tRNA-derived small RNA regulates cholesterol homeostasis and atherosclerosis development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月15日

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  • 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

摘要

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.