Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via β-Klotho and perilipin 2

Yonat Tzur, Katarzyna Winek, Nimrod Madrer, Serafima Dubnov, Estelle R. Bennett, David S. Greenberg, Geula Hanin, Asaad Gammal, Joseph Tam, Isaiah T. Arkin, Iddo Paldor, Hermona Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5′tRF transfer RNA fragments and microRNA miR-194-5p. Methods: Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5′tRF and miR-194-5p. Results: Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5′tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5′tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5′tRF mimic elevated mRNA levels of the metabolic regulator β-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5′tRF levels. Conclusion: Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5′tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

Original languageAmerican English
Article number101856
JournalMolecular Metabolism
Volume79
DOIs
StatePublished - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

  • KLB
  • LysTTT-5′tRFs
  • NAFLD
  • PLIN2
  • miR-194-5p
  • microRNAs
  • tRFs

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