Loss of Hepatic Oscillatory Fed microRNAs Abrogates Refed Transition and Causes Liver Dysfunctions

Cell Rep. 2019 Feb 19;26(8):2212-2226.e7. doi: 10.1016/j.celrep.2019.01.087.


Inability to mediate fed-fast transitions in the liver is known to cause metabolic dysfunctions and diseases. Intuitively, a failure to inhibit futile translation of state-specific transcripts during fed-fast cycles would abrogate dynamic physiological transitions. Here, we have discovered hepatic fed microRNAs that target fasting-induced genes and are essential for a refed transition. Our findings highlight the role of these fed microRNAs in orchestrating system-level control over liver physiology and whole-body energetics. By targeting SIRT1, PGC1α, and their downstream genes, fed microRNAs regulate metabolic and mitochondrial pathways. MicroRNA expression, processing, and RISC loading oscillate during these cycles and possibly constitute an anticipatory mechanism. Fed-microRNA oscillations are deregulated during aging. Scavenging of hepatic fed microRNAs causes uncontrolled gluconeogenesis and failure in the catabolic-to-anabolic switching upon feeding, which are hallmarks of metabolic diseases. Besides identifying mechanisms that enable efficient physiological toggling, our study highlights fed microRNAs as candidate therapeutic targets.

Keywords: PGC1α; SIRT1; energetics; fast; fatty acid oxidation; fed; gluconeogenesis; liver; microRNA; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Energy Metabolism
  • Fasting / metabolism*
  • Gluconeogenesis
  • HEK293 Cells
  • Hep G2 Cells
  • Homeostasis*
  • Humans
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mitochondria, Liver / metabolism
  • Periodicity
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Sirtuin 1 / metabolism


  • MicroRNAs
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Sirt1 protein, mouse
  • Sirtuin 1