Dicer-dependent production of microRNA221 in hepatocytes inhibits p27 and is required for liver regeneration in mice

Yuki Oya, Ryota Masuzaki, Daisuke Tsugawa, Kevin C. Ray, Yongchao Dou, Seth J. Karp

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Dicer processes microRNAs (miRs) into active forms in a wide variety of tissues, including the liver. To determine the role of Dicer in liver regeneration, we performed a series of in vivo and in vitro studies in a murine 2/3 hepatectomy model. Dicer was downregulated after 2/3 hepatectomy, and loss of Dicer inhibited liver regeneration associated with decreased cyclin A2 and miR-221, as well as increased levels of the cell cycle inhibitor p27. In vitro, miR-221 inhibited p27 production in primary hepatocytes and increased hepatocyte proliferation. Specific reconstitution of miR-221 in hepatocyte-specific Dicer-null mice inhibited p27 and restored liver regeneration. In wild type mice, targeted inhibition of miR-221 using a cholesterol-conjugated miR- 221 inhibited hepatocyte proliferation after 2/3 hepatectomy. These results identify Dicer production of miR-221 as an essential component of a miRNA-dependent mechanism for suppression of p27 that controls the rate of hepatocyte proliferation after partial hepatectomy. NEW & NOTEWORTHY Our findings demonstrate a direct role for microRNAs in controlling the rate of liver regeneration after injury. By deleting Dicer, an enzyme responsible for processing microRNAs into mature forms, we determined miR-221 is a critical micro- RNA in the physiological process of restoration of liver mass after injury. miR-221 suppresses p27, releasing its inhibitory effects on hepatocyte proliferation. Pharmaceuticals based on miR-221 may be useful to modulate hepatocyte proliferation in the setting of liver injury.

Original languageEnglish
Pages (from-to)G464-G473
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume312
Issue number5
DOIs
Publication statusPublished - 4 May 2017
Externally publishedYes

Keywords

  • Dicer
  • Liver
  • MiR-221
  • P27
  • Regeneration

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