Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein

Yasuhiro Miyamoto, Amy S. Mauer, Swarup Kumar, Justin L. Mott, Harmeet M Malhi

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Lipoapoptosis occurring due to an excess of saturated free fatty acids such as palmitate is a key pathogenic event in the initiation of nonalcoholic fatty liver disease. Palmitate loading of cells activates the endoplasmic reticulum stress response, including induction of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Furthermore, the loss of microRNAs is implicated in regulating apoptosis under conditions of endoplasmic reticulum (ER) stress. The aim of this study was to identify specific microRNAs regulating CHOP expression during palmitate-induced ER stress. Five microRNAs were repressed under palmitate-induced endoplasmic reticulum stress conditions in hepatocyte cell lines (miR-92b-3p, miR-328- 3p, miR-484, miR-574-5p, and miR-615-3p). We identified miR-615-3p as a candidate microRNA which was repressed by palmitate treatment and regulated CHOP protein expression, by RNA sequencing and in silico analyses, respectively. There is a single miR-615-3p binding site in the 39untranslated region (UTR) of the Chop transcript. We characterized this as a functional binding site using a reporter gene-based assay. Augmentation of miR-615-3p levels, using a precursor molecule, repressed CHOP expression; and under these conditions palmitate- or tunicamycin-induced cell death were significantly reduced. Our results suggest that palmitate-induced apoptosis requires maximal expression of CHOP which is achieved via the downregulation of its repressive microRNA, miR-615-3p. We speculate that enhancement of miR-615-3p levels may be of therapeutic benefit by inhibiting palmitate-induced hepatocyte lipoapoptosis.

Original languageEnglish (US)
Article numbere109637
JournalPLoS One
Volume9
Issue number10
DOIs
StatePublished - Oct 14 2014

Fingerprint

Transcription Factor CHOP
Palmitates
palmitates
MicroRNAs
microRNA
Endoplasmic Reticulum Stress
endoplasmic reticulum
proteins
protein synthesis
hepatocytes
binding sites
Hepatocytes
apoptosis
Binding Sites
Apoptosis
tunicamycin
Untranslated Regions
RNA Sequence Analysis
Tunicamycin
chops

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. / Miyamoto, Yasuhiro; Mauer, Amy S.; Kumar, Swarup; Mott, Justin L.; Malhi, Harmeet M.

In: PLoS One, Vol. 9, No. 10, e109637, 14.10.2014.

Research output: Contribution to journalArticle

Miyamoto, Yasuhiro ; Mauer, Amy S. ; Kumar, Swarup ; Mott, Justin L. ; Malhi, Harmeet M. / Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. In: PLoS One. 2014 ; Vol. 9, No. 10.
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