De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver

Liping Luo, Wanxiang Jiang, Hui Liu, Jicheng Bu, Ping Tang, Chongyangzi Du, Zhipeng Xu, Hairong Luo, Bilian Liu, Bo Xiao, Zhiguang Zhou, Feng Liu

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The growth factor receptor bound protein GRB10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. Our study demonstrates for the first time that the silenced Grb10 gene can be reactivated by acute ER stress and its reactivation plays an important role in the early development of hepatic steatosis.

Original languageEnglish (US)
Pages (from-to)285-297
Number of pages13
JournalJournal of Molecular Endocrinology
Volume60
Issue number4
DOIs
StatePublished - May 1 2018

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Keywords

  • ER stress
  • Grb10
  • Hepatic steatosis
  • Lipid metabolism
  • UPR

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Luo, L., Jiang, W., Liu, H., Bu, J., Tang, P., Du, C., Xu, Z., Luo, H., Liu, B., Xiao, B., Zhou, Z., & Liu, F. (2018). De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver. Journal of Molecular Endocrinology, 60(4), 285-297. https://doi.org/10.1530/JME-18-0018