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Publication : De-silencing <i>Grb10</i> contributes to acute ER stress-induced steatosis in mouse liver.

First Author  Luo L Year  2018
Journal  J Mol Endocrinol Volume  60
Issue  4 Pages  285-297
PubMed ID  29555819 Mgi Jnum  J:317070
Mgi Id  MGI:6844579 Doi  10.1530/JME-18-0018
Citation  Luo L, et al. (2018) De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver. J Mol Endocrinol 60(4):285-297
abstractText  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.
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