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Gcn5‐like Protein 1 (Gcn5L1) Regulates Unfolded Protein Response and Hepatic Glucose Production
Author(s) -
Wang Lingdi,
Scott Iain,
Han Kim,
Sack Michael
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.884.26
Subject(s) - unfolded protein response , endoplasmic reticulum , biology , gene knockdown , gluconeogenesis , medicine , endocrinology , microbiology and biotechnology , stimulation , metabolism , biochemistry , gene
The nutrient sensing Gcn5‐like 1 (Gcn5L1) protein is enriched in mitochondria and in the endoplasmic reticulum (ER), although its function in these distinct compartments has not been fully characterized. Cellular Gcn5L1 knockdown results in accelerated mitophagy whereas the genetic knockout of GCN5L1 is embryonic lethal in mice. To further characterize the role of Gcn5L1, protein interactions studies were performed. We identified a robust interaction between Gcn5L1 and the ER enriched molecular chaperone Grp78. As Grp78 modulates ER stress, we employed Cre‐loxP technology to generated hepatic specific Gcn5L1 knockout (GCN5L1 LKO) mice to explore the potential functional role of Gcn5L1 in Grp78 biology. We found that Gcn5L1 LKO mice were viable, had lower fasting blood glucose and displayed an exaggerated unfolded protein response (UPR) signature. Moreover using primary hepatocytes, glucose productions under basal conditions and in response to glucagon stimulation were dramatically decreased in Gcn5L1 LKO. We also found that the hepatic expression levels of the key gluconeogenic enzymes, PEPCK and G6Pase, were significantly down regulated in Gcn5L1 LKO hepatocytes. The restoration of Gcn5L1 in LKO hepatocytes rescued decreased hepatic glucose production and attenuated ER stress. Our findings provide novel insights into a potential in vivo ER‐compartment role of Gcn5L1 in regulating hepatic gluconeogenesis and ER stress.