Activation of G0/G1 switch gene 2 by endoplasmic reticulum stress enhances hepatic steatosis

Yunqin Ma, Mingliang Zhang, Haoyong Yu, Junxi Lu, Kenneth K.Y. Cheng, Jian Zhou, Haibing Chen, Weiping Jia

Research output: Journal article publicationJournal articleAcademic researchpeer-review

8 Citations (Scopus)


Background: Perturbed endoplasmic reticulum (ER) homeostasis and increased levels of G0/G1 Switch Gene 2 (G0S2) have been documented in animal models with fatty liver disease. In this study, we investigated whether G0S2 is regulated by branch of the unfolded protein response (UPR) and contributes to ER stress-induced hepatic steatosis. Methods: We first analyzed G0S2 expression and the state of the three canonical UPR branches in several hepatic steatosis models, tunicamycin-treated C57BL/6J mice and HepG2 cells, where ER homeostasis was perturbed. We pretreated HepG2 cells with tauroursodeoxycholic acid (TUDCA) to validate whether G0S2 was the downstream target of ER stress. Loss or gain function analysis was conducted to identify which UPR branch specifically linked to G0S2 transcription. The transcription mechanism was estimated by luciferase reporter assay and ChIP assay. Results: Here we showed that the activation of ER stress was accompanied by elevation of G0S2 expression in the occurrence of fatty liver disease. Furthermore, G0S2 was found to be a novel target gene of activating transcription factor 4(ATF4). We also localized one conserved ATF4-binding sequence in the 5′ regulatory region of G0S2, which was responsible for transcriptional activating G0S2 by ATF4. Conclusion: G0S2 is regulated by the PERK-eIF2α-ATF4 branch of the UPR and mediates ER stress-induced hepatic steatosis.

Original languageEnglish
Pages (from-to)32-44
Number of pages13
JournalMetabolism: Clinical and Experimental
Early online dateJul 2019
Publication statusPublished - Oct 2019


  • Activating transcription factor 4
  • ER stress
  • G0/G1 switch gene 2
  • Nonalcoholic fatty liver disease

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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