Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression

Yi Zhu, Shangang Zhao, Yingfeng Deng, Ruth Gordillo, Alexandra L. Ghaben, Mengle Shao, Fang Zhang, Ping Xu, Yang Li, Huachuan Cao, Olga Zagnitko, David A. Scott, Rana K Gupta, Chao Xing, Bei B. Zhang, Hua V. Lin, Philipp E Scherer

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Transcripts of key enzymes in the Leloir pathway of galactose metabolism in mouse livers are significantly increased after chronic high-fat/high-sucrose feeding. UDP-galactose-4-epimerase (GALE) is the last enzyme in this pathway that converts UDP-galactose to UDP-glucose and was previously identified as a downstream target of the endoplasmic reticulum (ER) stress effector spliced X-box binding protein 1, suggesting an interesting cross talk between galactose and glucose metabolism in the context of hepatic ER stress and whole-body metabolic fitness. However, its specific role in glucose metabolism is not established. Using an inducible and tissue-specific mouse model, we report that hepatic overexpression of Gale increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of Gale in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (Tff3) as one of the downstream targets of GALE. Restoration of Tff3 expression corrects glucose intolerance in Gale-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic Tff3 expression.

Original languageEnglish (US)
Pages (from-to)2789-2799
Number of pages11
JournalDiabetes
Volume66
Issue number11
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Zhu, Y., Zhao, S., Deng, Y., Gordillo, R., Ghaben, A. L., Shao, M., Zhang, F., Xu, P., Li, Y., Cao, H., Zagnitko, O., Scott, D. A., Gupta, R. K., Xing, C., Zhang, B. B., Lin, H. V., & Scherer, P. E. (2017). Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression. Diabetes, 66(11), 2789-2799. https://doi.org/10.2337/db17-0323