@article{abd73d5a5c8148c59ce99e1e18937f28,
title = "Hepatic gale regulates whole-body glucose homeostasis by modulating tff3 expression",
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.",
author = "Yi Zhu and Shangang Zhao and Yingfeng Deng and Ruth Gordillo and Ghaben, {Alexandra L.} and Mengle Shao and Fang Zhang and Ping Xu and Yang Li and Huachuan Cao and Olga Zagnitko and Scott, {David A.} and Gupta, {Rana K} and Chao Xing and Zhang, {Bei B.} and Lin, {Hua V.} and Scherer, {Philipp E}",
note = "Funding Information: Acknowledgments. The authors thank Chen Zhang and Steven Connell (Touchstone Diabetes Center, UTSW Medical Center) for technical assistance, the UTSW Medical Center Molecular Pathology Core for assistance in histology, the UTSW Metabolic Phenotyping Core facility for assistance in metabolic phenotyping, and the Genomics and Microarray Core at McDermott Center for Human Growth and Development for assistance in RNA-Seq. Funding. This study was supported by a Lilly Innovation Fellowship Award to Y.Z., a Fonds de Recherche du Qu{\'e}bec–Sant{\'e} postdoctoral fellowship to S.Z., American Heart Association postdoctoral fellowship 16POST26420136 to M.S., National Institutes of Health (NIH) grant R01-DK104789 to R.K.G., and National Institute of Diabetes and Digestive and Kidney Diseases grants R01-DK55758, R01-DK099110, P01-DK088761, and P01-AG051459 as well as a grant from the Cancer Prevention and Research Institute of Texas (RP140412) to P.E.S. R.G. was partially supported by a Core C grant (7685) under P01-DK088761. C.X. was partially supported by NIH grant UL1TR001105. Duality of Interest. Y.Z., P.X., Y.L., H.C., B.B.Z., and H.V.L. are employees and may hold stocks of Eli Lilly and Company. This does not alter the authors{\textquoteright} adherence to Diabetes policies on sharing data and materials. No other potential conflicts of interest relevant to this article were reported. Author Contributions. Y.Z. designed the studies, performed the research, interpreted the results, and wrote the manuscript. S.Z., R.G., A.L.G., M.S., F.Z., P.X., Y.L., H.C., and O.Z. helped to perform the research and interpret the results. Y.D. generated and verified TRE-Gale mouse. D.A.S., R.K.G., and B.B.Z. provided reagents and consultation to the project and reviewed the manuscript. C.X. performed RNA-seq analysis. H.V.L. and P.E.S. designed and supervised the study and reviewed and revised the manuscript. All authors approved the final version of the manuscript. H.V.L. and P.E.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Publisher Copyright: {\textcopyright} 2017 by the American Diabetes Association.",
year = "2017",
doi = "10.2337/DB17-0323",
language = "English (US)",
volume = "66",
pages = "2789--2799",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "11",
}