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

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.

[1]  P. Scherer,et al.  VEGF-A–Expressing Adipose Tissue Shows Rapid Beiging and Enhanced Survival After Transplantation and Confers IL-4–Independent Metabolic Improvements , 2017, Diabetes.

[2]  Hua V. Lin,et al.  Connexin 43 Mediates White Adipose Tissue Beiging by Facilitating the Propagation of Sympathetic Neuronal Signals. , 2016, Cell metabolism.

[3]  Lora J. H. Bean,et al.  Epimerase Deficiency Galactosemia , 2016 .

[4]  P. Scherer,et al.  Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements , 2015, Nature Communications.

[5]  E. Barroso,et al.  Targeting endoplasmic reticulum stress in insulin resistance , 2015, Trends in Endocrinology & Metabolism.

[6]  Y. Lian,et al.  Distinct Regulatory Mechanisms Govern Embryonic versus Adult Adipocyte Maturation Hhs Public Access Introduction , 2022 .

[7]  Li Yang,et al.  Trefoil Factor 3 (TFF3) Is Regulated by Food Intake, Improves Glucose Tolerance and Induces Mucinous Metaplasia , 2015, PloS one.

[8]  D. Timson,et al.  The metastability of human UDP-galactose 4'-epimerase (GALE) is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding. , 2014, Archives of biochemistry and biophysics.

[9]  C. Klaassen,et al.  Effect of Diet on Expression of Genes Involved in Lipid Metabolism, Oxidative Stress, and Inflammation in Mouse Liver–Insights into Mechanisms of Hepatic Steatosis , 2014, PloS one.

[10]  Li-Qun Zhang,et al.  Trefoil Factor 3 as an Endocrine Neuroprotective Factor from the Liver in Experimental Cerebral Ischemia/Reperfusion Injury , 2013, PloS one.

[11]  An-fang Cui,et al.  Tff3, as a Novel Peptide, Regulates Hepatic Glucose Metabolism , 2013, PloS one.

[12]  J. Repa,et al.  The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism. , 2013, The Journal of clinical investigation.

[13]  I. Shiojima,et al.  Cardiac PI3K-Akt impairs insulin-stimulated glucose uptake independent of mTORC1 and GLUT4 translocation. , 2013, Molecular endocrinology.

[14]  F. Foufelle,et al.  New insights into ER stress-induced insulin resistance , 2012, Trends in Endocrinology & Metabolism.

[15]  J. Fridovich-Keil,et al.  UDP-Galactose 4′-Epimerase Activities toward UDP-Gal and UDP-GalNAc Play Different Roles in the Development of Drosophila melanogaster , 2012, PLoS genetics.

[16]  Xiaowei Wang,et al.  PrimerBank: a PCR primer database for quantitative gene expression analysis, 2012 update , 2011, Nucleic Acids Res..

[17]  Q. Zhai,et al.  Gene Expression Profile Change and Associated Physiological and Pathological Effects in Mouse Liver Induced by Fasting and Refeeding , 2011, PloS one.

[18]  G. Hotamisligil,et al.  Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease , 2010, Cell.

[19]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[20]  G. Boden,et al.  Endoplasmic Reticulum Stress: Another Link Between Obesity and Insulin Resistance/Inflammation? , 2009, Diabetes.

[21]  S. Pääbo,et al.  Human and Chimpanzee Gene Expression Differences Replicated in Mice Fed Different Diets , 2008, PloS one.

[22]  I. Rayment,et al.  Structure and Function of Enzymes of the Leloir Pathway for Galactose Metabolism* , 2003, Journal of Biological Chemistry.

[23]  D. Podolsky.  Mechanisms of regulatory peptide action in the gastrointestinal tract: trefoil peptides. , 2000, Journal of gastroenterology.

[24]  T. Fujioka.  Clarithromycin resistance in Helicobacter pylori: implications for therapy , 2000, Journal of Gastroenterology.

[25]  B. Dallapiccola,et al.  Human UDP-galactose 4' epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia. , 1998, Molecular genetics and metabolism.

[26]  W. Hsueh,et al.  Characterization of a putative receptor for intestinal trefoil factor in rat small intestine: identification by in situ binding and ligand blotting. , 1997, Biochemical and biophysical research communications.

[27]  R. Poulsom,et al.  Trefoil peptides , 1999, Bailliere's clinical gastroenterology.

[28]  R. Poulsom,et al.  The gene encoding human intestinal trefoil factor (TFF3) is located on chromosome 21q22.3 clustered with other members of the trefoil peptide family. , 1996, Genomics.

[29]  M. Simon,et al.  A third P-domain peptide gene (TFF3), human intestinal trefoil factor, maps to 21q22.3. , 1996, Cytogenetics and cell genetics.

[30]  E. Newsholme,et al.  The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. , 1963, Lancet.