Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating <i>Tff3</i> 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 <i>Gale</i> increases gluconeogenesis from pyruvate and impairs glucose tolerance. Conversely, genetic reduction of <i>Gale</i> in liver improves glucose tolerance. Transcriptional profiling identifies trefoil factor 3 (<i>Tff3</i>) as one of the downstream targets of GALE. Restoration of <i>Tff3</i> expression corrects glucose intolerance in <i>Gale</i>-overexpressing mice. These studies reveal a new link between hepatic GALE activity and whole-body glucose homeostasis via regulation of hepatic <i>Tff3</i> expression.