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

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

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