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

Transcripts of key enzymes in the Leloir pathway of
galactose metabolism in mouse livers are significantly increased
after chronic high-fat/high-sucrose feeding. UDPgalactose-
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



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