The Tumor Suppressor Gene Lkb1 Is Essential For Glucose Homeostasis In Zebrafish

The liver kinase B1 (LKB1) is a serine-threonine kinase encoded by STK11, the tumor suppressor gene responsible for Peutz-Jeghers Syndrome (PJS). Lkbl plays indispensable roles in various biological processes including cell growth control and proliferation, cell polarity, tumorgenesis. and energy homeostasis. However, how Lkbl regulates energy homeostasis in vivo remains to be fully understood.To explore how Lkbl regulates energy homeostasis during early development, we generated a zebrafish gene-trapping lkbl mutant in which expression of lkbl is blocked. Depletion of Lkbl leads to lethality of lkbl mutant larvae, lkb1 mutant embryos were morphologically indistinguishable from their wild type or heterozygous siblings for the first 5 days. However, under normal feeding condition, lkbl mutant larvae gradually died from 7 dpf, and all died within four weeks. Furthermore, under fasting state, all the lkbl mutants died before 12 dpf, whereas wild type larvae can survive without food for up to 2 weeks. In addition, lkbl mutants at 7 dpf showed dark liver and loss of intestinal folding under starvation condition. And lkbl mutants were less resistant to starvation.Loss of lkbl causes glucose homeostasis defects and elevated expression of key rate-limiting genes phosphoenolpyruvate carboxykinasel (pepckl) and glucose-6-phosphatase (g6pase) in gluconeogenesis even before yolk consumption under normal physiological condition.Lkbl negatively regulates transcription of pyruvate dehydrogenase kinase 2 (pdk2), deletion of lkbl results in increasing pdk2 gene expression, which leads to inactive pyruvate dehydrogenase complex (Pdc) by elevating phosphorylated pyruvate dehydrogenase (Pdh) level, and in turn, promotes enhanced glycolysis in terms of lactate production. This phenotype highly resembles the aerobic glycolysis; also known as the Warburg effect, the characterizing metabolic status in cancer cells. Inhibition of Pdk2 with DCA (dichloroacetate), a promising candidate anti-cancer small molecular drug in clinical trails, rescues the lactate production abnormality caused by loss of Lkbl. This provides an exemplar that the lkbl mutant could serve as a valuable platform for chemical genetic screen for compounds that target aerobic glycolysis in cancer therapy.