FASEB J. 2014 Aug;28(8):3339-50. doi: 10.1096/fj.13-243634. Epub 2014 Apr 22.
Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids.
Cicerchi C1, Li N1, Kratzer J2, Garcia G1, Roncal-Jimenez CA1, Tanabe K1, Hunter B1, Rivard CJ1, Sautin YY3, Gaucher EA2, Johnson RJ1, Lanaspa MA4.
Reduced
AMP kinase (AMPK) activity has been shown to play a key deleterious
role in increased hepatic gluconeogenesis in diabetes, but the mechanism
whereby this occurs remains unclear. In this article, we document that
another AMP-dependent enzyme, AMP deaminase (AMPD)
is activated in the liver of diabetic mice, which parallels with a
significant reduction in AMPK activity and a significant increase in
intracellular glucose accumulation in human HepG2 cells.
AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 × 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under conditions of near starvation, but today likely has a role in the pathogenesis of diabetes.
AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 × 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under conditions of near starvation, but today likely has a role in the pathogenesis of diabetes.
© FASEB.
Kommentti:
Metformiini estää AMPD entsyymiä hajoittamasta AMP:tä, jolloin solun AMP kertyy ja antaa parempaa energiaa solulle.
Samalla IMP muodostustien alavirran metabolittia, virtsahappoa, muodostuu vähemmän mikä taas alentaa sitä inhibitiovaikutusta, jota virtsahapolla on AMP-kinaasiin ja täten myös maksan glukoosin tuotanto ei saa niin paljon sitmuluksia ( Virtsahaposta johtuva AMPK- inhibitio stimuloisi maksan glukoosituotantnon).
