Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression.
To elucidate the role of AMPK in hepatic glucose metabolism, dominant negative (DN), constitutively active (CA) forms of the AMPKalpha1 subunit and control vector LacZ were overexpressed by means of adenovirus-mediated gene transfer. Five days after virus injection, hepatic AMPK activity was five-fold higher in CA mice than in DN mice. DN mice were apparently glucose intolerant with a higher fasting plasma glucose level (DN 82.3+/-0.7mg/dl, CA 42.5+/-4.8mg/dl and LacZ 54.3+/-2.4mg/dl). PEPCK, a gluconeogenic key enzyme, mRNA was increased 131.54% and 48.92% in DN mice compared to that of CA and LacZ, respectively. Thus, hepatic AMPK activation plays a role in the suppression of gluconeogenesis and this might be the cause of decreased fasting plasma glucose level in CA mice. We also investigated the effects of dexamethasone on hepatic AMPK expression and activity in rat liver, mice liver, as well as primary cultured hepatocytes. Subcutaneously injecting mice with dexamethasone (1mg/day) for 5 days significantly upregulated hepatic AMPKalpha1 and alpha2 expressions. Similarly, the treatment of primary cultured rat hepatocytes with dexamethasone (1microM) increased expression of the AMPKalpha1 subunit, AICAR-induced AMPK phosphorylation and kinase activity. Although increased AMPK expression cannot be attributed to dexamethasone-induced glucose intolerance, taken together our results raise the possibility that AMPK control liver glucose output and its expression in liver might be modulated by various hormones and growth factors.
Viana
Amelia Y I
AY
Department of Sports Medicine, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Sakoda
Hideyuki
H
Anai
Motonobu
M
Fujishiro
Midori
M
Ono
Hiraku
H
Kushiyama
Akifumi
A
Fukushima
Yasushi
Y
Sato
Yuzo
Y
Oshida
Yoshiharu
Y
Uchijima
Yasunobu
Y
Kurihara
Hiroki
H
Asano
Tomoichiro
T
D055372:AMP-Activated Protein Kinases; D000256:Adenoviridae; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation; D005822:Genetic Vectors; D005938:Glucocorticoids / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000139:chemically induced; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D005938:Glucocorticoids; D009097:Multienzyme Complexes; D003907:Dexamethasone; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose