AICAR positively regulate glycogen synthase activity and LDL receptor expression through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 signaling cascade.
5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.
Wang
Hsiang-Ming
HM
Department of Molecular and Cellular Biochemistry, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, 464 Hamilton Hall, Columbus, OH 43210, United States.
Mehta
Sonya
S
Bansode
Rishipal
R
Huang
Wei
W
Mehta
Kamal D
KD
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006006:Glycogen Synthase / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D009097:Multienzyme Complexes / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D011973:Receptors, LDL / Q000032:analysis*; D012265:Ribonucleotides / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D009097:Multienzyme Complexes; D011973:Receptors, LDL; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D006006:Glycogen Synthase; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C031143:AICA ribonucleotide