AICAR, an activator of AMP-activated protein kinase, down-regulates the insulin receptor expression in HepG2 cells.
The liver is one of the major target organs of insulin in which the expression of insulin receptor is abundant. We analyzed the effect of AICAR, an AMPK activator, on the expression of insulin receptor in a human hepatoma cell line, HepG2 cells. AICAR treatment for 48 h significantly decreased the expression of the insulin receptor protein in a dose-dependent manner, however, this same effect of AICAR was not observed in either 3T3-L1 adipocytes or CHO cells. The expression of insulin receptor mRNA also decreased after AICAR treatment. In addition, the transcriptional activity of the insulin receptor gene promoter investigated with a luciferase assay was down-regulated by AICAR treatment. Dipyridamole, an adenosine transporter inhibitor, and 5'-amino-5'-deoxyadenosine, an adenosine kinase inhibitor, blocked the effect of AICAR on the down-regulation of the insulin receptor protein, mRNA, and promoter activity. Our findings suggest, for the first time, that AMPK activation could reduce the expression of insulin receptor, at least in part, by a down-regulation of the transcriptional level, and this effect may be liver specific.
Nakamaru
Kazuhiko
K
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
Matsumoto
Kazuya
K
Taguchi
Tetsuya
T
Suefuji
Mihoshi
M
Murata
Yusuke
Y
Igata
Motoyuki
M
Kawashima
Junji
J
Kondo
Tatsuya
T
Motoshima
Hiroyuki
H
Tsuruzoe
Kaku
K
Miyamura
Nobuhiro
N
Toyonaga
Tetsushi
T
Araki
Eiichi
E
D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*
D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide