Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes.
OBJECTIVE
A lipid-lowering agent, fenofibrate, has been reported to reduce hepatic glucose production and the expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme for gluconeogenesis in the liver. However, the precise mechanisms of these effects have remained unclear.


METHODS
Rat hepatoma-derived H4IIE cells and murine myoblast-derived C2C12 cells were incubated with the ester form of fenofibrate and fenofibric acid, a metabolite of fenofibrate ester, and the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC), PEPCK mRNA expression and glucose production were assessed.


RESULTS
Incubation of H4IIE hepatoma cells with the ester form of fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) and decreased PEPCK mRNA expression and glucose production. Fenofibrate-induced reductions in PEPCK expression and glucose production were abrogated by compound C, a specific AMPK inhibitor. Fenofibric acid, a metabolite of fenofibrate ester, had no effects on AMPK phosphorylation, PEPCK gene expression, or glucose production in H4IIE cells. Fenofibrate-treated mice exhibited increases in AMPK phosphorylation and a decrease in PEPCK expression in the liver but not in skeletal muscles, suggesting that unmetabolized fenofibrate accumulated and affected AMPK only in the liver.


CONCLUSIONS
These results demonstrate that fenofibrate inhibits PEPCK gene expression and hepatic glucose production in the liver via AMPK activation, even though the metabolite loses its effects on AMPK and does not work in vivo in myocytes. This novel feature of fenofibrate may provide additional benefit for the treatment of patients with disorders of both lipid and glucose metabolism.
Murakami
Ryuichiro
R
Department of Cardiology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466-8550, Japan.
Murakami
Hisashi
H
Kataoka
Hiroki
H
Cheng
Xian Wu
XW
Takahashi
Ryotaro
R
Numaguchi
Yasushi
Y
Murohara
Toyoaki
T
Okumura
Kenji
K
D055372:AMP-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D011345:Fenofibrate / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000187:drug effects* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats
D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D055372:AMP-Activated Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose; D011345:Fenofibrate