title: Enhancement of liver regeneration by adenosine triphosphate-sensitive K⁺ channel opener (diazoxide) after partial hepatectomy.
abstract: BACKGROUND
  Enhancement of liver regeneration is a matter of importance after partial liver transplantation including small-for-size grafting. Mitochondrial adenosine triphosphate (ATP)-sensitive K⁺ (mitoKATP) channel plays an important role in mitochondrial bioenergetics, which is a prerequisite for liver regeneration. However, the ATP-sensitive K⁺ (KATP) channel in hepatocytes is incompletely understood. We investigated the KATP channel in hepatocytes and examined the effects of diazoxide, a potent KATP channel opener, on liver regeneration using a rat model.
  
  
  METHODS
  Using rat primary hepatocytes, expression and localization of KATP channel subunits, Kir6.x and sulfonylurea receptor (SUR)x, were studied by polymerase chain reaction, Western blotting, and immunostaining. To investigate the role of KATP channel openers in liver regeneration, we allocated rats into four groups: control (vehicle) (n=24), diazoxide (n=24), vehicle plus channel blocker (n=6), and diazoxide plus channel blocker (n=6) groups. After 70% partial hepatectomy, hepatic tissue ATP levels, liver-to-body weight ratio, and proliferation rate of hepatocytes were examined.
  
  
  RESULTS
  KATP channel subunits, Kir6.1 and SUR1, were detected on hepatic mitochondria. During liver regeneration, liver-to-body weight ratio, proliferation rate of hepatocytes, and the hepatic ATP level were significantly higher in the diazoxide group than the control group at 2 days after partial hepatectomy. These effects of diazoxide were neutralized by a KATP channel blocker.
  
  
  CONCLUSIONS
  We demonstrated the existence of a mitoKATP channel in hepatocytes composed of Kir6.1 and SUR1. Diazoxide could enhance liver regeneration by keeping a higher ATP content of the liver tissue. These results suggest that diazoxide will sustain the mitochondrial energetics through the mitoKATP channel opening.
authors.affiliation: Department of Gastroenterological Surgery, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Masato
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Yuki
authors.initials: Y
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ohba
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ono
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D054086:KATP Channels / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016133:Polymerase Chain Reaction; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D015415:Biomarkers; D054086:KATP Channels; D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate; D003981:Diazoxide