title: Therapeutic effect of bezafibrate against biliary damage: a study of phospholipid secretion via the PPARalpha-MDR3 pathway.
abstract: OBJECTIVE
  Bezafibrate (BF) has been used to treat biliary damage, particularly in patients with primary biliary cirrhosis (PBC), and its clinical efficacy has been demonstrated. The mechanism of action is thought to involve activation of the PPARalpha-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease.
  
  
  METHODS
  The levels of serum gamma-glutamyl transpeptidase and alkaline phosphatase, and those of bile components were examined before and after BF administration in patients with obstructive jaundice undergoing percutaneous transhepatic biliary drainage (PTBD). Hepatic expression of PPARalpha and MDR3 was quantified by real-time PCR in patients with PBC or non-alcoholic fatty liver disease (NAFLD).
  
  
  RESULTS
  In patients with obstructive jaundice, BF decreased the serum levels of biliary enzymes and increased the bile concentration of PL. In patients with PBC or NAFLD, the expression levels of MDR3 were already up-regulated before starting the BF treatment. Although BF treatment did not further up-regulate MDR3 expression in NAFLD patients, PPARalpha expression was significantly increased.
  
  
  CONCLUSIONS
  BF enhanced the secretion of PL into bile in cholestatic patients undergoing PTBD. However, in patients with PBC or NAFLD, diseases that represent cholesterol overload, MDR3 was already expressed at a high level to compensate for bile acids overproduction, and its expression was hardly affected by BF. In patients with chronic liver diseases such as PBC, BF may induce clinical effects via mechanisms independent of PL secretion.
authors.affiliation: Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakamuta
authors.forename: T
authors.initials: T
authors.lastname: Fujino
authors.forename: R
authors.initials: R
authors.lastname: Yada
authors.forename: K
authors.initials: K
authors.lastname: Yasutake
authors.forename: T
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: N
authors.initials: N
authors.lastname: Harada
authors.forename: M
authors.initials: M
authors.lastname: Yada
authors.forename: N
authors.initials: N
authors.lastname: Higuchi
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Kohjima
authors.forename: A
authors.initials: A
authors.lastname: Taketomi
authors.forename: Y
authors.initials: Y
authors.lastname: Maehara
authors.forename: T
authors.initials: T
authors.lastname: Nishinakagawa
authors.forename: K
authors.initials: K
authors.lastname: Machida
authors.forename: K
authors.initials: K
authors.lastname: Matsunaga
authors.forename: M
authors.initials: M
authors.lastname: Nakashima
authors.forename: K
authors.initials: K
authors.lastname: Kotoh
authors.forename: M
authors.initials: M
authors.lastname: Enjoji
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D001629:Bezafibrate / Q000494:pharmacology* / Q000627:therapeutic use; D002779:Cholestasis / Q000188:drug therapy / Q000503:physiopathology / Q000601:surgery; D004322:Drainage / Q000379:methods; D005234:Fatty Liver / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D041781:Jaundice, Obstructive / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D010743:Phospholipids; C095122:multidrug resistance protein 3; D005723:gamma-Glutamyltransferase; D000469:Alkaline Phosphatase; D001629:Bezafibrate