Therapeutic effect of bezafibrate against biliary damage: A study of phospholipid secretion via the PPARα-MDR3 pathway

M. Nakamuta, T. Fujino, R. Yada, K. Yasutake, T. Yoshimoto, N. Harada, M. Yada, N. Higuchi, M. Kato, M. Kohjima, A. Taketomi, Y. Maehara, T. Nishinakagawa, K. Machida, K. Matsunaga, M. Nakashima, K. Kotoh, M. Enjoji

Research output: Contribution to journalArticle

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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 PPARα-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease. Methods: The levels of serum -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 PPARα 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, PPARα 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.

Original languageEnglish
Pages (from-to)22-28
Number of pages7
JournalInternational Journal of Clinical Pharmacology and Therapeutics
Volume48
Issue number1
Publication statusPublished - Jan 1 2010

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Bezafibrate
Peroxisome Proliferator-Activated Receptors
Therapeutic Uses
Phospholipids
Biliary Liver Cirrhosis
Bile
Obstructive Jaundice
Drainage
gamma-Glutamyltransferase
Secretory Pathway
Bile Acids and Salts
Serum
Alkaline Phosphatase
Liver Diseases
Real-Time Polymerase Chain Reaction
Chronic Disease
Up-Regulation
Cholesterol

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Therapeutic effect of bezafibrate against biliary damage : A study of phospholipid secretion via the PPARα-MDR3 pathway. / Nakamuta, M.; Fujino, T.; Yada, R.; Yasutake, K.; Yoshimoto, T.; Harada, N.; Yada, M.; Higuchi, N.; Kato, M.; Kohjima, M.; Taketomi, A.; Maehara, Y.; Nishinakagawa, T.; Machida, K.; Matsunaga, K.; Nakashima, M.; Kotoh, K.; Enjoji, M.

In: International Journal of Clinical Pharmacology and Therapeutics, Vol. 48, No. 1, 01.01.2010, p. 22-28.

Research output: Contribution to journalArticle

Nakamuta, M, Fujino, T, Yada, R, Yasutake, K, Yoshimoto, T, Harada, N, Yada, M, Higuchi, N, Kato, M, Kohjima, M, Taketomi, A, Maehara, Y, Nishinakagawa, T, Machida, K, Matsunaga, K, Nakashima, M, Kotoh, K & Enjoji, M 2010, 'Therapeutic effect of bezafibrate against biliary damage: A study of phospholipid secretion via the PPARα-MDR3 pathway', International Journal of Clinical Pharmacology and Therapeutics, vol. 48, no. 1, pp. 22-28.
Nakamuta, M. ; Fujino, T. ; Yada, R. ; Yasutake, K. ; Yoshimoto, T. ; Harada, N. ; Yada, M. ; Higuchi, N. ; Kato, M. ; Kohjima, M. ; Taketomi, A. ; Maehara, Y. ; Nishinakagawa, T. ; Machida, K. ; Matsunaga, K. ; Nakashima, M. ; Kotoh, K. ; Enjoji, M. / Therapeutic effect of bezafibrate against biliary damage : A study of phospholipid secretion via the PPARα-MDR3 pathway. In: International Journal of Clinical Pharmacology and Therapeutics. 2010 ; Vol. 48, No. 1. pp. 22-28.
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AU - Nakamuta, M.

AU - Fujino, T.

AU - Yada, R.

AU - Yasutake, K.

AU - Yoshimoto, T.

AU - Harada, N.

AU - Yada, M.

AU - Higuchi, N.

AU - Kato, M.

AU - Kohjima, M.

AU - Taketomi, A.

AU - Maehara, Y.

AU - Nishinakagawa, T.

AU - Machida, K.

AU - Matsunaga, K.

AU - Nakashima, M.

AU - Kotoh, K.

AU - Enjoji, M.

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N2 - 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 PPARα-MDR3-phospholipid (PL) secretion pathway. We tried to confirm this hypothesis in patients with hepatobiliary disease. Methods: The levels of serum -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 PPARα 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, PPARα 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.

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