Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis

Kenichi Harada, Yuko Kakuda, Yasunori Sato, Hiroko Ikeda, Shinji Shimoda, Yasuhiko Yamamoto, Hiroshi Inoue, Hajime Ohta, Satomi Kasashima, Atsuhiro Kawashima, Yasuni Nakanuma

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Abstract

Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRa) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRa axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRa axis to clarify PDC dysfunction in CNSDC of PBC. Methods: The expression of PGC-1α, Bcl-3, ERRa, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results: The nuclear expression of PGC-1α, Bcl-3 and ERRa was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reversetranscription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions: In CNSDC of PBC, the activation of the ERRa-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.

Original languageEnglish
Pages (from-to)396-402
Number of pages7
JournalJournal of Clinical Pathology
Volume67
Issue number5
DOIs
Publication statusPublished - Jan 1 2014

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Biliary Liver Cirrhosis
Bile Ducts
Pyruvate Dehydrogenase Complex
Energy Metabolism
Pyruvate Dehydrogenase (Lipoamide)
Isoenzymes
Oxidoreductases
Up-Regulation
Fatty Acids
Epithelial Cells
Acetyl Coenzyme A
Peroxisome Proliferator-Activated Receptors
Starvation
Pyruvic Acid
Estrogen Receptors

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis. / Harada, Kenichi; Kakuda, Yuko; Sato, Yasunori; Ikeda, Hiroko; Shimoda, Shinji; Yamamoto, Yasuhiko; Inoue, Hiroshi; Ohta, Hajime; Kasashima, Satomi; Kawashima, Atsuhiro; Nakanuma, Yasuni.

In: Journal of Clinical Pathology, Vol. 67, No. 5, 01.01.2014, p. 396-402.

Research output: Contribution to journalArticle

Harada, K, Kakuda, Y, Sato, Y, Ikeda, H, Shimoda, S, Yamamoto, Y, Inoue, H, Ohta, H, Kasashima, S, Kawashima, A & Nakanuma, Y 2014, 'Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis', Journal of Clinical Pathology, vol. 67, no. 5, pp. 396-402. https://doi.org/10.1136/jclinpath-2013-201815
Harada, Kenichi ; Kakuda, Yuko ; Sato, Yasunori ; Ikeda, Hiroko ; Shimoda, Shinji ; Yamamoto, Yasuhiko ; Inoue, Hiroshi ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Nakanuma, Yasuni. / Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis. In: Journal of Clinical Pathology. 2014 ; Vol. 67, No. 5. pp. 396-402.
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abstract = "Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRa) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRa axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRa axis to clarify PDC dysfunction in CNSDC of PBC. Methods: The expression of PGC-1α, Bcl-3, ERRa, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results: The nuclear expression of PGC-1α, Bcl-3 and ERRa was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reversetranscription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions: In CNSDC of PBC, the activation of the ERRa-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.",
author = "Kenichi Harada and Yuko Kakuda and Yasunori Sato and Hiroko Ikeda and Shinji Shimoda and Yasuhiko Yamamoto and Hiroshi Inoue and Hajime Ohta and Satomi Kasashima and Atsuhiro Kawashima and Yasuni Nakanuma",
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T1 - Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis

AU - Harada, Kenichi

AU - Kakuda, Yuko

AU - Sato, Yasunori

AU - Ikeda, Hiroko

AU - Shimoda, Shinji

AU - Yamamoto, Yasuhiko

AU - Inoue, Hiroshi

AU - Ohta, Hajime

AU - Kasashima, Satomi

AU - Kawashima, Atsuhiro

AU - Nakanuma, Yasuni

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRa) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRa axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRa axis to clarify PDC dysfunction in CNSDC of PBC. Methods: The expression of PGC-1α, Bcl-3, ERRa, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results: The nuclear expression of PGC-1α, Bcl-3 and ERRa was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reversetranscription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions: In CNSDC of PBC, the activation of the ERRa-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.

AB - Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRa) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRa axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRa axis to clarify PDC dysfunction in CNSDC of PBC. Methods: The expression of PGC-1α, Bcl-3, ERRa, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results: The nuclear expression of PGC-1α, Bcl-3 and ERRa was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reversetranscription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions: In CNSDC of PBC, the activation of the ERRa-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.

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