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

Abstract：

AIM:Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase complex (PDC) and chronic non-suppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRα) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRα 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-ERRα axis to clarify PDC dysfunction in CNSDC of PBC. METHODS:The expression of PGC-1α, Bcl-3, ERRα, 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 ERRα 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 reverse-transcription-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 ERRα-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.

journal_name

J Clin Pathol

journal_title

Journal of clinical pathology

authors

Harada K,Kakuda Y,Sato Y,Ikeda H,Shimoda S,Yamamoto Y,Inoue H,Ohta H,Kasashima S,Kawashima A,Nakanuma Y

doi

10.1136/jclinpath-2013-201815

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

396-402

issue

eissn

0021-9746

issn

1472-4146

pii

jclinpath-2013-201815

journal_volume

pub_type

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