Energy Metabolic Change Induced by ERRα-PGC-1α Axis in Chronic Non-Suppurative Destructive Cholangitis of Primary Biliary Cirrhosis
Kenichi Harada, Yasunori Sato, Yuko Kakuda, Hiroko Ikeda, Yasuni Nakanuma. Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan; Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
Background: Primary biliary cirrhosis (PBC) is characterized by anti-mitochondrial antibody (AMA) against pyruvate dehydrogenase complex (PDC) and chronic non-suppurative destructive cholangitis (CNSDC). PDC catalyzes the conversion of pyruvate to acetyl-CoA and is an important control point in glucose and pyruvate metabolism. Estrogen-related receptor α (ERRα) is associated with the fatty acid degradation system, such as fatty acid oxidation, electron transport, and oxidative phosphorylation, and is functionally activated by a inducible coactivator, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Moreover, the PGC-1α/ERRα axis interrupts glycolytic metabolism via the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α by phosphorylation. In this study, we investigated the PGC-1α/ERRα axis to clarify the alteration of the energy metabolism in CNSDC of PBC.
Design: Using liver sections obtained from patients with PBC and control diseases, the expression of PGC-1α, ERRα, PDK4, and PDC-E1α was examined by immunohistochemistry. Using cultured human biliary epithelial cells (BECs), the mRNA expression of PGC-1α, ERRα, PDK4, and PDC-E1α and their alterations by starvation (treatment inducing PGC-1α expression) were examined by RT-PCR and real-time PCR, respectively.
Results: Immunohistochemistry revealed that the nuclear expression of ERRα and PGC-1α was exclusively found in CNSDC of PBC, but not normal bile ducts of PBC or any bile ducts in controls. Moreover, the expression of PDK4 was enhanced in CNSDC of PBC. The expression of PDC-E1α was constantly found in all bile ducts, irrespective of having a diseased or normal liver. Cultured human BECs expressed mRNAs of PGC-1α, ERRα, PDK4, and PDC-E1α and the mRNA of PDK4 increased according the upregulation of PGC-1α by starvation.
Conclusions: In CNSDC of PBC, the expression and activation of the ERRα-PGC-1α axis were found exclusively, suggesting an increase in the fatty acid degradation system and also the supply of acetyl-CoA from this system. Moreover, the upregulation of PDK4 accompanying PGC-1α expression in CNSDC of PBC suggests the interference of PDC-E1α function. The alteration of the energy system from glycolytic to fatty acid degradation was possibly associated with the pathogenesis of CNSDC and AMA in PBC.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 155, Tuesday Afternoon