An impaired biliary bicarbonate umbrella may be involved in dysregulated autophagy in primary biliary cholangitis

Abstract

Dysregulated autophagy may be a central player in trehe pathogenesis of primary biliary cholangitis (PBC) by inducing autoimmune processes via abnormal expression of mitochondrial antigens such as pyruvate dehydrogenase complex, E2 component (PDC-E2) and also by inducing cellular senescence in biliary epithelial cells (BECs) in bile duct lesions in PBC. We examined the association of an impaired “biliary bicarbonate umbrella” due to dysfunction of anion exchanger 2 (AE2) with dysregulated autophagy and cellular senescence in PBC. The expression of AE2 was examined in cultured BECs treated with bile acids such as glycochenodeoxycholic acid (GCDC) and tauro-ursodeoxycholic acid (TUDCA), various cytokines (IL-4, IL-13, IFNγ, TNFα, TGFβ), and serum deprivation. The effect of AE2 knockdown using siRNA on autophagy, cell surface expression of PDC-E2, and cellular senescence was also examined. The expression of AE2 and its association with autophagy-related markers and senescent markers p16INK4a and p21WAF1/Cip1 were immunohistochemically determined in livers taken from the patients with PBC (n = 50) and 69 control diseased and normal livers. The expression of AE2 was significantly induced in the cultured BECs shortly treated with GCDC and other stresses, whereas it was significantly decreased in senescent BECs induced by GCDC and other stresses (p < 0.05). Dysregulated autophagy, cell surface expression of PDC-E2, and cellular senescence were significantly increased by knockdown of AE2 (p < 0.05). The expression of AE2 was significantly decreased in cholangitis in PBC, compared to control livers (p < 0.05). The decreased expression of AE2 was correlated with dysregulated autophagy, abnormal expression of PDC-E2, and cellular senescence in bile duct lesions in PBC. In conclusion, an impaired biliary bicarbonate umbrella may be involved in the pathogenesis of PBC by inducing dysregulated autophagy.