Sasaki Motoko, Nakanuma Yasuni
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Dig Dis. 2017;35(3):210-216. doi: 10.1159/000450913. Epub 2017 Mar 1.
Primary biliary cholangitis (PBC) is characterized by a high prevalence of serum anti-mitochondrial antibodies against the E2 subunit of the pyruvate dehydrogenase complex and bile duct lesions called chronic non-suppurative destructive cholangitis (CNSDC) in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. Macroautophagy (a major type of autophagy) is a process of cellular self-digestion that plays a critical role in energy homeostasis and in the cytoprotection to various stresses. Deregulated autophagy is thought to be associated with various human diseases. Key Messages: Accumulating evidences suggest that deregulated autophagy may be a central player in the pathogenesis of PBC. Damaged cholangiocytes involved in CNSDC show vesicular expression of autophagy marker LC3 and accumulation of p62/sequestosome-1, suggesting deregulated autophagy. Deregulated autophagy may be involved in the autoimmune process via the abnormal expression of mitochondrial antigens and also in cholangiocyte senescence in bile duct lesions in PBC. In vitro study showed that hydrophobic bile acids, such as glycochenodeoxycholic acid (GCDC), as well as serum deprivation and oxidative stress, cause autophagy, deregulated autophagy and abnormal expression of mitochondrial antigens followed by cellular senescence in cholangiocytes. Although exact mechanisms of deregulated autophagy remain to be clarified, endoplasmic reticulum (ER) stress may be a plausible cause of deregulated autophagy induced by GCDC in cholangiocytes. Impaired 'biliary bicarbonate umbrella' may further exacerbate the toxicity of GCDC to cholangiocytes. Interestingly, pretreatment with ursodeoxycholic acid (UDCA) and tauro-UDCA, which is a chemical chaperone enhancing the adaptive capacity of the ER, significantly suppressed ER stress, deregulated autophagy and cellular senescence induced by GCDC and other stresses in cholangiocytes.
GCDC may play a role in the occurrence of deregulated autophagy and cellular senescence at least partly through the induction of ER stress in PBC. Deregulated autophagy and cellular senescence can be a promising therapeutic target in PBC.
原发性胆汁性胆管炎（PBC）的特征是血清中针对丙酮酸脱氢酶复合体E2亚基的抗线粒体抗体患病率高，以及小胆管出现称为慢性非化脓性破坏性胆管炎（CNSDC）的胆管病变，最终导致广泛的胆管丢失和胆汁性肝硬化。巨自噬（自噬的主要类型）是一种细胞自我消化过程，在能量稳态和对各种应激的细胞保护中起关键作用。自噬失调被认为与多种人类疾病有关。关键信息：越来越多的证据表明，自噬失调可能是PBC发病机制的核心因素。参与CNSDC的受损胆管细胞显示出自噬标志物LC3的囊泡样表达和p62/聚集体蛋白1的积累，提示自噬失调。自噬失调可能通过线粒体抗原的异常表达参与自身免疫过程，也可能参与PBC胆管病变中的胆管细胞衰老。体外研究表明，疏水性胆汁酸，如甘氨鹅去氧胆酸（GCDC），以及血清剥夺和氧化应激，可导致胆管细胞发生自噬、自噬失调和线粒体抗原异常表达，随后细胞衰老。尽管自噬失调的确切机制仍有待阐明，但内质网（ER）应激可能是GCDC诱导胆管细胞自噬失调的一个合理原因。受损的“胆汁碳酸氢盐伞”可能会进一步加剧GCDC对胆管细胞的毒性。有趣的是，用熊去氧胆酸（UDCA）和牛磺熊去氧胆酸（tauro-UDCA）进行预处理，这两种物质是增强ER适应能力的化学伴侣，可显著抑制GCDC和其他应激诱导的胆管细胞ER应激、自噬失调和细胞衰老。
GCDC可能至少部分通过诱导ER应激在PBC自噬失调和细胞衰老的发生中起作用。自噬失调和细胞衰老可能是PBC中一个有前景的治疗靶点。
