Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response
Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response
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DOI：
10.1172/jci.insight.90780
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发表时间：
2017-03-09
期刊：
影响因子：
8
通讯作者：
Boyer, James L.
中科院分区：
文献类型：
--
作者：
Cai, Shi-Ying;Ouyang, Xinshou;Boyer, James L.
胆汁淤积症中胆汁酸诱导(BA诱导)肝损伤的机制存在争议，限制了新疗法的发展。我们使用从人和小鼠分离的肝细胞和体内小鼠模型研究了BAS是如何引发肝损伤的。在病理生理浓度下，bas可诱导小鼠和人肝细胞表达促炎细胞因子，但不能在非实质细胞或胆管细胞中表达。这些肝细胞特异性细胞因子刺激中性粒细胞趋化。用BA治疗的CCL2(-/-)小鼠或胆管结扎后的小鼠炎症损伤减轻，中性粒细胞在肝脏中的渗透较少。胆汁淤积症患者肝门周围区域的中性粒细胞也与他们血清转氨酶的升高有关。这种肝脏特异性炎症反应需要BA通过基底外侧转运体Ntcp进入肝细胞。Bas诱导小鼠肝细胞内质网应激和线粒体损伤的病理生理水平。BAS诱导的TLR9(-/-)小鼠肝细胞趋化因子诱导减少，而常规和肝细胞特异性TLR9(-/-)小鼠的肝损伤均减轻，证实了TLR9在BA诱导的肝损伤中的作用。这些发现揭示了潜在的新机制，即BAS诱导肝细胞特异性细胞因子诱导的炎性肝损伤，涉及天然免疫，并为治疗淤胆性肝病指明了可能的新途径。
Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated in Ccl2(-/-) mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected. Neutrophils in periportal areas of livers from cholestatic patients also correlated with elevations in their serum aminotransferases. This liver-specific inflammatory response required BA entry into hepatocytes via basolateral transporter Ntcp. Pathophysiologic levels of BAs induced markers of ER stress and mitochondrial damage in mouse hepatocytes. Chemokine induction by BAs was reduced in hepatocytes from Tlr9(-/-) mice, while liver injury was diminished both in conventional and hepatocyte-specific Tlr9(-/-) mice, confirming a role for Tlr9 in BA-induced liver injury. These findings reveal potentially novel mechanisms whereby BAs elicit a hepatocyte-specific cytokine-induced inflammatory liver injury that involves innate immunity and point to likely novel pathways for treating cholestatic liver disease.