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Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response
Shi-Ying Cai, … , Dhanpat Jain, James L. Boyer
Shi-Ying Cai, … , Dhanpat Jain, James L. Boyer
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e90780. https://doi.org/10.1172/jci.insight.90780.
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Research Article Hepatology Inflammation

Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response

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Abstract

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.

Authors

Shi-Ying Cai, Xinshou Ouyang, Yonglin Chen, Carol J. Soroka, Juxian Wang, Albert Mennone, Yucheng Wang, Wajahat Z. Mehal, Dhanpat Jain, James L. Boyer

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Figure 1

Bile acids stimulate chemokine mRNA expression in both human and mouse hepatocytes.

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Bile acids stimulate chemokine mRNA expression in both human and mouse h...
(A) Mouse hepatocytes (mH) and nonparenchymal cells (NPCs) were treated with 100 μM taurocholic acid (TCA), tauroursodeoxycholic acid (TUDCA), or LPS for 6 hours. Results are the mean ± SD, n ≥ 4. *P < 0.05, **P < 0.01 vs. medium control (Ctrl) . (B) Bile acid–induced cytokine expression in mouse hepatocytes was time (100 μM TCA) and dose dependent. Hepatocytes were treated for 6 hours to demonstrate dose dependency of Ccl2 expression and 24 hours to show dose dependency for expression of Cxcl2 (mean ± SD, n ≥ 4). (C) A number of different major vertebrate-endogenous bile salts also induced Cxcl2 mRNA expression in mouse hepatocytes (24-hour treatment, mean ± SD, *P < 0.05 vs. Ctrl, n ≥ 4). CPS, cryprinol sulfate; GCA, glycocholic acid; GCDCA, glycochenodeoxycholic acid; PZS, petromyzonol sulfate; SMS, scymnol sulfate; TCDCA, taurochenodeoxycholic acid; TDHCA, taurodehydrocholic acid. (D) GCDCA (50 μM, 24 hours) induced chemokine mRNA expression in human hepatocytes. Data presented as fold change by defining medium control as 1 (mean ± SD, *P < 0.05, **P < 0.01 vs. Ctrl, n ≥ 5) by 1-way ANOVA.

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