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

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.

SUBMITTER: Cai SY

PROVIDER: S-EPMC5333973 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Bile salt export pump (Bsep) (Abcb11)-/- mice are protected from acquired cholestatic injury due to metabolic preconditioning with a hydrophilic bile acid (BA) pool with formation of tetrahydroxylated bile acids (THBAs). We aimed to explore whether loss of Bsep and subsequent elevation of THBA levels may have immunomodulatory effects, thus improving liver injury in the multidrug resistance protein 2 (Mdr2) (Abcb4)-/- mouse. Cholestatic liver injury in Mdr2-/- Bsep-/- double knockout (DKO), Mdr2-/- , Bsep-/- , and wild-type mice was studied for comparison. Mdr2-/- mice were treated with a THBA (3α,6α,7α,12α-Tetrahydroxycholanoic acid). RNA/protein expression of inflammatory/fibrotic markers were investigated. Serum BA-profiling was assessed by ultra-performance liquid chromatography tandem mass spectrometry. Hepatic immune cell profile was quantified by flow cytometric analysis (FACS). In vitro, the THBA effect on chenodeoxycholic acid (CDCA)-induced inflammatory signaling in hepatocyte and cholangiocytes as well as lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced macrophage activation was analyzed. In contrast to Mdr2-/- , DKO mice showed no features of sclerosing cholangitis. Sixty-seven percent of serum BAs in DKO mice were polyhydroxylated (mostly THBAs), whereas Mdr2-/- mice did not have these BAs. Compared with Mdr2-/- , DKO animals were protected from hepatic inflammation/fibrosis. THBA feeding in Mdr2-/- mice improved liver injury. FACS analysis in DKO and Mdr2-/- THBA-fed mice showed changes of the hepatic immune cell profile towards an anti-inflammatory pattern. Early growth response 1 (EGR1) protein expression was reduced in DKO and in Mdr2-/- THBA-fed mice compared with Mdr2-/- control mice. In vitro, THBA-reduced CDCA induced EGR1 protein and mRNA expression of inflammatory markers in hepatocytes and cholangiocytes. LPS/IFN-γ-induced macrophage activation was ameliorated by THBA. THBAs repress EGR1-related key pro-inflammatory pathways. Conclusion: THBA and their downstream targets may represent a potential treatment strategy for cholestatic liver diseases.

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

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