Activation of Liver X Receptor alpha Sensitizes Mice to T-Cell Mediated Hepatitis

Abstract

Autoimmune hepatitis (AIH) is an inflammatory disease of the liver. Liver X receptors (LXRs), including the alpha and beta isoforms, are previously known for their anti-inflammatory activities. The goal of this study is to determine whether and how LXR plays a role in AIH. LXR alpha gain-of-function and loss-of-function mouse models were used, in conjunction with the concanavalin A (ConA) model of T-cell mediated hepatitis. We first showed that the hepatic expression of LXR alpha was decreased in the ConA model of hepatitis and in human patients with AIH. In the ConA model, we were surprised to find that activation of LXR alpha in the constitutively activated VP-LXR alpha whole-body knock-in (LXR alpha-KI) mice exacerbated ConA-induced AIH, whereas the LXR alpha(-/-) mice showed attenuated ConA-induced AIH. Interestingly, hepatocyte-specific activation of LXR alpha in the fatty acid binding protein-VP-LXR alpha transgenic mice did not exacerbate ConA-induced hepatitis. Mechanistically, the sensitizing effect of the LXR alpha-KIallele was invariant natural killer T (iNKT)-cell dependent, because the sensitizing effect was abolished when theLXR alpha-KIallele was bred into the NKT-deficientCD1d(-/-) background. In addition, LXR alpha-enhanced ConA-induced hepatitis was dependent on interferon gamma. In contrast, adoptive transfer of hepatic iNKT cells isolated fromLXR alpha-KImice was sufficient to sensitizeCD1d(-/-)mice to ConA-induced AIH.Conclusion:Activation of LXR alpha sensitizes mice to ConA-induced AIH in iNKT and interferon gamma-dependent manner. Our results suggest that LXR alpha plays an important role in the development of AIH.