One of the central features of the hepatic response to inflammation is the suppression of a broad array of core physiological functions, including those essential to maintaining hepatobiliary transport of bile acids. In addition to post-translational regulation of transporter protein membrane expression and function, inflammation-based cell signaling pathways act on nuclear targets to transcriptionally suppress the expression of the essential bile acid transporters Ntcp and Bsep. The central Type II NR superfamily member and heterodimer partner RXRalpha is a major transcriptional activator of these two genes, and its nuclear activity is rapidly suppressed by inflammation-based cell signaling. Reduced RXRalpha target gene expression leads to multiple functional impairments and damage to hepatocytes. How cell signaling pathways suppress RXRalpha function is unknown, and forms the basis for the explorations and interventions proposed in this application. The overall unifying hypothesis is that inflammatory cell signaling pathways reduce nuclear activity of RXRalpha via a coordinated cascade of post-translational modification, nuclear export and proteasomal degradation. The following four aims will determine the underlying physiology and pathophysiology of inflammation-mediated cholestasis and explore novel therapeutics.
Aim 1 : Define the molecular mechanisms mediating IL-1beta-induced nuclear export of RXRalpha.
Aim 2 : Determine roles for ubiquitination and proteasomal degradation of RXRalpha in response to IL-1beta- induced signaling pathways.
Aim 3 : Explore crosstalk between bile acid and IL-1beta-mediated pathways that modify RXRalpha function.
Aim 4 : Investigate the effects of anti-inflammatory agents on transporter gene and protein expression in the IPS model of hepatic inflammation. It is through a combined in vitro and in vivo approach that we can explore the mechanisms, mediators, and potential therapeutic interventions aimed at restoring RXRalpha function, hepatobiliary transporter function, and bile flow, in the setting of inflammation-mediated cell signaling in liver. The ultimate goal of these studies is to provide rational molecular targets for the testing of therapies specifically designed to interfere with the damaging consequences of inflammation-mediated pathways, which are engaged in nearly all forms of acute and chronic liver diseases. ? ? ?
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