Journal
TRANSPLANTATION
Volume 82, Issue 2, Pages 258-266Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.tp.0000226243.69023.54
Keywords
cholestasis; gadolinium chloride; cytokine; tumor necrosis factor alpha; hepatocyte nuclear factor 1 alpha
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Funding
- NIEHS NIH HHS [ES-07079, ES-09716, ES-09649] Funding Source: Medline
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Background. Hepatic ischemia-reperfusion (IR) injury is frequently followed by cholestatic liver disease. Cytokines released by Kupffer cells following hepatic IR injury may subsequently regulate hepatic transporter expression. The purpose of this study was to determine whether hepatic IR injury and the resultant Kupffer cell activation alters hepatic transporter expression. Methods. Rats were subjected to 60 minutes of partial hepatic ischemia followed by 0, 3, 6, 24, or 48 hours of reperfusion. After IR surgery, the following were determined: 1) serum bilirubin and bile acid levels; 2) serum levels of cytokines, such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL6; 3) expression of several hepatic transporters; and 4) nuclear protein levels of hepatocyte nuclear factor (HNF)-1 alpha and retinoid X receptor (RXR)-alpha to investigate whether altered expression of hepatic transporters following IR is associated with decreases in these transcription factors. Results. After reperfusion: 1) serum bilirubin and bile acids increased; 2) levels of all three cytokines increased; 3) mRNA expression of hepatic transporters organic anion transporting polypeptide (Oatp) 1a1, Oatp1a4, Oatp1b2, sodium taurocholate cotransporting polypeptide, multidrug resistance-associated protein (Mdr) 2, and bile salt export pump decreased, whereas Mdr1b expression increased; and 4) nuclear protein levels of HNF1 alpha decreased, whereas RXR alpha was not altered. Pretreatment with gadolinium chloride to deplete Kupffer cells before IR: 1) blocked the increase in serum bile acids, 2) attenuated TNF alpha but not IL1 beta/IL6 levels, 3) inhibited the altered hepatic transporter expression, and 4) blocked the decrease in HNF1 alpha nuclear protein levels. Conclusions. These results suggest that alterations in hepatic transporter expression during IR occur through Kupffer cell-mediated events, possibly involving a decrease in nuclear HNF1 alpha.
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