The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis

Abstract

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants and is characterized by an extensive hemorrhagic inflammatory necrosis of the distal ileum and proximal colon. We have previously shown that, during the development of experimental NEC, the liver plays an important role in regulating inflammation in the ileum, and accumulation of ileal bile acids (BA) along with dysregulation of ileal BA transporters contributes to ileal damage. Given these findings, we speculated that hepatic BA transporters would also be altered in experimental NEC. Using both rat and mouse models of NEC, levels of Cyp7a1, Cyp27a1, and the hepatic BA transporters Bsep, Ntcp, Oatp2, Oatp4, Mrp2, and Mrp3 were investigated. In addition, levels of hepatic BA transporters were also determined when the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-18, which are both elevated in NEC, are neutralized during disease development. Ntcp and Mrp2 were decreased in NEC, but elevated ileal BA levels were not responsible for these reductions. However, neutralization of TNF-α normalized Ntcp, whereas removal of IL-18 normalized Mrp2 levels. These data show that the hepatic transporters Ntcp and Mrp2 are downregulated, whereas Cyp27a1 is increased in rodent models of NEC. Furthermore, increased levels of TNF-α and IL-18 in experimental NEC may play a role in the regulation of Ntcp and Mrp2, respectively. These data suggest the gut-liver axis should be considered when therapeutic modalities for NEC are developed.

Selective and Cytokine-Dependent Regulation of Hepatic Transporters and Bile Acid Homeostasis during Infectious Colitis in Mice

“…Conversely, hepatic downregulation of Slco1a4 (Oatp1a4) has been reported in fatty-liver disease, extrahepatic cancer, and experimental sepsis (Sharma et al, 2008;Fisher et al, 2009;Bodeman et al, 2013) as well as in the present study, but was not observed in necrotizing enterocolitis (NEC) or colitis caused by dextran sulfate sodium (DSS) treatment (Jahnel et al, 2009;Cherrington et al, 2013). C. rodentium infection also decreased Slco1a1 (Oatp1a1 or Oatp1) gene expression, which finding is consistent with reported downregulation after treatment with LPS or subcutaneous turpentine (Siewert et al, 2004;Bodeman et al, 2013).…”

“…During live infection we observed a significant decrease in the mRNA expression of Abcc2 in C57BL/6J mice. Other inflammatory conditions have been reported to result in similar downregulation (Andrejko et al, 2008;Sharma et al, 2008;Cherrington et al, 2013). Multiple studies have indicated a role for IL-6 in the downregulation of Abcc2 (Siewert et al, 2004;Andrejko et al, 2008).…”

A Systematic Comparison of the Impact of Inflammatory Signaling on Absorption, Distribution, Metabolism, and Excretion Gene Expression and Activity in Primary Human Hepatocytes and HepaRG Cells

“…A slight upregulation of MDR1 (ABCB1), as observed previously (Poller et al, 2010), was not significant. Transcriptional downregulation of the hepatic bile acid transporter NTCP (SLC10A1) is in agreement with a former study (Cherrington et al, 2013). Somewhat more extended effects of IL-1b and TNF-a were also observed for HNF4A, PPARA, and POR.…”

Modeling Human Nonalcoholic Steatohepatitis-Associated Changes in Drug Transporter Expression Using Experimental Rodent Models

“…Interestingly, the models that used MCD feeding share the most similarity to drug transporter expression in human NASH. It is well known that MCD feeding causes significant induction of oxidative stress as well as the release of proinflammatory cytokines, both of which are mediators of drug transporter gene regulation (Leclercq et al, 2000;Chowdhry et al, 2010;Cherrington et al, 2013;Ikemura et al, 2013). Additionally, hepatic oxidative stress is increased in humans with NASH leading to aberrations in oxidative stress-mediated gene regulation (Hardwick et al, 2010).…”