Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice

Matthew D Merrell; Beatrice A Nyagode; John D Clarke; Nathan J Cherrington; Edward T Morgan

doi:10.1124/dmd.113.055525

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Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice

Journal article

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Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice

Matthew D Merrell, Beatrice A Nyagode, John D Clarke, Nathan J Cherrington and Edward T Morgan

Drug metabolism and disposition, Vol.42(4), pp.596-602

04/2014

DOI: https://doi.org/10.1124/dmd.113.055525

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https://hdl.handle.net/2376/107913

PMCID: PMC3965897

PMID: 24378326

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Abstract

Enterobacteriaceae Infections - metabolism

Enterobacteriaceae Infections - microbiology

Liver - metabolism

Mice, Inbred C57BL

Gene Expression Regulation

Homeostasis

Bile Acids and Salts - metabolism

Mice, Inbred C3H

Enterobacteriaceae Infections - immunology

Carrier Proteins - genetics

Liver - immunology

Animals

Colitis - microbiology

Colitis - metabolism

Citrobacter - pathogenicity

Female

Mice

Colitis - immunology

Cytokines - immunology

Various disease models have been shown to alter hepatic drug-metabolizing enzyme (DME) and transporter expression and to induce cholestasis through altered enzyme and transporter expression. Previously, we detailed the regulation of hepatic DMEs during infectious colitis caused by Citrobacter rodentium infection. We hypothesized that this infection would also modulate hepatic drug transporter expression and key genes of bile acid (BA) synthesis and transport. Mice lacking Toll-like receptor 4 (TLR4), interleukin-6 (IL-6), or interferon-gamma (IFNγ) and appropriate wild-type animals were orally infected with C. rodentium and sacrificed 7 days later. In two wild-type strains, drug transporter mRNA expression was significantly decreased by infection for Slc22a4, Slco1a1, Slco1a4, Slco2b1, and Abcc6, whereas the downregulation of Abcc2, Abcc3, and Abcc4 were strain-dependent. In contrast, mRNA expressions of Slco3a1 and Abcb1b were increased in a strain-dependent manner. Expression of Abcb11, Slc10a1, the two major hepatic BA transporters, and Cyp7a1, the rate-limiting enzyme of BA synthesis, was also significantly decreased in infected animals. None of the above effects were caused by bacterial lipopolysaccharide, since they still occurred in the absence of functional TLR4. The downregulation of Slc22a4 and Cyp7a1 was absent in IFNγ-null mice, and the downregulation of Slco1a1 was abrogated in IL-6-null mice, indicating in vivo roles for these cytokines in transporter regulation. These data indicate that C. rodentium infection modulates hepatic drug processing through alteration of transporter expression as well as DMEs. Furthermore, this infection downregulates important genes of BA synthesis and transport and may increase the risk for cholestasis.

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Title: Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice
Creators: Matthew D Merrell - Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.D.M., B.A.N., E.T.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (J.D.C, N.J.C.)
Beatrice A Nyagode
John D Clarke
Nathan J Cherrington
Edward T Morgan
Publication Details: Drug metabolism and disposition, Vol.42(4), pp.596-602
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: HD062489 / NICHD NIH HHS R01 AI083927 / NIAID NIH HHS T32 ES007091 / NIEHS NIH HHS ES007091 / NIEHS NIH HHS ES012870 / NIEHS NIH HHS R01 HD062489 / NICHD NIH HHS AI083927 / NIAID NIH HHS P30 ES006694 / NIEHS NIH HHS T32 ES012870 / NIEHS NIH HHS R01 DK072372 / NIDDK NIH HHS DK072372 / NIDDK NIH HHS
Identifiers: 99900547233201842
Language: English
Resource Type: Journal article