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Author Notes:

Corresponding author: Astrid Kosters, PhD, 1760 Haygood Dr NE Suite E208, Atlanta, Georgia 30322, astrid.kosters@emory.edu, Phone: 404-727-4921, Fax: 404-727-4069

The authors would like to thank Dr. Andrew Feranchak (UT Southwestern, Dallas TX.) and Dr. Scott Friedman (Mount Sinai School of Medicine, New York, NY) for the kind gifts of the human cholangiocyte MzHA1 and stellate line LX2 cell lines respectively, as well as Ligand Pharmaceuticals and Intercept for kindly providing LG268 and Obeticholic acid respectively.

Dr. Dawson has served as a consultant for Lumena Pharmaceuticals in the past.

The other authors report no conflict of interest.

Subjects:

Research Funding:

Financial Support was from Emory Egleston Children's Research Center pilot grant (AK) and NIH: DK56239 (SJK).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • inflammation
  • liver
  • macrophages
  • nuclear receptor
  • Slc10a6
  • RETINOID-X-RECEPTOR
  • DEHYDROEPIANDROSTERONE DHEA
  • FUNCTIONAL-CHARACTERIZATION
  • OBSTRUCTIVE-JAUNDICE
  • HEPATIC STEATOSIS
  • DISEASE
  • ALPHA
  • ACTIVATION
  • EXPRESSION
  • MODEL

Inflammation-associated upregulation of the sulfated steroid transporter Slc10a6 in mouse liver and macrophage cell lines

Tools:

Journal Title:

Hepatology Research

Volume:

Volume 46, Number 8

Publisher:

, Pages 794-803

Type of Work:

Article | Post-print: After Peer Review

Abstract:

AIM: Slc10a6, an incompletely characterized member of the SLC10A bile acid transporter family, was one of the most highly induced RNA transcripts identified in a screen for inflammation-responsive genes in mouse liver. This study aimed to elucidate a role for Slc10a6 in hepatic inflammation. METHODS: Mice were treated with lipopolysaccharide (LPS; 2 mg/kg) or interleukin (IL)-1β (5 mg/kg) for various time points. Cells were treated with LPS (1 μg/mL) at various time points, with cell signaling inhibitors, nuclear receptor ligands and Slc10a6 substrates. All mRNA levels were determined by quantitative polymerase chain reaction. RESULTS: Slc10a6 mRNA levels were upregulated in mouse liver at 2 h (7-fold), 4 h (100-fold) and 16 h (50-fold) after LPS treatment, and 35-fold by the cytokine IL-1β (4 h). Both absence of the nuclear receptor Fxr and pretreating mice with the synthetic retinoid X receptor-α ligand LG268 attenuated the LPS upregulation of Slc10a6 mRNA by 60-75%. In vitro, Slc10a6 mRNA was induced 30-fold by LPS in mouse RAW264.7 macrophages in a time-dependent manner (maximum at 8 h). The Slc10a6 substrate dehydroepiandrosterone sulfate (DHEAS) enhanced LPS induction of CCL5 mRNA, a pro-inflammatory chemokine, by 50% in RAW264.7 cells. This effect was abrogated in the presence of anti-inflammatory nuclear receptor ligands 9-cis-retinoic acid and dexamethasone. CONCLUSION: Dramatic upregulation of Slc10a6 mRNA by LPS combined with enhanced LPS stimulation of CCL5 expression by the Slc10a6 substrate DHEAS in macrophages suggests that Slc10a6 function contributes to the hepatic inflammatory response.

Copyright information:

© 2015 The Japan Society of Hepatology

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