Effect of pharmacological inhibition of ASBT on bile composition and sclerosing cholangitis in mdr2 knockout mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Rebekah Karns
PROVIDER: E-GEOD-66231 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice.
Miethke Alexander G AG Zhang Wujuan W Simmons Julia J Taylor Amy E AE Shi Tiffany T Shanmukhappa Shiva Kumar SK Karns Rebekah R White Shana S Jegga Anil G AG Lages Celine S CS Nkinin Stephenson S Keller Bradley T BT Setchell Kenneth D R KD
Hepatology (Baltimore, Md.) 20150821 2
<h4>Unlabelled</h4>Deficiency of multidrug resistance 2 (mdr2), a canalicular phospholipid floppase, leads to excretion of low-phospholipid "toxic" bile causing progressive cholestasis. We hypothesize that pharmacological inhibition of the ileal, apical sodium-dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in mdr2(-/-) mice. Thirty-day-old, female mdr2(-/-) mice were fed high-fat chow containing 0.006% SC-435, a minimally absorbed, potent inhibitor of ASBT, ...[more]
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Project description:We report the effect of a potent pharmacological inhibition of ASBT in mdr2 -/- mice, compared to genetic and treatment controls using RNA-sequencing. Through quantification of mRNA in liver samples, we found significant upregulation of anti-inflammatory and anti-fibrotic gene signatures in mdr2-/- mice. Additionally, we report downregulation of pro-inflammatory genes invovled in leukocyte recruitment.
2016-02-17 | GSE66231 | GEO
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2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress
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2015-03-01 | E-GEOD-64097 | biostudies-arrayexpress
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2010-10-20 | GSE18759 | GEO
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2006-04-23 | GSE4612 | GEO
Project description:Background & Aims. Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, we explored the molecular mechanisms underlying the tumor-promoting effect of PHx in these mice. Methods. Using microarrays-based techniques, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. Results. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had only amplifications affecting multiple chromosomes and locating mainly near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we demonstrated that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Conclusions: PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC. To explore the mechanisms of the accelerated HCC development by PHx, we compared liver tumors and their matched non-tumor liver tissues between 9-month-old hepatectomized and 13-14-month-old untreated Mdr2-KO mice.
2015-04-01 | E-GEOD-61423 | biostudies-arrayexpress