Gene expression profiles reflect sclerosing cholangitis activity in abcb4 (-/-) mice.
OBJECTIVE
Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC), a condition that involves differential hepatic transcription of genes governing inflammation, tissue remodelling and fibrosis. The objective of this study was to test the hypothesis that genes involved in the regulation of tissue inflammation and fibrosis display transcription rates that parallel differences in abcb4 (-/-) SC activity. The activity of abcb4 (-/-) SC can be altered through dietary intervention: abcb4 (-/-) mice fed cholic acid (CA) display high SC activity, whereas ursodeoxycholic acid (UDCA)-fed mice display low SC activity.


METHODS
Differential hepatic transcription of genes was measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. Differential transcription of selected genes was verified by real-time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring.


RESULTS
Histopathology score, reflecting increased inflammation and fibrosis, was increased in CA-fed mice compared with UDCA-fed mice. cDNA microarray analysis showed up-regulation of 1582 genes in livers of CA-fed mice in contrast to 573 genes in UDCA-fed mice. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfkappab1, Nfkappab2, Tgfbeta1, Tgfbeta2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the unequal SC activities of CA- and UDCA-fed abcb4 (-/-) mice.


CONCLUSIONS
The numbers of differentially transcribed genes and the transcriptional activity of genes relating to inflammation, tissue remodelling and fibrosis parallel disease activity in CA- and UDCA-fed abcb4 (-/-) mice harbouring SC. Data on their hepatic transcription can gauge SC disease activity.
Nakken
Karl E
KE
Institute for Experimental Medical Research, Ullevål University Hospital and University of Oslo, Oslo, Norway. k.e.nakken@medisin.uio.no
Nygard
Stale
S
Haaland
Terese K
TK
Berge
Knut E
KE
Ødegaard
Annlaug
A
Labori
Knut J
KJ
Raeder
Morten G
MG
D000818:Animals; D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D051379:Mice