Mouse model of sclerosing cholangitis

[Guest guest]

Trauner's group has previously shown that mice deficient in

the Abcb4 gene encoding a phosopholipid (phosphatidylcholine)

transporter, develop sclerosing cholangitis that is similar to human

PSC. You may recall that he used this mouse model to show that nor-

urso is superior to urso in preventing bile duct injury in these

mice. You may also recall that expression of this transporter is

activated by PPAR-alpha, which is in turn activated by fibrates (and

likely also by fish oils). This may be the explanation for the

beneficial effects of fibrates (and docosahexaenoic acid (DHA)) in

cholestatic liver diseases like PBC, PSC and liver disease associated

with cystic fibrosis. A new study (below) shows that cholic acid

feeding aggravates liver injury in these abcb4 knock-out mice, and

that urso provokes less damage, as assessed by changes of

inflammatory gene and fibrosis-related gene expression.

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Scand J Gastroenterol. 2008 Sep 10:1-8. [Epub ahead of print]

Gene expression profiles reflect sclerosing cholangitis activity in

abcb4 (-/-) mice.

Nakken KE, Nygard S, Haaland TK, Berge KE, Odegaard A, Labori KJ,

Ræder MG

Institute for Experimental Medical Research, Ullevål University

Hospital and University of Oslo.

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. Material and 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. Result. 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. PMID: 18785065.

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What's staggering is that one gene knock-out combined with a diet

rich in cholic acid, can trigger changes of expression of 1582 genes

in the liver. Hopefully, this will help unravel some of the

inflammation pathways, and provide a rapid way to assess how new

medications (such as nor-urso) may block this inflammatory cascade?

Dave

(father of (23); PSC 07/03; UC 08/03)