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. 2019 Nov 26;400(12):1551-1565.
doi: 10.1515/hsz-2019-0204.

Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver

Martha Paluschinski  1 , Mirco Castoldi  1 , David Schöler  1 , Nils Bardeck  1 , Jessica Oenarto  1 , Boris Görg  1 , Dieter Häussinger  1
Affiliations

Tauroursodeoxycholate protects from glycochenodeoxycholate-induced gene expression changes in perfused rat liver

Martha Paluschinski et al. Biol Chem. .

Abstract

Tauroursodeoxycholate (TUDC) is well known to protect against glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes. In the present study, we analyzed whether TUDC also exerts protective effects by modulating GCDC-induced gene expression changes. For this, gene array-based transcriptome analysis and quantitative polymerase chain reaction (qPCR) were performed on RNA isolated from rat livers perfused with GCDC, TUDC or a combination of both (each 20 μm for 2 h). GCDC led to a significant increase of lactate dehydrogenase (LDH) into the effluent perfusate, which was prevented by TUDC. GCDC, TUDC and co-perfusion induced distinct gene expression changes. While GCDC upregulated the expression of several pro-inflammatory genes, co-perfusion with TUDC increased the expression of pro-proliferative and anti-apoptotic p53 target genes. In line with this, levels of serine20-phosphorylated p53 and of its target gene p21 were elevated by GCDC in a TUDC-sensitive way. GCDC upregulated the oxidative stress surrogate marker 8OH(d)G and the pro-apoptotic microRNAs miR-15b/16 and these effects were prevented by TUDC. The upregulation of miR-15b and miR-16 in GCDC-perfused livers was accompanied by a downregulation of several potential miR-15b and miR-16 target genes. The present study identified changes in the transcriptome of the rat liver which suggest, that TUDC is hepatoprotective by counteracting GCDC-induced gene expression changes.

Keywords: GCDC; TUDC; liver protection; miRNA; β1-integrin.

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