Suppression of bile acid-CoA:amino acid N-acyltransferase gene expression by Oncostatin M

Question:

Chronic inflammatory diseases have been associated with an altered serum bile acid composition which by acting on farnesoid X receptor or G-protein-coupled bile acid receptor 1 (GPBAR1) might act as signaling molecules to affect disease progression. While primary bile acid synthesis and conjugation take place in the liver, secondary bile acids are generated by microbiota in the gut. Therefore, diseases affecting liver metabolism or microbiota composition, like non-alcoholic fatty liver disease, might directly alter the expression of enzymes involved in bile acid synthesis and/or conjugation. Here, we investigated the influence of interleukin-6 (IL-6) and oncostatin M (OSM) on gene expression of bile acid-CoA:amino acid N-acyltransferase (BAAT) which catalyzes the taurine/glycine-conjugation of primary bile acids in the liver.

Methods:

Immortalized human hepatocytes (IHH) and human hepatoma cells (HepG2) were stimulated with IL-6 or OSM in different concentrations and for different periods of time. Quantitative real-time PCR was performed to evaluate gene expression. Pharmacological inhibitors were used to address the signaling pathways involved in gene regulation.

Results:

We found a pronounced decrease in the expression of BAAT in response to OSM, while stimulation with IL-6 had a much weaker effect. The OSM-mediated suppression of BAAT expression persisted over at least 24h even after wash-out of the cytokine. This long-lasting effect of OSM most likely relies on the strong adhesion of bio-active OSM to the extracellular matrix, in particular to collagen. Using pharmacological inhibitors, we could show that abrogation of the Janus kinase activity completely blocks the suppressive effect of OSM, while inhibition of the stress-activated MAP kinases p38 and JNK had no effect. Inhibition of ERK1/2 activation partially restored gene expression of BAAT indicating a contributing effect of these MAPK to the suppressive activity of OSM.

Conclusions:

We could identify a so far unrecognized suppressive activity of the interleukin-6-type cytokine OSM on the gene expression of the enzyme catalyzing the final step in taurine/glycine-conjugation of bile acids in the liver, BAAT. This could indicate an involvement of OSM in altered bile acid conjugation resulting in potential increased liver injury upon intrahepatic OSM release.