Elevated plasma bile acids coincide with cardiac stress and inflammation in young Cyp2c70^−/− mice

Background

High plasma bile acids (BAs), for instance due to intrahepatic cholestasis of pregnancy or neonatal cholestasis, are associated with cardiac abnormalities. Here, we exploited the variability in plasma BA levels in Cyp2c70^−/− mice with a human-like BA composition to investigate the acute effects of elevated circulating BAs on the heart.

Methods

RNA sequencing was performed on hearts of 3-week-old Cyp2c70^−/− mice lacking mouse-specific BA species that show features of neonatal cholestasis. Cardiac transcriptomes were compared between wild-type pups, Cyp2c70^−/− pups with low or high plasma BAs, and Cyp2c70^−/− pups from dams that were perinatally treated with ursodeoxycholic acid (UDCA).

Results

We identified 1355 genes that were differentially expressed in hearts of Cyp2c70^−/− mice with high versus low plasma BAs with enrichment of inflammatory processes. Strikingly, expression of 1053 (78%) of those genes was normalized in hearts of pups of UDCA-treated dams. Moreover, 645 cardiac genes strongly correlated to plasma BAs, of which 172 genes were associated with cardiovascular disease.

Conclusions

Elevated plasma BAs alter gene expression profiles of hearts of mice with a human-like BA profile, revealing cardiac stress and inflammation. Our findings support the notion that high plasma BAs induce cardiac complications in early life.

Impact

Cyp2c70^−/− mice with a human-like bile acid composition show features of neonatal cholestasis but the extrahepatic consequences hereof have so far hardly been addressed

Elevated plasma bile acids in Cyp2c70^−/− pups coincide with cardiac stress and inflammation

Perinatal treatment with UDCA prevents dysregulated cardiac gene expression patterns in Cyp2c70^−/− pups