Fig. 8.

BA metabolism in mouse models with hydrophobic BA composition. A: Compared with WT and 2a12KO mice, 2c70KO and DKO mice had reduced BA synthesis and smaller BA pool sizes. FXR was not significantly activated in 2c70KO and DKO mice. In 2c70KO mice, unconjugated CDCA induced inflammatory cytokines (TNFα, IL-1β, etc.) in hepatic macrophages (Kupffer cells). The released cytokines inhibit CYP7A1 and CYP8B1 in hepatocytes through signaling pathways, including the JNK pathway. In DKO mice, LCA directly or indirectly activated PXR, CAR, and PPARα, which coordinately downregulates CYP7A1, upregulates CYP8B1, and inhibits cytokine production in Kupffer cells. B: The ratio of CA-derived BAs (CA and DCA) to CDCA-derived BAs (CDCA, LCA, and MCAs) in enterohepatic circulation. Each column and error bar represents the mean and SEM. *P < 0.01 and **P < 0.0001 were considered significantly different by the Tukey-Kramer test.