Figure 7.

Bile acids and FGF19 increase stability of hepatic SHP by inhibiting ubiquitin–proteasomal degradation and activating ERK pathway. SHP is rapidly degraded by the ubiquitin–proteasomal pathway with a half-life <30 min. Bile acids not only increase SHP gene induction by activation of the nuclear bile acid receptor FXR, but also substantially increase SHP stability by activating ERK and inhibiting proteasomal degradation. Treatment with a primary bile acid, CDCA, increases phosphorylation of SHP at Ser26 and inhibits ubiquitination at Lys122/Lys123, which results in increased SHP stability. Bile acid-induced intestinal FGF19 predominantly increases SHP stability, with little effect on SHP gene induction, by activating ERK and inhibiting ubiquitination and proteasomal degradation.