Deletion of intestinal SHP impairs short-term response to cholic acid challenge in mice.

Abstract

Small heterodimer partner (SHP) is a crucial regulator of bile acid (BA) transport and synthesis; however, its intestine-specific role is not fully understood. Here, we report that Intestine-specific Shp knockout (IShpKO) mice have higher intestinal and hepatic BAs, but not serum BAs when challenged with an acute (5-day) 1% cholic acid (CA) diet. Consistent with this finding, BA synthetic genes Cyp7A1 and Cyp8b1 are not repressed to the same extent in IShpKO compared to control mice post-CA challenge. Loss of intestinal SHP did not alter Fxr mRNA but increased Asbt (BA ileal uptake transporter) and Ost (BA ileal efflux transporter) expression even under chow-fed conditions. Surprisingly, the acute CA diet in IShpKO did not elicit the expected induction of Fgf15 but was able to maintain the suppression of Asbt, and Ost/{beta} mRNA levels. At the protein level, ASBT was downregulated, while OST/{beta} expression was induced and maintained regardless of diet. Examination of ileal histology in IShpKO mice challenged with acute CA diet revealed reduced villus length and goblet cell numbers. However, no difference in goblet cell number, villus morphology, crypt depth, and the expression of BA regulator and transporter genes was seen between f/f Shp and IShpKO mice after chronic (14-day) CA diet suggesting an adaptive response. We found the upregulation of the Ppar-Ugt axis, which can reduce the BA burden and compensate for the ileal SHP function. Thus, our study reveals that ileal SHP expression contributes to both overall intestinal structure and BA homeostasis.