Liver-specific Deletion Of Small Heterodimer Partner Alters Enterohepatic Bile Acid Levels And Promotes Bile Acid-Mediated Proliferation In Male Mice

Abstract

ABSTRACTSmall heterodimer partner (Shp) regulates several metabolic processes, including bile acid levels, but lacks the conserved DNA binding domain. Phylogenetic analysis revealed conserved genetic evolution of Shp, Fxr, Cyp7a1 and Cyp27a1, underscoring the importance of these molecules in maintaining bile acid homeostasis. Shp, although primarily studied as a downstream target of Farnesoid X Receptor (Fxr), has a distinct hepatic role that is poorly understood. Here we report that liver-specific Shp knockout (LShpKO) mice have impaired negative feedback of Cyp7a1 and Cyp8b1 upon bile acid challenge and demonstrate that a single copy of the Shp gene is sufficient to maintain this response. LShpKO mice also exhibit elevated total bile acid pool with higher bile acid fraction in the intestine mimicking the 1% cholic acid (CA) fed control mice. Agonistic activation of Fxr (GW4064) in the LShpKO did not alter the elevated basal expression of Cyp8b1 but lowered Cyp7a1 expression. We found that deletion of Shp led to an enrichment of distinct motifs and pathways associated with circadian rhythm, amino and carboxylic acid metabolism, copper ion transport, and DNA synthesis. LShpKO livers displayed a higher basal proliferation that was exacerbated specifically with bile acid challenge but not with another liver mitogen, TCPOBOP (TC). Overall, our data indicate that hepatic SHP uniquely regulates certain proliferative and metabolic cues.