TY - JOUR
T1 - Loss of Hepatic Small Heterodimer Partner Elevates Ileal Bile Acids and Alters Cell Cycle-related Genes in Male Mice
AU - Shaw, Ryan Philip Henry
AU - Kolyvas, Peter
AU - Dang, Nathanlown
AU - Hyon, Angela
AU - Bailey, Keith
AU - Anakk, Sayeepriyadarshini
N1 - Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - Small 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 CYP8B1. 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 on 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 ileal bile acid composition mimicking that of cholic acid-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, copper ion transport, and DNA synthesis. We confirmed increased expression of metallothionein genes that can regulate copper levels in the absence of SHP. LShpKO livers also displayed a higher basal proliferation that was exacerbated specifically with bile acid challenge either with cholic acid or 3,5-diethoxycarbonyl-1,4-dihydrocollidine but not with another liver mitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. Overall, our data indicate that hepatic SHP uniquely regulates certain proliferative and metabolic cues.
AB - Small 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 CYP8B1. 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 on 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 ileal bile acid composition mimicking that of cholic acid-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, copper ion transport, and DNA synthesis. We confirmed increased expression of metallothionein genes that can regulate copper levels in the absence of SHP. LShpKO livers also displayed a higher basal proliferation that was exacerbated specifically with bile acid challenge either with cholic acid or 3,5-diethoxycarbonyl-1,4-dihydrocollidine but not with another liver mitogen, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene. Overall, our data indicate that hepatic SHP uniquely regulates certain proliferative and metabolic cues.
KW - bile acids
KW - enterohepatic recirculation
KW - nuclear receptor
KW - proliferation
KW - small heterodimer partner
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U2 - 10.1210/endocr/bqac052
DO - 10.1210/endocr/bqac052
M3 - Article
C2 - 35451003
AN - SCOPUS:85130645588
SN - 0013-7227
VL - 163
JO - Endocrinology (United States)
JF - Endocrinology (United States)
IS - 6
M1 - bqac052
ER -