Loss of Hepatic Small Heterodimer Partner Elevates Ileal Bile Acids and Alters Cell Cycle-related Genes in Male Mice

小异二聚体伴侣 CYP8B1 法尼甾体X受体 胆固醇7α羟化酶 胆汁酸 G蛋白偶联胆汁酸受体 内科学 胆酸 内分泌学 生物 细胞生物学 化学 生物化学 基因 核受体 转录因子 医学
作者
Ryan Philip Henry Shaw,Peter Kolyvas,Nathanlown Dang,Angela Hyon,K. I. Bailey,Sayeepriyadarshini Anakk
出处
期刊:Endocrinology [The Endocrine Society]
卷期号:163 (6) 被引量:5
标识
DOI:10.1210/endocr/bqac052
摘要

Abstract 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.
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