小异二聚体伴侣(Shp)调节几个代谢过程,包括胆汁酸水平,但缺乏保守的DNA结合结构域。系统发育分析揭示了SHP的保守遗传进化,FXR,CYP7A1和CYP8B1。Shp,虽然主要作为法尼醇X受体(Fxr)的下游靶标进行研究,具有独特的肝脏作用,对此知之甚少。这里,我们报道了肝脏特异性Shp敲除(LShpKO)小鼠对胆汁酸攻击时Cyp7a1和Cyp8b1的负反馈受损,并证明Shp基因的单个拷贝足以维持这种反应.LShpKO小鼠还表现出升高的总胆汁酸池,其回肠胆汁酸组成与胆酸喂养的对照小鼠的相似。LShpKO中Fxr(GW4064)的激动激活并未改变Cyp8b1的基础表达升高,但降低了Cyp7a1的表达。我们发现Shp的缺失导致与昼夜节律相关的不同基序和途径的富集,铜离子传输,和DNA合成。我们证实了在没有SHP的情况下可以调节铜水平的金属硫蛋白基因的表达增加。LShpKO肝脏还显示出更高的基础增殖,尤其是胆汁酸或3,5-二乙氧基羰基-1,4-二氢可三丁的胆汁酸攻击而不是另一种肝有丝分裂原,1,4-双[2-(3,5-二氯吡啶氧基)]苯。总的来说,我们的数据表明,肝脏SHP独特地调节某些增殖和代谢线索。
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.