Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Hepatology. 2010 Jan;51(1):277-85. doi: 10.1002/hep.23289.
Cholesterol 7alpha-hydroxylase (Cyp7a1) and the bile acid pool size are increased 2 to 3-fold in lactating postpartum rats. We investigated the interaction of nuclear receptors with the Cyp7a1 proximal promoter and the expression of regulatory signaling pathways in postpartum rats at day 10 (PPd10) versus female controls to identify the mechanisms of increased expression of Cyp7a1, which is maximal at 16 hours. Liver X receptor (LXRalpha) and RNA polymerase II (RNA Pol II) recruitment to Cyp7a1 chromatin were increased 1.5- and 2.5-fold, respectively, at 16 hours on PPd10. Expression of nuclear receptors farnesoid X receptor (FXR), LXRalpha, liver receptor homolog (LRH-1), hepatocyte nuclear factor 4alpha (HNF4alpha), and short heterodimer partner (SHP) messenger RNA (mRNA) and coactivator peroxisome proliferators-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA was unchanged in PPd10 versus controls at 16 hours, whereas chicken ovalbumin upstream transcription factor II (COUP-TFII) was decreased 40% at 16 hours. Investigation of a repressive signaling pathway, the c-Jun-N-terminal kinase (JNK) signaling pathway in PPd10 versus controls, showed decreased mRNA expression of hepatocyte growth factor (HGF; decreased 60% at 16 hours) and tyrosine kinase receptor c-Met (decreased 44%-50% at 16 hours), but these were not accompanied by decreased expression of phosphorylated c-Jun. Importantly, expression of fibroblast growth factor 15 (FGF15) mRNA in the ileum was decreased 70% in PPd10 versus controls, whereas phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Erk1/2) protein expression in liver was decreased 88% at 16 hours.
The increased recruitment of LXRalpha, a Cyp7a1 stimulatory pathway, and decreased expression of FGF15 and phosphorylated Erk1/2, a Cyp7a1 repressive pathway, combined to increase Cyp7a1 expression during lactation.
胆固醇 7alpha-羟化酶（Cyp7a1）和胆汁酸池大小在哺乳期产后大鼠中增加 2 至 3 倍。我们研究了核受体与 Cyp7a1 近端启动子的相互作用以及产后第 10 天（PPd10）与雌性对照相比产后大鼠调节信号通路的表达，以确定 Cyp7a1 表达增加的机制，Cyp7a1 在 16 小时达到最大值。肝 X 受体（LXRalpha）和 RNA 聚合酶 II（RNA Pol II）在 PPd10 的 16 小时分别募集 Cyp7a1 染色质增加 1.5-和 2.5 倍。核受体法尼醇 X 受体（FXR）、LXRalpha、肝受体同源物（LRH-1）、肝细胞核因子 4alpha（HNF4alpha）和短异二聚体伴侣（SHP）信使 RNA（mRNA）和共激活物过氧化物酶体增殖物激活受体γ共激活因子-1alpha（PGC-1alpha）mRNA在 PPd10 与对照相比在 16 小时时不变，而鸡卵清蛋白上游转录因子 II（COUP-TFII）在 16 小时时减少 40%。在 PPd10 与对照相比研究抑制性信号通路，即 c-Jun-N-末端激酶（JNK）信号通路，显示肝细胞生长因子（HGF；在 16 小时减少 60%）和酪氨酸激酶受体 c-Met（在 16 小时减少 44%-50%）的 mRNA 表达减少，但这些并未伴有磷酸化 c-Jun 的表达减少。重要的是，回肠中纤维母细胞生长因子 15（FGF15）mRNA 的表达在 PPd10 中比对照减少 70%，而肝中磷酸化丝裂原活化蛋白激酶/细胞外信号调节激酶 1/2（Erk1/2）蛋白的表达在 16 小时减少 88%。
在哺乳期，LXRalpha 的募集增加，这是 Cyp7a1 的一种刺激途径，而 FGF15 和磷酸化 Erk1/2 的表达减少，这是 Cyp7a1 的一种抑制途径，共同增加了 Cyp7a1 的表达。
