Cholesterol 7␣-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 (LXR␣) 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), LXR␣, liver receptor homolog (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), and short heterodimer partner (SHP) messenger RNA (mRNA) and coactivator peroxisome proliferators-activated receptor ␥ coactivator-1␣ (PGC-1␣) 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. Conclusion: The increased recruitment of LXR␣, a Cyp7a1 stimulatory pathway, and decreased expression of FGF15 and phosphorylated Erk1/2, a Cyp7a1 repressive pathway, combined to increase Cyp7a1 expression during lactation. (HEPATOLOGY 2010;51: 277-285.)
C holesterol 7␣-hydroxylase (Cyp7a1) catalyzes the rate-limiting step of the classical pathway of bile acid synthesis and is the major mechanism for cholesterol catabolism and removal from the body. 1 Bile acids form mixed micelles with phospholipids and cholesterol in bile, which is essential for both the absorption and biliary excretion of cholesterol. Rodent Cyp7a1 expression increases in response to cholesterol-enriched diets, [2][3][4] resulting in increased bile acid synthesis, whereas feedback inhibition prevents the accumulation of cytotoxic hydrophobic bile acids. The regulation of Cyp7a1 expression is thus critical for maintenance of cholesterol and bile acid homeostasis.
Several nuclear receptors activate transcription of Cyp7a1. Liver X receptor alpha (LXR␣) binds to LXR response elements in the proximal rat 5,6 and mouse 7