Mechanisms for increased expression of cholesterol 7alpha-hydroxylase (Cyp7a1) in lactating rats.
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.


CONCLUSIONS
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.
Wooton-Kee
Clavia Ruth
CR
Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Coy
Donna J
DJ
Athippozhy
Antony T
AT
Zhao
Tianyong
T
Jones
Brett R
BR
Vore
Mary
M
D000818:Animals; D001647:Bile Acids and Salts / Q000502:physiology*; D051837:COUP Transcription Factor II / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D002940:Circadian Rhythm; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007774:Lactation / Q000502:physiology*; D000071518:Liver X Receptors; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D049590:Postpartum Period; D011401:Promoter Regions, Genetic / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D001647:Bile Acids and Salts; D051837:COUP Transcription Factor II; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2; D017228:Hepatocyte Growth Factor; D002790:Cholesterol 7-alpha-Hydroxylase; D019859:Proto-Oncogene Proteins c-met; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048370:MAP Kinase Kinase 2