[PMID]: | 29175453 |
[Au] Autor: | Zhang Y; Lickteig AJ; Csanaky IL; Klaassen CD |
[Ad] Endereço: | School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China. Electronic address: youcai.zhang@tju.edu.cn. |
[Ti] Título: | Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion. |
[So] Source: | Toxicol Appl Pharmacol;338:112-123, 2018 01 01. |
[Is] ISSN: | 1096-0333 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport. |
[Mh] Termos MeSH primário: |
Ácidos e Sais Biliares/metabolismo Bile/metabolismo Fígado/metabolismo PPAR alfa/fisiologia
|
[Mh] Termos MeSH secundário: |
Animais Colesterol/metabolismo Colesterol 7-alfa-Hidroxilase/genética Clofibrato/farmacologia Feminino Íleo/metabolismo Camundongos Camundongos Endogâmicos C57BL
|
[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL |
[Nm] Nome de substância:
| 0 (Bile Acids and Salts); 0 (PPAR alpha); 97C5T2UQ7J (Cholesterol); EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase); EC 1.14.14.23 (Cyp7a1 protein, mouse); HPN91K7FU3 (Clofibrate) |
[Em] Mês de entrada: | 1801 |
[Cu] Atualização por classe: | 180311 |
[Lr] Data última revisão:
| 180311 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 171128 |
[St] Status: | MEDLINE |
|
|