title: Differential regulation of cyclin D1 and cell death by bile acids in primary rat hepatocytes.
abstract: Ursodeoxycholic (UDCA) and tauroursodeoxycholic (TUDCA) acids modulate apoptosis and regulate cell-cycle effectors, including cyclin D1. In contrast, deoxycholic acid (DCA) induces cell death and cyclin D1. In this study, we explored the role of cyclin D1 in DCA-induced toxicity and further elucidated the antiapoptotic function of UDCA and TUDCA in primary rat hepatocytes. Cells were incubated with DCA and with or without UDCA or TUDCA for 8-30 h. In addition, hepatocytes were transfected with either an adenovirus expressing cyclin D1 or with a cyclin D1 reporter plasmid with or without bile acids. Finally, cells were cotransfected with short interfering RNA targeting p53. Unlike DCA, both UDCA and TUDCA reduced cyclin D1 expression and transcriptional activation, confirming our previous DNA microarray data. Furthermore, UDCA and TUDCA prevented DCA-induced cyclin D1 and cell death. Cyclin D1 overexpression increased DCA-induced Bax translocation, cytochrome c release, and apoptosis. However, UDCA and TUDCA were less efficient at decreasing cyclin D1 levels as well as DCA-induced changes with overexpression. Finally, after p53 silencing, the effects of cyclin D1 overexpression were almost completely abrogated, whereas UDCA and TUDCA cytoprotective potential was reestablished. In conclusion, cyclin D1 is a relevant player in modulating apoptosis by bile acids, in part through a p53-dependent mechanism.
authors: Centro de Patogénese Molecular, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600-083 Lisbon, Portugal.
authors: Rui E
authors: RE
authors: Castro
authors: Joana D
authors: JD
authors: Amaral
authors: Susana
authors: S
authors: Solá
authors: Betsy T
authors: BT
authors: Kren
authors: Clifford J
authors: CJ
authors: Steer
authors: Cecília M P
authors: CM
authors: Rodrigues
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D003840:Deoxycholic Acid / Q000633:toxicity; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D008297:Male; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003840:Deoxycholic Acid; D019938:Cyclin D1; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D014580:Ursodeoxycholic Acid; D045304:Cytochromes c