title: Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice.
abstract: Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Reija
authors.initials: R
authors.lastname: Silvennoinen
authors.affiliation: IIB Sant Pau, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona-CIBER de Diabetes y Enfermedades Metabolicas Asociadas, Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Quesada
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kareinen
authors.affiliation: IIB Sant Pau, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona-CIBER de Diabetes y Enfermedades Metabolicas Asociadas, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Julve
authors.affiliation: Internal Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Kaipiainen
authors.affiliation: Internal Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Gylling
authors.affiliation: IIB Sant Pau, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona-CIBER de Diabetes y Enfermedades Metabolicas Asociadas, Barcelona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco-Vaca
authors.affiliation: IIB Sant Pau, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona-CIBER de Diabetes y Enfermedades Metabolicas Asociadas, Barcelona, Spain.
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: Escola-Gil
authors.affiliation: Wihuri Research Institute, Helsinki, Finland petri.kovanen@wri.fi.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lee-Rueckert
keywords: Bile acids; physical restraint; psychological stress; reverse cholesterol transport