title: Expression patterns of nuclear receptors in parenchymal and non-parenchymal mouse liver cells and their modulation in cholestasis.
abstract: Nuclear receptors (NR), the largest family of transcription factors, control many physiological and pathological processes. To gain insight into hepatic NR and their potential as therapeutic targets in cholestatis, we determined their expression in individual cell types of the mouse liver in normal and cholestatic conditions. Hepatocytes, cholangiocytes, hepatic stellate cells (HSC), sinusoidal endothelial cells (SEC) and Kupffer cells (KC) were isolated from the liver of mice with acute or chronic cholestasis (i.e. bile duct-ligated or Abcb4-/-mice, respectively) and healthy controls. The expression of 43 out of the 49 NR was evidenced by RT-qPCR in one or several liver cell types. Expression of four NR was restricted to non-parenchymal liver cells. In normal conditions, NR were expressed at higher levels in individual cell types when compared to total liver. Half of the NR expressed in the liver had maximal expression in non-parenchymal cells. After bile duct ligation, NR mRNA changes occurred mostly in non-parenchymal cells and mainly consisted in down-regulations. In Abcb4-/-mice, NR mRNA changes were equally frequent in hepatocytes and non-parenchymal cells. Essentially down-regulations were found in hepatocytes, HSC and cholangiocytes, as opposed to up-regulations in SEC and KC. While undetectable in total liver, Vdr expression was up-regulated in all non-parenchymal cells in Abcb4-/-mice. In conclusion, non-parenchymal liver cells are a major site of NR expression. During cholestasis, NR expression is markedly altered mainly by down-regulations, suggesting major changes in metabolic activity. Thus, non-parenchymal cells are important new targets to consider in NR-directed therapies.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), F-75012 Paris, France. Electronic address: ester.gonzalez@upmc.fr.
authors.forename: Ester
authors.initials: E
authors.lastname: Gonzalez-Sanchez
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), F-75012 Paris, France. Electronic address: delphine.firrincieli@orange.fr.
authors.forename: Delphine
authors.initials: D
authors.lastname: Firrincieli
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), F-75012 Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Centre de Référence Maladies Rares des Maladies Inflammatoires des Voies Biliaires & Service d'Hépatologie, F-75012 Paris, France. Electronic address: chantal.housset@inserm.fr.
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), F-75012 Paris, France; Inovarion, F-75013 Paris, France. Electronic address: nicolas.chignard@inovarion.com.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chignard
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000818:Animals; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D059467:Transcriptome; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018160:Receptors, Cytoplasmic and Nuclear; D000097202:ATP-Binding Cassette Sub-Family B Member 4
keywords: Abcb4 knockout mice; Bile duct ligation; Hepatocytes; Non-parenchymal liver cells