title: FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model.
abstract: It has been established that bile salts play a role in the regulation of hepatic lipid metabolism. Accordingly, overt signs of steatosis have been observed in mice with reduced bile salt synthesis. The aim of this study was to identify the mechanism of hepatic steatosis in mice with bile salt deficiency due to a liver specific disruption of cytochrome P450 reductase. In this study mice lacking hepatic cytochrome P450 reductase (Hrn) or wild type (WT) mice were fed a diet supplemented with or without either 0.1% cholic acid (CA) or 0.025% obeticholic acid, a specific FXR-agonist. Feeding a CA-supplemented diet resulted in a significant decrease of plasma ALT in Hrn mice. Histologically, hepatic steatosis ameliorated after CA feeding and this was confirmed by reduced hepatic triglyceride content (115.5±7.3mg/g liver and 47.9±4.6mg/g liver in control- and CA-fed Hrn mice, respectively). The target genes of FXR-signaling were restored to normal levels in Hrn mice when fed cholic acid. VLDL secretion in both control and CA-fed Hrn mice was reduced by 25% compared to that in WT mice. In order to gain insight in the mechanism behind these bile salt effects, the FXR agonist also was administered for 3weeks. This resulted in a similar decrease in liver triglycerides, indicating that the effect seen in bile salt fed Hrn animals is FXR dependent. In conclusion, steatosis in Hrn mice is ameliorated when mice are fed bile salts. This effect is FXR dependent. Triglyceride accumulation in Hrn liver may partly involve impaired VLDL secretion.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Cindy
authors.initials: C
authors.lastname: Kunne
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands; Department of Pharmacology, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Acco
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Duijst
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: de Waart
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Coen C
authors.initials: CC
authors.lastname: Paulusma
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Gaemers
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: r.p.oude-elferink@amc.uva.nl.
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000378:metabolism; D002793:Cholic Acids / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism*; D015870:Gene Expression; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000103:Acetyl-CoA Carboxylase; D001647:Bile Acids and Salts; D015243:Cholesterol, VLDL; D002793:Cholic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D000099150:Receptor, Farnesoid X-Activated; C454739:Scarb1 protein, mouse; C498191:Acacb protein, mouse
keywords: Bile acid; CYP450-reductase; FXR; Fatty liver; Hrn