title: Simple steatosis sensitizes cholestatic rats to liver injury and dysregulates bile salt synthesis and transport.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. It is uncertain if simple steatosis, the initial and prevailing form of NAFLD, sensitizes the liver to cholestasis. Here, we compared the effects of obstructive cholestasis in rats with a normal liver versus rats with simple steatosis induced by a methionine/choline-deficient diet. We found that plasma liver enzymes were higher and hepatic neutrophil influx, inflammation, and fibrosis were more pronounced in animals with combined steatosis and cholestasis compared to cholestasis alone. Circulating bile salt levels were markedly increased and hepatic bile salt composition shifted from hydrophilic tauro-β-muricholate to hydrophobic taurocholate. This shift was cytotoxic for HepG2 hepatoma cells. Gene expression analysis revealed induction of the rate-limiting enzyme in bile salt synthesis, cytochrome P450 7a1 (CYP7A1), and modulation of the hepatic bile salt transport system. In conclusion, simple steatosis sensitizes the liver to cholestatic injury, inflammation, and fibrosis in part due to a cytotoxic shift in bile salt composition. Plasma bile salt levels were elevated, linked to dysregulation of bile salt synthesis and enhanced trafficking of bile salts from the liver to the systemic circulation.
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Daniël A
authors.initials: DA
authors.lastname: Lionarons
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Michal
authors.initials: M
authors.lastname: Heger
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Rowan F
authors.initials: RF
authors.lastname: van Golen
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Lindy K
authors.initials: LK
authors.lastname: Alles
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.|Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: van der Mark
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Kloek
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: de Waart
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Hendrik A
authors.initials: HA
authors.lastname: Marsman
authors.affiliation: Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Henny
authors.initials: H
authors.lastname: Rusch
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Joanne
authors.initials: J
authors.lastname: Verheij
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Coen C
authors.initials: CC
authors.lastname: Paulusma
authors.affiliation: Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: van Gulik
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001693:Biological Transport, Active; D002779:Cholestasis / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051381:Rats; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; C037351:tauromuricholic acid; D013656:Taurocholic Acid; C532838:CYP7A1 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase