title: Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal.
abstract: OBJECTIVE
  There is a growing evidence that bile acids are involved in the regulation of triglyceride-, cholesterol-homoeostasis and fat absorption. In this study organ-specific Fxr knockout mice were used to further investigate the influence of farnesoid X receptor FXR in lipogenesis.
  
  
  METHODS
  Liver- and intestine-specific Fxr knockout mice were fed a 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E, BODIPY staining and liver X receptor (LXR) immunohistochemistry. Liver triglycerides, serum cholesterol, serum bile acids and nuclear LXR protein were measured. mRNA expression of several genes involved in bile acid-, cholesterol-homoeostasis and lipogenesis was quantified by real-time PCR.
  
  
  RESULTS
  Hepatic FXR deficiency contributes to lipid accumulation under 1% cholesterol administration which is not observed in intestinal Fxr knockout mice. Strong lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr knockout mice show no histological difference to controls. In addition, these mice have the ability to maintain normal serum cholesterol and bile acid levels. Hepatic Fxr knockouts were characterized by elevated triglycerides and bile acid levels. Expression level of LXR was significantly elevated under control and 1% cholesterol diet in hepatic Fxr knockout mice and was followed by concomitant lipogenic target gene induction such as Fas and Scd-1. This protective FXR effect against hepatic lipid accumulation was independent of intestinal Fgf15 induction.
  
  
  CONCLUSIONS
  These results show that the principal site of protective bile acid signalling against lipid accumulation is located in the liver since the absence of hepatic but not intestinal FXR contributes to lipid accumulation under cholesterol diet.
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, DE-97080 Wuerzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Department of Pharmacology and Toxicology Ernest Mario School of Pharmacy Rutgers University Piscataway, NJ 08854, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich (USZ), CH-8091 Zurich, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.affiliation: Division of Endocrinology, Diabetes, & Nutrition, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Tschopp
authors.affiliation: Division of Endocrinology, Diabetes, & Nutrition, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Simon M
authors.initials: SM
authors.lastname: Schultze
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, DE-97080 Wuerzburg, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Rau
authors.affiliation: Department of Pathology, Institute of Surgical Pathology, University Hospital Zurich (USZ), Zurich, Switzerland.
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Department of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Müllhaupt
authors.affiliation: Department of Pharmacology and Toxicology Ernest Mario School of Pharmacy Rutgers University Piscataway, NJ 08854, USA.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, DE-97080 Wuerzburg, Germany.|Department of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002791:Cholesterol, Dietary; D005346:Fibroblast Growth Factors; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013230:Stearoyl-CoA Desaturase; D014280:Triglycerides; D019014:fas Receptor; D000099150:Receptor, Farnesoid X-Activated; C491899:Fas protein, mouse; C108526:fibroblast growth factor 15, mouse; C490333:Scd1 protein, mouse
keywords: FXR; NAFLD; bile acids; lipogenesis