title: Bile salt sequestration induces hepatic de novo lipogenesis through farnesoid X receptor- and liver X receptor alpha-controlled metabolic pathways in mice.
abstract: Diabetes is characterized by high blood glucose levels and dyslipidemia. Bile salt sequestration has been found to improve both plasma glycemic control and cholesterol profiles in diabetic patients. Yet bile salt sequestration is also known to affect triglyceride (TG) metabolism, possibly through signaling pathways involving farnesoid X receptor (FXR) and liver X receptor alpha (LXRalpha). We quantitatively assessed kinetic parameters of bile salt metabolism in lean C57Bl/6J and in obese, diabetic db/db mice upon bile salt sequestration using colesevelam HCl (2% wt/wt in diet) and related these to quantitative changes in hepatic lipid metabolism. As expected, bile salt sequestration reduced intestinal bile salt reabsorption. Importantly, bile salt pool size and biliary bile salt secretion remained unchanged upon sequestrant treatment due to compensation by de novo bile salt synthesis in both models. Nevertheless, lean and db/db mice showed increased, mainly periportally confined, hepatic TG contents, increased expression of lipogenic genes, and increased fractional contributions of newly synthesized fatty acids. Lipogenic gene expression was not induced in sequestrant-treated Fxr(-/-) and Lxralpha(-/-) mice compared with wild-type littermates, in line with reports indicating a regulatory role of FXR and LXRalpha in bile salt-mediated regulation of hepatic lipid metabolism.
  
  
  CONCLUSIONS
  Bile salt sequestration by colesevelam induces the lipogenic pathway in an FXR- and LXRalpha-dependent manner without affecting the total pool size of bile salts in mice. We speculate that a shift from intestinal reabsorption to de novo synthesis as source of bile salts upon bile salt sequestration affects zonation of metabolic processes within the liver acinus.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. h.j.herrema@med.umcg.nl
authors.forename: Hilde
authors.initials: H
authors.lastname: Herrema
authors.forename: Maxi
authors.initials: M
authors.lastname: Meissner
authors.forename: Theo H
authors.initials: TH
authors.lastname: van Dijk
authors.forename: Gemma
authors.initials: G
authors.lastname: Brufau
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.forename: Maaike H
authors.initials: MH
authors.lastname: Oosterveer
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Reijngoud
authors.forename: Michael
authors.initials: M
authors.lastname: Müller
authors.forename: Frans
authors.initials: F
authors.lastname: Stellaard
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000499:Allylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D000069472:Colesevelam Hydrochloride; D050155:Lipogenesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000499:Allylamine; D001647:Bile Acids and Salts; D000069472:Colesevelam Hydrochloride; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C000605214:Nr1h3 protein, mouse