title: Liver X receptors regulate de novo lipogenesis in a tissue-specific manner in C57BL/6 female mice.
abstract: The liver X receptors (LXRs) play a key role in cholesterol and bile acid metabolism but are also important regulators of glucose metabolism. Recently, LXRs have been proposed as a glucose sensor affecting LXR-dependent gene expression. We challenged wild-type (WT) and LXRαβ(-/-) mice with a normal diet (ND) or a high-carbohydrate diet (HCD). Magnetic resonance imaging showed different fat distribution between WT and LXRαβ(-/-) mice. Surprisingly, gonadal (GL) adipocyte volume decreased on HCD compared with ND in WT mice, whereas it slightly increased in LXRαβ(-/-) mice. Interestingly, insulin-stimulated lipogenesis of isolated GL fat cells was reduced on HCD compared with ND in LXRαβ(-/-) mice, whereas no changes were observed in WT mice. Net de novo lipogenesis (DNL) calculated from Vo(2) and Vco(2) was significantly higher in LXRαβ(-/-) than in WT mice on HCD. Histology of HCD-fed livers showed hepatic steatosis in WT mice but not in LXRαβ(-/-) mice. Glucose tolerance was not different between groups, but insulin sensitivity was decreased by the HCD in WT but not in LXRαβ(-/-) mice. Finally, gene expression analysis of adipose tissue showed induced expression of genes involved in DNL in LXRαβ(-/-) mice compared with WT animals as opposed to the liver, where expression of DNL genes was repressed in LXRαβ(-/-) mice. We thus conclude that absence of LXRs stimulates DNL in adipose tissue, but suppresses DNL in the liver, demonstrating opposite roles of LXR in DNL regulation in these two tissues. These results show tissue-specific regulation of LXR activity, a crucial finding for drug development.
authors.affiliation: Department of Biosciences and Nutrition and Center for Biosciences at NOVUM, Karolinska Institutet, Lipid Laboratory, Huddinge, Sweden. marion.korach-andre@ki.se
authors.forename: Marion
authors.initials: M
authors.lastname: Korach-André
authors.forename: Amena
authors.initials: A
authors.lastname: Archer
authors.forename: Chiara
authors.initials: C
authors.lastname: Gabbi
authors.forename: Rodrigo P
authors.initials: RP
authors.lastname: Barros
authors.forename: Matteo
authors.initials: M
authors.lastname: Pedrelli
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Amanda T
authors.initials: AT
authors.lastname: Pettersson
authors.forename: Jurga
authors.initials: J
authors.lastname: Laurencikiene
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000818:Animals; D050218:Body Fat Distribution; D002478:Cells, Cultured; D005260:Female; D050155:Lipogenesis / Q000235:genetics*; D008066:Lipolysis / Q000235:genetics / Q000502:physiology; D000071518:Liver X Receptors; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors