title: The liver X receptor modulator 22(S)-hydroxycholesterol exerts cell-type specific effects on lipid and glucose metabolism.
abstract: The aim of this study was to explore the effects of 22(S)-hydroxycholesterol (22(S)-HC) on lipid and glucose metabolism in human-derived cells from metabolic active tissues. Docking of T0901317 and 22(S)-HC showed that both substances fitted into the ligand binding domain of liver X receptors (LXR). Results show that while several lipogenic genes were induced by T0901317 in myotubes, HepG2 cells and SGBS cells, effect of 22(S)-HC varied more between cell types. In myotubes, most lipogenic genes were downregulated or unchanged by 22(S)-HC, whereas a more diverse pattern was found in HepG2 and SGBS cells. Treatment with 22(S)-HC induced sterol regulatory element binding transcription factor 1 in SGBS and HepG2 cells, but not in myotubes. Fatty acid synthase was downregulated by 22(S)-HC in myotubes, upregulated in SGBS and unchanged in HepG2 cells. De novo lipogenesis was increased by T0901317 in all cell models, whereas differently affected by 22(S)-HC depending on the cell type; decreased in myotubes and HepG2 cells, whereas increased in SGBS cells. Oxidation of linoleic acid was reduced by 22(S)-HC in all cell models while glucose uptake increased and tended to increase in myotubes and SGBS cells, respectively. Cholesterol efflux was unaffected by 22(S)-HC treatment. These results show that 22(S)-HC affects LXR-regulated processes differently in various cell types. Ability of 22(S)-HC to reduce lipogenesis and lipid accumulation in myotubes and hepatocytes indicate that 22(S)-HC might reduce lipid accumulation in non-adipose tissues, suggesting a potential role for 22(S)-HC or a similar LXR modulator in the treatment of type 2 diabetes.
authors: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors: Nina Pettersen
authors: NP
authors: Hessvik
authors: Siril Skaret
authors: SS
authors: Bakke
authors: Robert
authors: R
authors: Smith
authors: Aina Westrheim
authors: AW
authors: Ravna
authors: Ingebrigt
authors: I
authors: Sylte
authors: Arild Christian
authors: AC
authors: Rustan
authors: G Hege
authors: GH
authors: Thoresen
authors: Eili Tranheim
authors: ET
authors: Kase
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D000071518:Liver X Receptors; D008958:Models, Molecular; D008968:Molecular Conformation; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; C003585:22-hydroxycholesterol; D005947:Glucose