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.