Effects of 22-S-hydroxycholesterol (a liver X receptor modulator) on Lipid Metabolism

Liver X receptors (LXRs) play a crucial role in regulation of cholesterol, lipid and carbohydrate metabolism. 22-S-hydroxycholesterol (22-S-HC) has been shown to act as an LXR antagonist and to reduce de novo lipogenesis and lipid accumulation, as well as to increase glucose uptake in human skeletal muscle cells (myotubes). The aim of the present study was to further investigate the effects of 22-S-HC on lipid and glucose metabolism in human-derived cell lines from metabolic active tissues important for development of obesity and type 2 diabetes. We also wanted to explore the effects of 22-S-HC on plasma lipids in vivo in rats. The results show that de novo lipogenesis from [14C]acetate was decreased by 22-S-HC in myotubes and HepG2 (liver) cells, whereas increased in SGBS cells (adipocytes) and unaffected in CaCo-2 cells (intestinal cells). This was partly reflected by regulation of the lipogenic genes, sterol regulatory element binding transcription factor 1 (SREBF1) and fatty acid synthase (FASN), as measured by RT qPCR. Live imaging showed that the number of lipid droplets (LDs) was increased in SGBS cells, decreased in HepG2 cells and unaffected in myotubes by 22-S-HC treatment. Furthermore, exposure to 22-S-HC increased and tended to increase glucose uptake in myotubes and SGBS cells, respectively. However, apoA1-dependent cholesterol efflux was unaffected by 22-S-HC. These observations show that 22-S-HC differently affect distinct LXR-regulated processes, and that 22-S-HC not solely acts as an antagonist to LXR, but also stimulate some LXR-regulated processes. Furthermore, the results suggest that 22-S-HC might reduce ectopic fat accumulation and result in a more favorable lipid distribution. To investigate the effects of 22-S-HC in vivo, high-fat fed Wistar rats were given 30 mg/kg/day of 22-S-HC for 3 weeks. The 22-S-HC treated rats showed significantly reduced body weight gain compared to the control animals and reduced plasma levels of free fatty acids and triacylglycerol. Therefore, compounds with properties similar to 22-S-HC may be of importance in search towards better treatments for obesity and type 2 diabetes.