Liver X receptor activation increases hepatic fatty acid desaturation by the induction of SCD1 expression through an LXRα-SREBP1c-dependent mechanism

BackgroundLiver X receptors (LXRs) including LXR and LXR are members of the nuclear hormone receptor superfamily of ligand activated transcription factors, which serve as lipid sensors to regulate expression of genes controlling many aspects of cholesterol and fatty acid metabolism. The liver is the central organ in controlling lipid metabolism. In the present study, we aimed at elucidating the role of LXR activation in hepatic fatty acid homeostasis. MethodsWe treated C57BL/6 mice with a synthetic non-selective LXR agonist TO901317. Fatty acid profile of lipid esters in the livers was analyzed by gas-liquid chromatography. Real-time polymerase chain reaction (PCR) and western blot were used to determine the expression of SREBP1c and SCD1 in TO901317-treated livers and HepG2 cells. ResultsOral administration of TO901317 resulted in increased fatty acid desaturation in the liver, with concomitant increase in hepatic stearoyl CoA desaturase-1 (SCD1) expression. TO901317-induced SCD1 expression was observed in LXR-/- mice, but not in LXR-/- mice. Furthermore, TO901317 significantly increased expression of sterol regulatory element-binding protein 1c (SREBP1c), the deficiency of which almost completely abolished the induction of SCD1 by TO901317. This drug induced both SREBP1c and SCD1 expression in HepG2 cells. Overexpression of SREBP1c resulted in a significant increase in SCD1 promoter activity and expression. ConclusionsTaken together, the present studies demonstrate that pan-LXR activation increases hepatic fatty acid desaturation via the induction of SCD1 expression in an LXR-dependent and SREBP1c-mediated manner. ?? ???X??(liver X receptors,LXRs)??LXR?LXR????????????,????????????,????LXR??????????,??????????????????????????????????????,??????LXR??????????????? ????????LXR???????TO901317??C57BL/6?????????????????????????????PCR????????????TO901317?????????HepG2??SREBP1c?SCD1???? ????TO901317???????????????,???????A????1(stearoyl CoA desaturase-1,SCD1)??????????LXR-/-??,TO901317??????SCD1???,??LXR-/-?????????????,?????,TO901317??SCD1?????????????????-1c(sterol regulatory element-binding protein1c,SREBP1c)?????,???SREBP1c-/-??TO901317??????SCD1????????HepG2??,TO901317????SREBP1c?SCD1???;SREBP1c??????SCD1?????????????? ???????LXR??????????????????????SCD1??????,?????LXR??SREBP1c???