t0901317 and darglitazone

The pivotal role of liver X receptors (LXRs) in the metabolic conversion of cholesterol to bile acids in mice is well established. More recently, the LXRalpha promoter has been shown to be under tight regulation by peroxisome proliferator-activated receptors (PPARs), implying a role for LXRalpha in mediating the interplay between cholesterol and fatty acid metabolism. We have studied the role of LXR in fat cells and demonstrate that LXR is regulated during adipogenesis and augments fat accumulation in mature adipocytes. LXRalpha expression in murine 3T3-L1 adipocytes as well as in human adipocytes was up-regulated in response to PPARgamma agonists. Administration of a PPARgamma agonist to obese Zucker rats also led to increased LXRalpha mRNA expression in adipose tissue in vivo. LXR agonist treatment of differentiating adipocytes led to increased lipid accumulation. An increase of the expression of the LXR target genes, sterol regulatory binding protein-1 and fatty acid synthase, was observed both in vivo and in vitro after treatment with LXR agonists for 24 h. Finally, we demonstrate that fat depots in LXRalpha/beta-deficient mice are smaller than in age-matched wild-type littermates. These findings imply a role for LXR in controlling lipid storage capacity in mature adipocytes and point to an intriguing physiological interplay between LXR and PPARgamma in controlling pathways in lipid handling.

Topics: Adipocytes; Adipose Tissue; Animals; Anticholesteremic Agents; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; Desmosterol; DNA-Binding Proteins; Fatty Acid Synthases; Female; Gene Expression Regulation; Humans; Hydrocarbons, Fluorinated; Lipid Metabolism; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Orphan Nuclear Receptors; Rats; Rats, Zucker; Receptors, Cytoplasmic and Nuclear; Sterol Regulatory Element Binding Protein 1; Sulfonamides; Thiazoles; Thiazolidinediones; Transcription Factors; Transcription, Genetic; Up-Regulation