Lipid homeostasis and inflammation are key determinants in atherogenesis, exemplified by the requirement of lipid-laden, foam cell macrophages for atherosclerotic lesion formation. Although the nuclear receptor PPAR␦ has been implicated in both systemic lipid metabolism and macrophage inflammation, its role as a therapeutic target in vascular disease is unclear. We show here that orally active PPAR␦ agonists significantly reduce atherosclerosis in apoE ؊/؊ mice. Metabolic and gene expression studies reveal that PPAR␦ attenuates lesion progression through its HDLraising effect and anti-inflammatory activity within the vessel wall, where it suppresses chemoattractant signaling by downregulation of chemokines. Activation of PPAR␦ also induces the expression of regulator of G protein signaling (RGS) genes, which are implicated in blocking the signal transduction of chemokine receptors. Consistent with this, PPAR␦ ligands repress monocyte transmigration and macrophage inflammatory responses elicited by atherogenic cytokines. These results reveal that PPAR␦ antagonizes multiple proinflammatory pathways and suggest PPAR␦-selective drugs as candidate therapeutics for atherosclerosis.inflammation ͉ ligand ͉ mouse ͉ nuclear ͉ receptor

Three new scalarane-based sesterterpenes, 1- 3, were isolated from a marine sponge of the genus Spongia, and their chemical structures were elucidated by analysis of HRMS and 2-D NMR spectra. The isolated compounds 1 and 3 showed inhibition against the farnesoid X-activated receptor (FXR) with IC50 values of 2.4 and 24 microM, respectively. In particular, compound 3 directly inhibited the interaction between FXR and a coactivator peptide (SRC-1) as determined by surface plasmon resonance (SPR) spectroscopy.

One isoprenoid, tuberatolide A (1), meroterpenoids tuberatolide B (2) and 2'-epi-tuberatolide B (3), and the known meroterpenoids yezoquinolide (4), (R)-sargachromenol (5), and (S)-sargachromenol (6) were isolated from the Korean marine tunicate Botryllus tuberatus. The structures of these compounds were elucidated by NMR, MS, and CD spectroscopic analyses. These terpenoids antagonized the chenodeoxycholic acid (CDCA)-activated human farnesoid X receptor (hFXR) in a cell-based co-transfection assay with IC(50) values as low as 1.5 μM without significant effect on steroid receptors. Furthermore, they released the co-activator peptide from the CDCA-bound hFXR ligand binding domain in cell-free surface plasmon resonance experiments.