RESUMEN
The mechanism of the hypocholesterolemic action of N-[4-(2-chlorophenyl)-6,7-dimethyl-3-quinolyl]-N'-(2, 4-difluorophenyl) urea (TMP-153), a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was studies in Golden hamsters. TMP-153 (0.5-1.5 mg/kg) dose-dependently reduced plasma total- and low density lipoprotein (LDL)-cholesterol without affecting high density lipoprotein (HDL)-cholesterol. TMP-153 markedly reduced the cholesterol influx into the plasma upon intravenous injection of Triton WR-1339. The compound also decreased cholesterol absorption calculated from dietary intake, biliary secretion and the absorption co-efficient. Hepatic cholesterol secretion was calculated by substracting the cholesterol absorption from the cholesterol influx. In hamsters, the liver accounted for 92% of the cholesterol influx with the remaining 8% coming from the intestine, and both were markedly decreased by TMP-153. Thus, it is likely that TMP-153 lowers plasma cholesterol through its hepatic action. In the liver, the compound significantly reduced the unesterified cholesterol content in addition to markedly reducing the content of esterified cholesterol. In accordance with this reduction, the half-life time of [125I]-LDL was significantly shortened by the compound, suggesting an increase in LDL receptors. However, the hepatic cholesterogenesis from [14C]acetate was decreased by TMP-153 treatment. This effect seems to be secondary, since the compound did not inhibit cholesterogenesis from [14C]acetate in HepG2 cells. From the data described above, the contribution of hepatic secretion and intestinal absorption of cholesterol to the plasma cholesterol level in Golden hamsters are discussed.
Asunto(s)
Anticolesterolemiantes/farmacología , Colesterol/sangre , Hígado/metabolismo , Compuestos de Fenilurea/farmacología , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Células Cultivadas , Colesterol/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Cricetinae , Relación Dosis-Respuesta a Droga , Esterificación , Absorción Intestinal , Hígado/efectos de los fármacos , Lovastatina/farmacología , Masculino , Mesocricetus , Polietilenglicoles/farmacologíaRESUMEN
Recognition of the exposure of phosphatidylserine (PS) on the outer surface of plasma membrane has been implicated in the phagocytosis of aged/apoptotic cells. Because oxidized low-density lipoprotein (OxLDL) has been reported to block the phagocytosis, here we examined whether lectin-like OxLDL receptor 1 (LOX-1), the OxLDL receptor in endothelial cells, mediates phagocytosis of aged/apoptotic cells by endothelial cells. Cultured bovine aortic endothelial cells (BAE) and Chinese hamster ovary (CHO) cells expressing bovine LOX-1 (BLOX-1-CHO), but not wild-type CHO-K1 cells, bound aged red blood cells (RBC) and apoptotic cells, which were further phagocytosed. The binding of aged RBC and the phagocytosis of apoptotic cells were inhibited by OxLDL, acetyl LDL, and other LOX-1 ligands in both BAE and BLOX-1-CHO. mAb against LOX-1 blocked the binding of aged RBC to BAE, suggesting a role for LOX-1 in the recognition of aged cells. The recombinant soluble LOX-1 inhibited the interactions of aged/apoptotic cells with both BLOX-1-CHO and BAE and distinguished aged RBC from native RBC and apoptotic cells from native cells. PS liposome inhibited these LOX-1-mediated interactions with aged/apoptotic cells, suggesting LOX-1 recognizes PS of the apoptotic cells. PS exposed on the surface of apoptotic cells is known to be procoagulant. Accordingly, increased OxLDL may be one of the reasons for enhanced coagulation in atherosclerosis, inhibiting the removal of apoptotic cells.