A NOVEL COMPOUND THAT ELEVATES HIGH-DENSITY-LIPOPROTEIN AND ACTIVATESTHE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR

In the current studies we describe the effects of PD 72953 and related compounds on lipoprotein levels in chow fed male rats. After 2 weeks, 10 mg/kg of PD 72953 daily was as effective as 100 mg/kg gemfibrozil for elevating HDL cholesterol. At 100 mg/kg, PD 72953 further elevated HDL cholesterol to 232% of control levels, and was associated with in creased HDL size and plasma apoE (169% of control), despite no change in hepatic apoE mRNA. ApoA-I rose transiently (at 1 week), but by 2 we eks only apoE remained elevated. PD 72953 dose-dependently reduced pla sma apoB, VLDL-cholesterol, LDL-cholesterol, and triglyceride. Hepatic apoC-III mRNA reduction parallelled triglyceride lowering. After 1 we ek, 30 and 100 mg/kg per day PD 72953 reduced plasma apoC-III levels b y 30 and 34%, and triglycerides by 60 and 83%, respectively. PD 72953 treatment had no effect on triglyceride production rates; however, I-1 25-labeled VLDL apoB disappearance was enhanced. We compared PD 72953 to a structurally similary diacid, PD 69405, that also reduced VLDL an d LDL, but had no effect on HDL elevation. Compared to PD 72953, PD 69 405 further accelerated I-125-labeled VLDL apoB disappearance, decreas ed triglyceride production, and elevated the ratio of post-heparin hep atic to lipoprotein lipase activity. Whole animal studies, transient t ransfection studies in HepG2 cells, and chimeric receptor studies in k idney 293 cells suggest that PD 72953 is a ligand for the peroxisomal proliferation activated receptor alpha (PPAR alpha), and PPAR gamma. O verall, PD 72953 may act through a peroxisomal proliferation activated receptor and result in plasma triglycerides and apoB-containing lipop rotein reduction, while also raising HDL cholesterol. Reduced apoC-III may allow triglyceride-rich remnants to more efficiently bind and pre sent substrate to peripheral tissue lipoprotein lipase, and therefore allow enhanced shedding of remnant phospholipid surface for HDL produc tion.