A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor

In the current studies we describe the effects of PD 72953 and related compounds on lipoprotein levels in chowfed male rats. After 2 weeks, 10 mg/kg of PD 72953 daily was as effective as 100 mg/kg gemfibrozil for elevating HDLcholesterol. At 100 mg/kg, PD 72953 further elevated HDLcholesterol to 232% of control levels, and was associated with increased 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 weeks only apoE remained elevated. PD 72953 dose-dependently reduced plasma apoB, VLDL-cholesterol, LDL-cholesterol, and triglyceride. Hepatic apoC-III mRNA reduction parallelled triglyceride lowering. After 1 week, 30 and 100 mg/kg per day PD 72953 reduced plasma apoC-III levels by 30 and 34%, and triglycerides by 60 and 83%, respectively. PD 72953 treatment had no effect on triglyceride production rates; however, 125 I-labeled VLDL apoB disappearance was enhanced. We compared PD 72953 to a structurally similary diacid, PD 69405, that also reduced VLDL and LDL, but had no effect on HDL elevation. Compared to PD 72953, PD 69405 further accelerated 125 I-labeled VLDL apoB disappearance, decreased triglyceride production, and elevated the ratio of post-heparin hepatic to lipoprotein lipase activity. Whole animal studies, transient transfection studies in HepG2 cells, and chimeric receptor studies in kidney 293 cells suggest that PD 72953 is a ligand for the peroxisomal proliferation activated receptor alpha (PPAR a ), and PPAR g . Overall, PD 72953 may act through a peroxisomal proliferation activated receptor and result in plasma triglycerides and apoB-containing lipoprotein reduction, while also raising HDL cholesterol. Reduced apoC-III may allow triglyceride-rich remnants to more efficiently bind and present substrate to peripheral tissue lipoprotein lipase, and therefore allow enhanced shedding of remnant phospholipid surface for HDL production.— Bisgaier, C. L., A. D. Essenburg, B. C. Barnett, B. J. Auerbach, S. Haubenwallner, T. Leff, A. D. White, P. Creger, M. E. Pape, T. J. Rea, and R. S. Newton. A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor. J. Lipid Res. 1998. 39: 17–30. Supplementary key words PD72953 • apoC-III • triglyceride • gemfibrozil • HepG2 cells • fibrates • lipoproteins Fibric acids are generally indicated for the treatment of hypertriglyceridemia (1–3); however, these compounds have variable effects on HDL apolipoprotein and cholesterol elevation. These compounds may mimic the natural ligands for nuclear receptors that act through peroxisomal proliferation response elements (PPREs) that are present on a variety of genes associated with peroxisomal enzymes, lipoprotein metabolizing enzymes, and apolipoproteins, including apoC-III which appears to be downregulated by fibrates (4–6) and MEDICA 16 (7). In comparative studies of select fibrates in chow-fed (5, 8) and cholesterol-fed (8, 9) male rats, it was previously observed that gemfibrozil, unlike the other fibrates tested at similar doses, caused an elevation of HDL cholesterol and particle size and was associated with apoE elevation. The plasma elevation of apoE occurred despite no change in its hepatic mRNA levels (5, 10), which suggested increased synthesis at extrahepatic sites or a decreased catabolism of this protein from plasma. Abbreviations: ACO, acyl CoA oxidase; ANOVA, analysis of variance; apo, apolipoprotein; CMC/Tween, 1.5% carboxymethylcellulose plus 0.2% Tween-20; CMV, cytomegalovirus; EPA, eicosapentaenoic acid; FBS, fetal bovine serum; gal, b -galactosidase; HDL, high density lipoprotein; HL, hepatic lipase; HPGC, high performance gel filtration chromatography; HSV, herpes simplex virus; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; LPL, lipoprotein lipase; MEM, minimum essenial media; PHLA, post-heparin lipolytic activity; PPAR, peroxisome proliferator activated receptor; PPRE, peroxisomal proleferation response elements; VLDL, very low density lipoprotein. 1 To whom correspondence should be addressed.