Abstract 9805: Lack of Correlation Between HDL Level and Fecal Cholesterol in Multiple Mouse Models Suggests Importance of HDL Functionality in Atherosclerosis Attenuation
To circumvent the residual cardiovascular disease burden in patients receiving statin therapy, HDL-raising was suggested as a plausible approach. However, lack of benefits of CETP inhibitors, Torcetrapib and Dalcetrapib, despite substantial increase in HDL, and lack of efficacy of CER-001, an apoA-I mimetic, proved disappointing. Paradoxically, apoA-I Milano subjects with low HDL have reduced CVD risk. These findings shifted the focus from HDL level to HDL function. Promoting reverse cholesterol transport (RCT) is one of the main functions of HDL, which is measured in an in vivo assay as macrophage-derived fecal 3H-cholesterol. Non-radioisotopic method to quantitate fecal cholesterol (chol) as an RCT index was found to correlate with macrophage radioisotopic method in mice. Using this method, we carried out a number of studies in several mouse models, including C57Bl, apoA-I-Tg, LDLr KO, and ob/ob, using tool compounds, LXR and PPAR-α agonists, known to enhance RCT. Animals were treated with LXR and PPAR-α agonists alone or in combination, and lipid profile, HDL level, serum chol efflux, fecal chol, and, in appropriate animal models, aortic lipid contents were measured. In C57Bl mice, LXR agonist, T1317, raised HDL by 30%, while feno decreased HDL by 30%, but fecal chol showed a 2-fold increase in both cases. Interestingly, combination (comb) treatment with LXR and PPAR-α agonists did not change HDL, but fecal chol increased by 4.5-fold. HDL in apoA-I-Tg mice increased by 40%, 80%, and 80% in LXR, PPAR-α, and comb treated groups; respective fecal chol increases were 1.8, 1.8, and 5-fold, suggesting a lack of correlation between HDL level and fecal chol. LXR, PPAR-α, and comb-treated ob/ob mice showed 40%, 35%, and 40% rise in HDL, but 3-, 3-, and 20-fold increases in fecal chol, respectively. No correlations in HDL level and fecal chol contents were noticed in LDLr KO mice as well. Atherosclerosis attenuation by LXR and PPAR-α agonists in LDLr KO and ob.ob/LDLr DKO mice was associated with increased fecal chol, but not HDL level. These data suggest: a) a lack of correlation between HDL level and fecal chol; b) synergistic effect of LXR and PPAR-α agonists on RCT; c) reduced lesion area associated with increased fecal chol; and d) RCT influenced by additional mechanisms.
Author Disclosures: R.K. Srivastava: Employment; Modest; 25%. Ownership Interest; Modest; 25%. A.B. Cefalu: None. D. Noto: None. D. Panno: None. A. Giammanco: None. M.R. Averna: None.
- © 2015 by American Heart Association, Inc.