A number of clinical findings suggested HDL-raising as a plausible approach to treat residual risk of CVD. However, lack of CVD risk reduction by elevated HDL cholesterol (HDL-C) through cholesterol ester transfer protein (CETP) inhibition and enhanced risk reduction in apolipoprotein A-I Milano (apoAI-M) individuals with low HDL-C shifted the focus from HDL-C level to HDL function. In the present study, we investigated correlations between HDL-C, HDL function, fecal cholesterol excretion, and ex vivo plasma cholesterol efflux capacity (CEC) in animal models using two HDL modulators, LXR and PPAR-α agonists. In C57Bl mice, LXR agonist, T1317, raised HDL-C by 30%, while PPAR-α agonist, fenofibrate, reduced HDL-C by 30%, but fecal cholesterol showed twofold increase in both cases. CEC showed a 30–40% increase. Combination of LXR and PPAR-α agonists showed no changes in HDL-C, but, interestingly, fecal cholesterol increased by 4.5-fold, and CEC by 40%, suggesting existence of additional pathway for fecal cholesterol excretion. Regression analysis showed a lack of correlation between HDL-C and fecal cholesterol and CEC, while fecal cholesterol showed significant correlation with CEC, a measure of HDL function. ABCA1 and G1, the two important players in RCT showed greater induction with LXR agonist than PPAR-α agonist. HDL-C increased by 40 and 80% in LXR and PPAR-α treated apoA-I transgenic mice, respectively, with 80% increase in fecal cholesterol. A fivefold increase in fecal cholesterol with no correlation with either plasma HDL-C or CEC following co-treatment with LXR and PPAR-α agonists suggested existence of an HDL-independent pathway for body cholesterol elimination. In hyperlipidemic diabetic ob/ob mice also combination of LXR and PPAR-α agonists showed marked increases in fecal cholesterol content (10–20-fold), while HDL-C rise was only 40%, further suggesting HDL-independent elimination of body cholesterol in mice treated with combination of LXR and PPAR-α agonists. Atherosclerosis attenuation by LXR and PPAR-α agonists in LDLr-deficient mice was associated with increased fecal cholesterol, but not HDL-C. However, fecal cholesterol counts showed inverse correlation with aortic cholesteryl ester content. These data suggest: (a) lack of correlation between HDL-C and fecal or aortic cholesterol content; (b) HDL function (CEC) correlated with fecal cholesterol content; (c) association of reduced aortic lipids in LDLr−/− mice with increased fecal cholesterol, but not with HDL-C, and (d) existence of an HDL-independent pathway for fecal cholesterol excretion following co-treatment with LXR and PPAR-α agonists.

Srivastava, N., Cefalu, A.B., Averna, M., Srivastava, R.A.K. (2018). Lack of Correlation of Plasma HDL With Fecal Cholesterol and Plasma Cholesterol Efflux Capacity Suggests Importance of HDL Functionality in Attenuation of Atherosclerosis. FRONTIERS IN PHYSIOLOGY, 9 [10.3389/fphys.2018.01222].

Lack of Correlation of Plasma HDL With Fecal Cholesterol and Plasma Cholesterol Efflux Capacity Suggests Importance of HDL Functionality in Attenuation of Atherosclerosis

Srivastava, Neelam
Writing – Original Draft Preparation
;
Cefalu, Angelo B.
Methodology
;
Averna, Maurizio
Writing – Review & Editing
;
2018-01-01

Abstract

A number of clinical findings suggested HDL-raising as a plausible approach to treat residual risk of CVD. However, lack of CVD risk reduction by elevated HDL cholesterol (HDL-C) through cholesterol ester transfer protein (CETP) inhibition and enhanced risk reduction in apolipoprotein A-I Milano (apoAI-M) individuals with low HDL-C shifted the focus from HDL-C level to HDL function. In the present study, we investigated correlations between HDL-C, HDL function, fecal cholesterol excretion, and ex vivo plasma cholesterol efflux capacity (CEC) in animal models using two HDL modulators, LXR and PPAR-α agonists. In C57Bl mice, LXR agonist, T1317, raised HDL-C by 30%, while PPAR-α agonist, fenofibrate, reduced HDL-C by 30%, but fecal cholesterol showed twofold increase in both cases. CEC showed a 30–40% increase. Combination of LXR and PPAR-α agonists showed no changes in HDL-C, but, interestingly, fecal cholesterol increased by 4.5-fold, and CEC by 40%, suggesting existence of additional pathway for fecal cholesterol excretion. Regression analysis showed a lack of correlation between HDL-C and fecal cholesterol and CEC, while fecal cholesterol showed significant correlation with CEC, a measure of HDL function. ABCA1 and G1, the two important players in RCT showed greater induction with LXR agonist than PPAR-α agonist. HDL-C increased by 40 and 80% in LXR and PPAR-α treated apoA-I transgenic mice, respectively, with 80% increase in fecal cholesterol. A fivefold increase in fecal cholesterol with no correlation with either plasma HDL-C or CEC following co-treatment with LXR and PPAR-α agonists suggested existence of an HDL-independent pathway for body cholesterol elimination. In hyperlipidemic diabetic ob/ob mice also combination of LXR and PPAR-α agonists showed marked increases in fecal cholesterol content (10–20-fold), while HDL-C rise was only 40%, further suggesting HDL-independent elimination of body cholesterol in mice treated with combination of LXR and PPAR-α agonists. Atherosclerosis attenuation by LXR and PPAR-α agonists in LDLr-deficient mice was associated with increased fecal cholesterol, but not HDL-C. However, fecal cholesterol counts showed inverse correlation with aortic cholesteryl ester content. These data suggest: (a) lack of correlation between HDL-C and fecal or aortic cholesterol content; (b) HDL function (CEC) correlated with fecal cholesterol content; (c) association of reduced aortic lipids in LDLr−/− mice with increased fecal cholesterol, but not with HDL-C, and (d) existence of an HDL-independent pathway for fecal cholesterol excretion following co-treatment with LXR and PPAR-α agonists.
2018
Srivastava, N., Cefalu, A.B., Averna, M., Srivastava, R.A.K. (2018). Lack of Correlation of Plasma HDL With Fecal Cholesterol and Plasma Cholesterol Efflux Capacity Suggests Importance of HDL Functionality in Attenuation of Atherosclerosis. FRONTIERS IN PHYSIOLOGY, 9 [10.3389/fphys.2018.01222].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/299035
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