Abstract 482: Peroxisome Proliferator-Activated Receptor α Modulation with Fenofibrate Does Not Alter the Clinical or Inflammatory Responses to Evoked Endotoxemia in Humans
Introduction: Inflammation plays a crucial role in the pathophysiology of cardiometabolic disease. Some experimental data and clinical trials suggest that PPAR-α activation and fibrate therapy suppress inflammation in humans, potentially promoting anti-atherogenic actions. Human experimental endotoxemia provides a controlled model for the study of atherogenic inflammatory responses and their modulation in vivo. We hypothesized that fenofibrate would suppress the inflammatory responses to endotoxin (LPS) in healthy humans.
Methods: In the Fenofibrate and Omega-3 Fatty Acid Modulation of Endotoxemia study, 36 healthy volunteers (mean age 26 ± 7 years; mean BMI 24 ± 3 kg/m2; 56% male; 72% Caucasian, 19% African, 8% Asian ancestry) were randomized to fenofibrate 145 mg or placebo daily. After 8 weeks of treatment, subjects underwent a low-dose LPS challenge (0.6 ng/kg intravenous bolus). Anthropometric, clinical, and blood measures were collected at baseline, pre-LPS, and serially for 24 hours after LPS exposure.
Results: Compared to placebo, fenofibrate reduced total cholesterol (170 ± 35 to 137 ± 31 mg/dL, p=0.009) and tended to decrease triglycerides (78 ± 40 to 57 ± 23 mg/dL, p=0.611) prior to LPS. LPS induced a modest clinical response with increased temperature, heart rate, and blood pressure (p<0.001 for all). Cytokines and chemokines increased significantly, peaking 2 to 4 hours post-LPS (TNFα 12-fold, IL-6 13-fold, IL-10 9-fold, MCP-1 10-fold; p<0.001 for all). Acute phase reactants also increased, peaking at 24 hours (serum amyloid A (SAA) 14-fold, C-reactive protein (CRP) 9-fold; both p<0.001). Compared to placebo, fenofibrate had no effect on LPS-induced clinical responses, cytokine or chemokine release as measured by peak response or area under the curve (AUC). Fenofibrate also had no effect on plasma CRP or lipid parameters following LPS. Although peak SAA and SAA AUC tended to be lower with fenofibrate vs. placebo, the differences were not statistically significant (p=0.08 for both).
Conclusions: PPAR-α modulation with fenofibrate did not attenuate clinical or inflammatory responses during low-grade human endotoxemia. These data suggest the anti-inflammatory properties of fenofibrate at clinically-relevant dosing are limited.
- © 2012 by American Heart Association, Inc.