Effect of Gemfibrozil on Serum Glycosylphosphatidylinositol (GPI) Phospholipase D and Triglycerides
Condition: Hypertriglyceridemia
MeSH terms: Hypertriglyceridemia
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to examine the role of glycosylphosphatidylinositol-specific
      phospholipase D (GPI-PLD) in triglyceride metabolism.
    

Detailed description: 
      Increased fasting serum triglyceride levels are associated with an increased risk of coronary
      artery disease. However, triglyceride levels in the postprandial state are a more sensitive
      marker of coronary artery disease. Postprandial elevations in triglycerides result from a
      decrease in the catabolism of triglyceride-rich lipoproteins, i.e. chylomicrons and very low
      density lipoproteins (VLDL). This leads to an accumulation of atherogenic remnants of
      triglyceride-rich lipoproteins. Although fasting triglycerides are the best predictors of
      postprandial triglycerides, differences in fasting triglycerides only partially account for
      the variation in magnitude of postprandial triglycerides. Recently, we have identified a new
      protein involved in triglyceride-rich lipoprotein catabolism,
      glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD). We have shown that elevated
      levels of GPI-PLD are associated with increased fasting triglyceride levels. Serum GPI-PLD is
      associated with high density lipoproteins (HDL) in the fasting state and exchange onto VLDL
      in the postprandial state. Hepatic GPI-PLD decreases triglyceride-rich lipoprotein catabolism
      in the liver. Hepatic and serum GPI-PLD levels are decreased by peroxisome proliferator
      receptor (PPAR) alpha agonist treatment, which also reduces fasting and postprandial
      triglycerides. The central hypothesis of this application is that variations in GPI-PLD
      expression account for a portion of the differences in fasting and postprandial triglycerides
      among humans.

      The objective of this proposal is to determine the role of GPI-PLD in regulating fasting
      triglycerides and post-prandial hypertriglyceridemia in humans. This will be accomplished by
      conducting a double blind, placebo controlled study in humans examining the effect of
      gemfibrozil on fasting and postprandial triglycerides in relationship to the variation and
      changes in GPI-PLD before and after gemfibrozil.

      Our specific objectives are:

        -  1a) Determine the extent to which variations in GPI-PLD account for differences in
           fasting and postprandial triglycerides

        -  1b) Establish the degree to which the lowering of fasting and postprandial triglycerides
           by gemfibrozil is accounted for by changes in GPI-PLD.

        -  2) Quantify the changes in serum GPI-PLD and distribution of GPI-PLD among lipoproteins
           in the postprandial state.

      This will be the first prospective bench-to-bedside study examining the role of GPI-PLD in
      triglyceride metabolism. This proposal will be the first in humans examining 1) the role of a
      novel protein, GPI-PLD, in triglyceride metabolism, and 2) the effect of gemfibrozil, a drug
      currently used clinically to lower triglyceride levels, on GPI-PLD levels in humans. It is
      expected that the results from this study will increase our understanding of triglyceride
      metabolism and develop new information in understanding the regulation of GPI-PLD and its
      relationship to triglyceride metabolism.
    

Intervention name(s): Gemfibrozil
Intervention type(s): Drug
Intervention MeSH terms: Gemfibrozil
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double
Primary purpose: Treatment
Keywords: hypertriglyceridemia; lipoproteins; triglycerides; serum GPI-PLD (glycosylphosphatidylinositol-specific phospholipase D)