Submitted on December 15, 2004
Accepted on October 4, 2005
Glycosylphosphatidylinositol-specific phospholipase D influences triglyceride-rich lipoprotein metabolism
Nandita S Raikwar1, Won Kyoo Cho2, Rosario F Bowen1, and Mark A Deeg3*
1 Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
2 Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Veterans Affairs, Roudebush VAMC, Indianapolis, IN, USA
3 Departments of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Veterans Affairs, Roudebush VAMC, Indianapolis, IN, USA
* To whom correspondence should be addressed. E-mail: mdeeg{at}iupui.edu.
Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is a minor high-density lipoprotein (HDL)-associated protein. Since many minor HDL-associated proteins exchange between different lipoprotein classes during the post-prandial state and are also involved in triglyceride metabolism, we hypothesized that GPI-PLD may play a role in the metabolism of triglyceride-rich lipoproteins. To test this hypothesis, we examined the distribution of GPI-PLD among lipoprotein classes during a fat tolerance test in C57BL/6 and low-density lipoprotein receptor (LDLR)-/- mice fed either a chow or high-fructose diet. In the fasting state in wild-type mice fed a chow diet, GPI-PLD was only present on HDL whereas in LDLR-/- mice, GPI-PLD was present in HDL and intermediate-density lipoproteins (IDL)/LDL. During the fat tolerance test, there was no change in total serum GPI-PLD levels in either model; however, a significant amount of GPI-PLD appeared in both very low-density lipoproteins (VLDL) (0.5-1% of total GPI-PLD) and IDL/LDL (5-10% of total GPI-PLD) in both models. The high-fructose diet increased both fasting and post-prandial triglycerides and serum GPI-PLD levels in both strains as well as the amount of GPI-PLD in VLDL. To determine if GPI-PLD plays a direct role in triglyceride metabolism, we increased liver GPI-PLD expression in C57BL/6 mice using adenovirus-mediated gene transfer which resulted in a 7-fold increase in serum GPI-PLD levels. This change was associated with an increase in fasting (30%) and post-prandial triglycerides (50%) and a 2-fold reduction in triglyceride-rich lipoprotein catabolism compared to saline or control adenovirus-treated mice. These studies demonstrate that GPI-PLD affects serum triglyceride levels by altering catabolism of triglyceride-rich lipoproteins.
