Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 100, Issue 5, Pages 2730-2735Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0538015100
Keywords
-
Categories
Funding
- NHLBI NIH HHS [HL50350, R01 HL050350] Funding Source: Medline
Ask authors/readers for more resources
Increased levels of triglyceride-rich lipoproteins provoke lipid accumulation in the artery wall, triggering early inflammatory responses central to atherosclerosis like endothelial adhesion molecule expression. The endogenous mechanisms limiting such reactions remain poorly defined. Lipoprotein lipase (LPL) plays a central role in lipid metabolism by hydrolyzing triglyceride rich lipoproteins and releasing fatty acids. We found that LPL treatment reversed tumor necrosis factor a and very low-density lipoprotein (VLDL)-stimulated endothelial vascular cell adhesion molecule 1 (VCAM1) induction and VCAM1 promoter responses, thus recapitulating effects reported with synthetic peroxisome proliferator-activated receptor (PPAR) agonists. In fact, these LPL effects on VCAM1 were absent in endothelial cells isolated from PPARalpha-deficient mice. This finding suggests a novel antiinflammatory role for LPL. Further studies reveal specificity for PPAR activation through lipolysis in regards to lipoprotein substrate (VLDL much greater than LDL > HDL), PPAR isoform (PPARalpha much greater than PPARdelta > PPARgamma), and among fatty acid-releasing lipases. These PPAR responses required intact LPL catalytic activity. In vivo, transgenic mice overexpressing LPL had increased peroxisome proliferation, but not in the genetic absence of PPARalpha. Although human plasma possesses minimal PPARalpha activation despite containing abundant free fatty acids, marked PPARalpha activation is seen with human plasma after LPL is added in vitro or systemically released in vivo. These data suggest a previously uncharacterized pathway in which the key lipolytic enzyme LPL can act on circulating lipoproteins to generate PPARalpha ligands, providing a potentially important link between lipoprotein metabolism and distal PPARalpha transcriptional effects.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available