Lipoprotein lipase (LPL) is the rate-limiting enzyme in the hydrolysis of serum triglycerides associated with the lipoprotein particles VLDL and chylomicrons. Patients with lowered levels of LPL, as seen in Type 2 diabetes mellitus and insulin resistance exhibit hypertriglyceridemia, often associated with vascular complications and coronary artery disease. The cell biology of LPL is complex. It functions while tethered to the extracellular matrix of the capillary endothelium. LPL is synthesized, however, in the adipocytes or muscle cells subtending the endothelium. Thus, after synthesis in and release by the parenchymal cell, LPL must move through/across the endothelial cell (EC) monolayer before expression at its physiologically relevant location. The expression of LPL is regulated by insulin, but muscle and adipose respond differently. Upon acute stimulation with insulin, LPL levels increase in adipose, but decrease in muscle. Under conditions of insulin resistance, LPL levels in adipose are depressed, but muscle levels are unchanged. It is unknown how the transit of LPL from the parenchymal cell to the luminal surface of the EC is regulated, either upon acute insulin stimulation, or under conditions of insulin resistance. Preliminary data indicate that acute insulin stimulation of ECs isolated from adipose tissue results in the rapid and transient release of a factor which subsequently stimulates the release of LPL from intact adipocytes. The long-term hypothesis of this work is that the primary locus for the insulin-regulated expression of LPL is the EC, and tissue specific differences in the expression of LPL and modified expression in insulin resistant states is attributable to changes in the insulin responsiveness of the EC. The short-term goal of this project is to characterize the factor released from the EC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK058083-02
Application #
6622819
Study Section
Metabolism Study Section (MET)
Program Officer
Blondel, Olivier
Project Start
2002-05-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2003
Total Cost
$148,666
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225