Lipoprotein lipase in fatty acid partitioning

University Of Colorado Denver, Aurora CO

Investigators

Abstract

DESCRIPTION (provided by applicant): Fatty acids are delivered to cells either circulating as free fatty acids (FFA) or esterified in triglycerides (TG) carried by lipoproteins. Lipoproteins interact with lipoprotein lipase (LPL), hydrolyzing their TG and making lipoprotein fatty acids (LPFA) available to cells. It is widely believed that once fatty acids enter cells, regardless of how they are delivered, they enter a common pool which is then partitioned to storage or oxidation based on the metabolic needs of the cell. However, there are examples in the literature that form a basis for hypothesizing that LPL may impact the uptake and metabolic partitioning of LPFA separately from FFA. In the proposed research, the following hypotheses will be tested: 1) By virtue of their interaction with LPL, LPFA are more likely to be esterified and stored as TG, while FFA are more likely to be partitioned toward oxidation. 2) Active LPL on the cell/endothelial surface is essential for this partitioning of LPFA to occur. 3) The partitioning of LPFA is less dependent on the metabolic environment than is the partitioning of FFA. 4) Overexpression of LPL leads to an intracellular TG pool that is not readily mobilized for oxidation. We plan to test these hypotheses utilizing myoblast and mouse models of LPL overexpression. Simultaneously providing separately labeled fatty acids as LPFA and FFA, we will be able to examine the partitioning toward storage or oxidation of each, and how disrupting normal LPL action affects this partitioning. We will also examine how LPL overexpression affects the mobilization of the intracellular TG pool, as stagnancy of this pool is felt to be associated with the development of insulin resistance.