Killer lipases and phat functions tied to atherosclerosis

Dietary and de novo synthesized lipids that are transported through the bloodstream by lipoproteins are subjected to hydrolysis by the extracellular lipases lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL). The products of hydrolysis are typically used by tissues for energy via oxidation, integration into cell membranes, and even intracellular signalling. However, the levels of LPL, HL, and EL in vivo at their various sites of expression are believed to be either protective or detrimental in atherosclerosis. Macrophages in atherosclerotic lesions highly express LPL and EL; previous studies have shown that macrophage LPL directly promotes lesion development in vivo, but the mechanisms behind lesion development by LPL (and possibly EL) are unknown. Using human THP-1 macrophages, our laboratory has identified a transcriptional regulator and signalling molecules previously linked to processes in atherosclerosis development, that are affected by extracellular lipoprotein hydrolysis products. Mass spectrometric analyses of hydrolysis products have revealed candidate lipids that may be responsible for modulating signalling. To possibly combat the processes associated with atherosclerotic lesion development, our laboratory is developing a novel method to affect HL levels in the bloodstream that could generate more HDL precursors and reduce atherosclerosis progression. Our laboratory's work will ultimately identify targets associated with extracellular lipases that may be modulated in conjunction with existing treatments to slow or reduce the rate atherosclerosis development.