Lipoprotein ig proteinml

Fig. 2. Lipoprotein lipase (LPL) as a mechanism for peroxisome proliferator-activated receptor (PPAR) ligand generation. Endogenous PPAR agonists are generated through the action of LPL on triglyceride-rich lipoproteins (79,80). (A) LPL treatment of various lipoproteins activates PPAR ligand-binding domains (LBDs) in an isoform specific manner. Concentration-dependent activation of PPAR-a-LBD by various lipoproteins in the presence or absence of LPL (30 U/mL) are shown. Endothelial cells (ECs) co-transfected with a PPAR-a-LBD, a luciferase reporter construct (pUASx4-TK-luc), and a p-galactosidase construct for normalization control and stimulated with increasing amounts of isolated human lipoproteins as shown; for comparison, PPAR-a-LBD activation by fenofibric acid (100 |M) was 16.2 ± 1.3-fold (33). (B) The PPAR LBD assays shown in (A) demonstrate the presence of a PPAR activator but not a PPAR ligand (i.e., a molecule that binds directly to the receptor). Ligand status can be determined through the use of various other assays, including displacement of known high-affinity PPAR radioligands from expressed PPAR proteins. Such experiments establish LPL-mediated PPAR ligand generation as shown (79). We find LPL action on very low-density lipoprotein preferentially generates PPAR-a ligands (79), although cellular responses may vary depending on many factors, including levels of different PPAR isoforms in a given cell type (80).

different cells and tissues. Although we observed LPL acted on VLDL to preferentially generate PPAR-a ligands, Evans and colleagues reported LPL-treatment of VLDL leads to PPAR-8 activation in macrophages (80). Of note, mouse macrophages may have relatively low levels of PPAR-a, which may contribute to the greater PPAR-8 response seen (81,82). Lipolytic PPAR activation may also be specific in regard to different lipases and specific fatty acids. For example, we found that other lipases, like phospholipases D, C, A2, failed to activate PPAR-a despite releasing equivalent amounts of fatty acids as LPL (24). Presumably this is as a result of the release of different fatty acids, as determined by both the lipase and the composition of different lipoprotein substrates.

Interestingly, LPL action also replicated the effects of synthetic PPAR-a agonists on inflammation, decreasing VCAM-1 expression in a PPAR-a-dependent manner (58,79). This data suggests a novel anti-inflammatory role for LPL, a mechanism that could explain the protection against atherosclerosis enjoyed by individuals with intact, efficient lipolytic pathways (i.e., individuals with normal triglyceride and higher HDL levels). Interestingly, extensive data establishes that patients with DM typically have elevated free fatty acids (83). Other lines of well-done and carefully executed studies indicate that LPL overexpression in muscle induces insulin resistance (84,85). Several possibilities might help reconcile these two sets of data. First, fatty acids are often referred to in a generic sense when, in fact, great differences exist between various fatty acids, for example ranging from the responses to omega-3 fatty acids, with their likely cardioprotective effects, to saturated fatty acids and their reported pro-atherosclerotic effects (86,87). Thus, the elevated fatty acids in the circulation of patients with diabetes may differ from fatty acids produced by LPL, a significant percentage of which would be taken up by tissues as opposed to being present in the circulation. Moreover, these elevated fatty acids arise not out of the physiological function of LPL but rather abnormal metabolism. The DM seen in animal models overexpressing LPL in skeletal muscle is also associated with massive accumulation of triglycerides in these tissues (88). Thus, the important observations from these experiments may not necessarily be a result of intact physiologic LPL action. Indeed, humans with LPL mutations that confer a gain of LPL function are associated with lower triglyceride levels, higher HDL, and apparent protection against atherosclerosis (89). The exciting recent observations regarding the role of mitochondria as the main site of fatty acid oxidation in humans by Shulman and colleagues will only add new insight into the role of fatty acids in determining biological responses (90-92).


The intense interest in PPARs as therapeutic targets is not surprising. PPARs are at the crossroads of metabolism, inflammation, and atherosclerosis, and suggest the possibility of modulating responses in all these pathways. The overwhelming impact abnormal metabolism—obesity, DM, dyslipidemia—is having in general, especially in terms of atherosclerosis, only heightens this interest. Moreover, PPARs, as transcription factors, raise the tantalizing prospect that PPAR ligands might achieve their effects by determining gene expression. Finally, the existence of PPAR ligands already in clinical use provides an established track that pharmaceutical and biotechnology concerns can hope to follow in bringing new agonists to market. Whether or not PPAR activation limits inflammation and atherosclerosis remains to be established; certainly the evidence to date supports the ongoing research examining the metabolic and cardiovascular effects of those PPAR agonists already approved and those in development.

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