The metabolic benefits seen with synthetic PPAR agonists frame a key biological question: what does the body make to activate these receptors? Presumably, such molecules might replicate the effects of synthetic PPAR drugs, possibly protecting individuals from diabetes mellitus, dyslipidemia, and/or atherosclerosis. Early studies into endogenous PPAR agonists focused mainly on specific candidate molecules.
Oxidized linoleic acid in the form of 9 or 13 hydroxyoctadecanoic acid (HODE) appears to activate PPAR-y (65), although it also has PPAR-a activity as well (58). The prostaglandin metabolite 15-deoxy-D12, 14-prostaglandin J2 (15d-PGJ2) (66,67) reportedly activates PPAR-y agonist, although it can also act on IkB kinase and is of unclear physiologic significance (68,69). The greater biological effects seen with 15d-PGJ2 despite its lower PPAR-y binding affinity may result from its PPAR-independent effects on IkB kinase (68,70). Oxidized linoleic acid (HODE) is generated by 15 lipoxygenase (71) and activates PPAR-y and -a (32,58,72). Leukotriene B4 may be an endogenous PPAR-a ligand that terminates inflammation (73).
The identity of endogenous PPAR-a ligands has also been investigated. Early landmark experiments reported that certain fatty acids could activate PPARs, a great advance in the field (74-76). However, the physiological significance of those important observations was less clear, because the fatty acid effects seen required high concentrations of fatty acids (100-300 mM) and were not tested in vivo. Moreover, the link between endogenous lipid metabolism and subsequent PPAR activation remained obscure as did the mechanisms that might underlie selective PPAR isoform activation by natural ligands-like fatty acids. Given that PPAR isoforms are differentially regulated, it seems unlikely that endogenous PPAR activation is indiscriminate as to PPAR isotype. Recent work has continued to advance insight into endogenous PPAR activation. Mclntyre and colleagues reported that lysophosphatidic acid could bind to and activate PPAR-y (77). Very recently, oleylethanolamide, a fatty acid analogue, was found to regulate feeding by activating PPAR-a (78).
An alternative approach to understanding PPAR agonists is to investigate not specific candidate molecules but rather pathways that might lead to the generation of PPAR ligands. Through such studies, insight might be gained into PPAR function under more physiological conditions, connect pathways of lipid metabolism to PPAR activation, and perhaps account for selective PPAR responses. Recently, we and others have established that lipoprotein lipase (LPL), the primary enzyme in triglyceride metabolism, acts on triglyceride-rich lipoproteins like very low-density lipoprotein (VLDL) to generate PPAR ligands (79,80). These effects depended on intact LPL catalytic activity and were absent in response to LPL's known noncatalytic lipid uptake (79). Moreover, these studies revealed striking specificity in regards to lipid substrate (VLDL>>LDL>HDL) (Fig. 2). LPL hydrolysis may also explain selective PPAR activation, perhaps as a function of
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