Isoflavones and PPAR Signaling: A Critical Target in Cardiovascular, Metastatic, and Metabolic Disease

Figure 5

Regulation of isoflavone-dependent activation of PPAR signaling. Isoflavone consumption has been shown to activate ERβ-, PPARα-, or PPARγ-dependent signaling pathways and in this way may exert control over diverse biological processes that are associated with health benefits of consuming these compounds. Summarized in this figure are the key factors that likely control how isoflavones modulate signaling. The core 7-hydroxy-benzopyran-4-one structure has recently been shown to be important for PPARα and PPARγ activation, and importantly this core is present in many plant-derived isoflavones that comprise natural and commercial preparations (shown are the structures of genistein, daidzein, and biochanin A as examples). Also indicated is the 7-hydroxy group on the A-ring that has been shown to be critical for PPARα and PPARγ activation [13, 14]). Modification of isoflavones, for example, via reactions with inflammatory oxidants can form a variety of halogenated isoflavones which in turn can alter the efficacy of isoflavone-dependent activation of signaling (shown as an example is 3′-chlorodaidzein). Note that multiple positional isomers of chlorine and bromine (other endogenous halogens and nitration products are possible [13, 61–63]. Moreover, gut microflora metabolism has been shown to be important in producing equol from daidzein and may have cardiovascular protective effects. We propose that a better understanding of isoflavone metabolism, the modifications that occur, and how they influence activation of ER/PPAR pathways is central to elucidating molecular mechanisms by which these compounds affect disease. Additional and important factors that will dictate the biological response to isoflavones include expression profiles and relative activities and interactions between of ERβ-, PPARα-, and PPARγ-dependent pathways.