Changes in gene expression

Fatty acids, especially PUFAs, are known to modulate the expression of a variety of genes coding for key regulatory proteins in numerous metabolic pathways in hepatocytes and adipocytes (Clarke and Jump, 1994). These effects are mediated by both indirect mechanisms (e.g. by eicosanoids, hor-

Arachidonic acid EPA

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Inflammation and immunity

  1. 4.9. Theoretical basis for the immunoregulatory effects of eicosapentaenoic acid (EPA).
  2. and direct effects on gene expression. There is now emerging evidence that PUFAs regulate the expression of genes for cytokines, adhesion molecules, COX, inducible nitric oxide synthase and other inflammatory proteins (Renier et al., 1993; de Caterina and Libby, 1996; Khair-el-Din et al., 1996; Robinson et al., 1996; Curtis et al., 2000; Miles et al., 2000; Wallace et al., 2001). Since the expression of many of these genes is regulated by the transcription factor nuclear factor kappa B (NFkB), these observations suggest that PUFAs might somehow affect the activity of this transcription factor. This might be through effects on cell signalling leading to NFkB activation. There is recent evidence that dietary fish oil affects NFkB activity (Lo et al., 1999; Xi et al., 2001), in a manner that is consistent with its ability to down-regulate the production of inflammatory mediators.

A second group of transcription factors currently undergoing scrutiny for their role in inflammation are the peroxisome proliferator-activated receptors (PPARs). The main members of this family are PPARa and PPAR7. PPARa and 7 play important roles in liver and adipose tissue, respectively (Schoonjans et al., 1996). However, they are also found in inflammatory cells (Chinetti et al., 1998; Ricote et al., 1998). PPARs can bind, and appear to be regulated by, PUFAs and eicosanoids (Kleiwer et al., 1995; Devchand et al., 1996). PPARa-deficient mice have a prolonged response to inflammatory stimuli (Devchand et al., 1996), suggesting that PPARa activation might be anti-inflammatory. More recently, activators of both PPARa and PPAR7 have been shown to inhibit the activation of a number of inflammatory genes (Jiang et al., 1998; Poynter and Daynes, 1998; Ricote et al., 1998; Jackson et al., 1999; Marx et al., 1999; Takano et al., 2000; Wang et al., 2001; Xu et al., 2001). Two mechanisms for the anti-inflammatory actions of PPARs have been proposed (for reviews, see Chinetti et al., 2000; Delerive et al., 2001). The first is that PPARs might stimulate the breakdown of inflammatory eicosanoids through the induction of peroxisomal p-oxidation. The second is that PPARs might interfere with/antagonize the activation of other transcription factors, including NFkB. Although the effect of fish oil on PPAR expression in inflammatory cells has not been reported, studies in other tissues (e.g. Berthou et al., 1995) suggest that n-3 PUFAs might act by increasing the level of these anti-inflammatory transcription factors in such cells.

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