Figure 2. Proposed molecular model of DHA and butyrate-induced apoptosis.

We have previously demonstrated that butyrate induces colonocyte apoptosis via a non-mitochondrial, Fas-mediated, extrinsic pathway which is antagonized by activated Ras [Fan, 1999]. DHA and butyrate work coordinately in the colon to initiate a distinct intrinsic proapoptotic cycle involving the activation of store-operated channels (SOC), leading to rapid entry of Ca²⁺ through the plasma membrane and mitochondrial Ca²⁺ loading. This directly or indirectly increases mitochondrial phospholipid hydroperoxides (PLOOH) and triggers the opening of the permeability transition pore (PTP) and release of pro-apoptotic molecules like cytochrome C. These effects culminate in the induction of apoptosis.