Acute Toxic Effects Of Fatty Acids

Abstract

One of the main risk factors in the development of adiposity, type II diabetes, and some cardiovascular diseases is a chronic increase in the level of lipids and free fatty acids (FFA) circulating in the blood. In the acute variant, urgent mobilization of FFA may cause cell death in ischemia/reperfusion and microvesicular steatosis of the liver. It is believed that the main mechanism underlying the cell death in the presence of toxic FFA (primarily palmitic acid and myristic acid) levels is the mitochondrial energetics destabilization. But some data suggest that FFA and their derivatives (acylCoAs or acylcarnitines) may activate reticular Ca2+ channels. In this work we showed that the major cause of cell death induced by the acute toxic action of fatty acids is the destabilization of Ca2+ homeostasis of excitable or nonexcitable cells, which is associated with the activation of sarcoendoplasmic reticulum Ca2+ release channels (RyR and IP3). Under these conditions, the contribution of the activation of L-type Ca2+ channels, NMDA channels, the reversion of the Na+/Ca2+−exchanger of the plasmalemma of excitable cells and the store-operated calcium channels (SOC) of nonexcitable cells is small. In this case, mitochondria act as a Ca2+ buffer system, which is capable of accumulating Ca2+ until the deenergization of mitochondria and a fall of Δφ due to the inhibition of the energetics through AcylCoA or the exhaustion of the Ca2+ capacity of mitochondria and the release of Ca2+ into the cytoplasm (opening of mPTP) followed by the necrotic cell death.