Fluidità di membrana, ossidazione delle lipoproteine ed invecchiamento

In the past 20 years evidence has been accumulated suggesting that oxidative stress and damage to cellular components from reactive oxygen species (ROS) play an integral role in the age-related deterioration of biochemical and physiologic processes and in the incidence of age-related disease. Mitochondria are the primary site for ROS generation as a by product of aerobic metabolism and the accumulation of mitochondrial oxidative damage over time diminishes the cellular efficiency in energy production (ATP). Moreover, oxidative stress contributes to functional and structural alterations of tissues and blood vessels that decrease the supply of oxygen and nutrients to the various organs and body systems, thus further reducing energy production. The deficiency of ATP decreases the bioavailability of all the molecules whose biosynthesis requires the intervention of ATP itself and slows down the process of repair and replacement of the various lipid or glycoprotein molecules, which make up the bilayer structural organization of the cell membrane. Current evidence suggests that the processe at the cell surface seem to be of comparable importance for the life of an individual as the nucleus for the preservation of the species. Oxidative stress leads to progressive structural alteration of membranes manifested by a progressive reduction of membrane fluidity that causes a secondary metabolic damage to the cells. The membrane hardening, in fact, limits the capacity of membrane proteins to collide with their ligands, thus reducing the activity of enzymes, receptors for hormone or neurotransmitter, ion channels and the trans-membrane carriers for amino acids and glucose. There is thus a spiral of structural and functional damage to cells and tissues, starting with the reduced efficiency in ATP synthesis which is further amplified by the decreased rate of synthesis of membrane macromolecules and lipids, the increase in intracellular calcium and potassium, and the increase in ROS-induced peroxidation processes. Moreover, significant correlations have been found between lipoprotein susceptibility to peroxidation, the degree of obesity, the peripheral resistance to insulin, and the risk to developing atherosclerosis and cardiovascular diseases. In particular, in the case of HDL it has been demonstrated that these lipoproteins serve as an acceptor of cholesterol efflux from foam cells by a mechanism similar to that of “reverse cholesterol transport” and that their oxidation significantly reduces the cholesterol efflux from macrophage-derived foam cells. In a previous work we demonstrated that pyrene derivatives can be used to selectively follow the kinetics of Cu++-catalyzed peroxidation in the hydrophilic envelope (pyrene dodecanoyl sulfatide) and in the hydrophobic core (cholesteryl pyrenyl hexanoate) of human LDL and HDL. With the aim to provide more detailed information on the correlation between lipoprotein susceptibility to peroxidation, membrane fluidity, obesity and risk of developing atherosclerosis, we performed a study in which the different envelope and core susceptibility to peroxidation of both LDL and HDL and membrane fluidity were measured in two adult female groups: overweight and obese patients and lean healthy subjects. The response of the hydrophobic core to oxidative stress induced by Cu++ in LDL and HDL was quite similar in both groups, whereas the envelope, and in particular that one of HDL lipoproteins, was by far more rapidly peroxidized in overweight and obese patients. The higher oxidability of the HDL envelope of obese patients could depend on several factors, including the concentration of envelope-specific antioxidants, the levels of peroxidable substrates, and the different catalyzing capacity of copper. How both the onset of this ROS-induced spiral and the membrane hardening in the obese patients could be kept under control with either an adequate diet or a supply of appropriate functional food will be the main issue of this presentation.