Plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I are largely determined by the rate at which apoA-I is catabolized. However, the physiologic factors which regulate the in vivo catabolism of apoA-I remain incompletely understood. Studies in humans and animals have suggested that factors which affect HDL lipid composition modulate apoA-I catabolism. Transfer of cholesteryl esters from HDL by the cholesteryl ester transfer protein and hydrolysis of HDL triglycerides and phospholipids by the enzyme hepatic lipase both result in altered lipid composition and smaller HDL particles, changes which are thought to contribute to faster catabolism of apoA-I in vivo. HDL metabolism is also influenced by the presence of apoA-II, which results in slower catabolism of HDL, perhaps in part by inhibiting hepatic lipase. HDL cholesterol and apoA-I levels are significantly decreased in both acute and chronic inflammatory states due at least in part to rapid catabolism. Although inflammation includes a wide variety of metabolic changes, two that may relate specifically to modulation of HDL and apoA-I catabolism include changes in the plasma levels of the serum amyloid A (SAA) protein and the secretory non-pancreatic phospholipase A2 (sPLA2). The central hypotheses to be tested are that hydrolysis of HDL phospholipids by secretory PLA2 results in accelerated catabolism of apoA-I in vivo, and that acute phase SAA serves as an activator and apoA- II an inhibitor of the metabolic effect of sPLA2 on HDL and apoA-I metabolism. In order to determine whether increased HDL phospholipid hydrolysis by human sPLA2 modulates in vivo HDL metabolism, a recombinant adenovirus will be used to express human sPLA2 cDNA in human apoA-I transgenic mice and effects on HDL particles and human apoA-I turnover will be studied. In order to determine whether any observed effects of the sPLA2 are due specifically to HDL phospholipid hydrolysis, the catalytic site of human sPLA2 will be mutated. In order to determine whether human acute-phase SAA serves as a physiologic activator of human sPLA2 in vivo, transgenic mice overexpressing human sPLA2 and human apoA- I will be injected with a recombinant adenovirus containing the human acute-phase SAA cDNA and control transgenic mice will be injected with a recombinant adenovirus containing the human constitutive SAA. In order to determine whether human apoA-II serves as an inhibitor of the metabolic effect of sPLA2 on HDL in vivo, a recombinant adenovirus will be used to express human sPLA2 in human apoA-I + apoA-II transgenic mice compared with mice expressing only apoA-I. These studies will be performed with the long-term goals of elucidating the role of HDL phospholipid hydrolysis in regulating the rate of apoA-I catabolism and the role of other apolipoproteins in modulating HDL phospholipid hydrolysis and apoA-I catabolism.
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