HIGH-DENSITY-LIPOPROTEIN - ARE ELEVATED LEVELS DESIRABLE AND ACHIEVABLE

In this review we focus on addressing two questions concerning high de nsity lipoproteins (HDL). First, are elevated levels of HDL a desirabl e clinical plasma endpoint and secondly, if so, can strategies be devi sed that would allow the identification of agents to elevate HDL. To a ddress the first question we briefly review the human epidemiologic an d prospective data that identifies HDL as a risk factor for coronary h eart disease (CHD). To introduce HDL elevating strategies, vie next pr ovide a brief review of the structural and enzymatic features of HDL f ollowed by a discussion on the current thinking of the metabolic origi n of the lipoprotein. We then turn to discussions on the key plasma an d cell associated proteins involved in the synthesis, catabolism, and remodeling of HDL by analyzing data derived from human mutations, gene tically engineered animal models with altered HDL metabolism and in vi tro experimental systems. Lastly, we propose approaches to raise HDL t hat are either based on identification of small Organic molecules or m ore unconventional approaches such as gene therapy or delivery of biol ogicals into plasma. This last section is based on an evaluation of th e putative mechanism of actions of both old and new HDL elevating comp ounds. Our review concludes with an optimistic view that agents can be identified which may have promise in the treatment of human hypoalpha lipoproteinemia and CHD.