ON THE ROLE OF LIPOPROTEIN LP(A) AND CETP (CHOLESTERYL ESTER TRANSFERPROTEIN) IN ATHEROGENESIS - INSIGHTS FROM TRANSGENIC MICE

Lipoprotein Lp(a) is a plurimolecular complex rich in cholesterol and composed of an LDL (low-density lipoprotein) particle to which is atta ched a large glycoprotein, apolipoprotein(a) (apo(a)). Numerous epidem iological studies have established a strong correlation between plasma levels of Lp(a) and the premature development of atheromatous vascula r disease in man, an association which has subsequently been confirmed by the detection of Lp(a) in human atherosclerotic plaques. Furthermo re, a marked structural resemblance has been demonstrated between apo( a) and plasminogen, a key protein of the fibrinolytic system and respo nsible for dissolution of blood clots. This discovery has provided evi dence, for the first time, that Lp(a) might constitute an important li nk between atherosclerosis and thrombosis. Intense research effort is now underway to provide further understanding of (I) the structural or ganisation of the Lp(a) particle; (II) the molecular genetics of apo(a ) ; (III) the processes involved in the synthesis, assembly intravascu lar metabolism and degradation of Lp(a) and apo(a) ; (IV) the nature o f the interactions of Lp(a) and apo(a) with cellular and non-cellular components of the arterial wall; (V) the role of Lp(a) in fibrinolysis , and (VI) the relationship between Lp(a) and certain metabolic disord ers such as familial hypercholesterolemia. These fascinating questions will be examined in the light of studies of different models of trans genic mice expressing human apo(a) alone, or both apo(a) and apo B100. In man, CETP assures the transfer of cholesteryl ester from high-dens ity lipoproteins (HDL) to lipoproteins containing apo-B, and notably V LDL, IDL and LDL. CETP equally effects transfer of triglycerides in th e opposite direction. In consequence, CETP plays a key role in reverse cholesterol transport, i.e. the transport of cholesterol from periphe ral tissues to the liver. The implication of CETP in the regulation of the metabolism and structure of HDL and apo-B-containing lipoproteins will be discussed in light of studies in transgenic mice expressing t he human gene coding for CETP alone or in association with the human a po AI gene.