Transcriptional Regulatory Mechanismsof the Human ApoA-I/ApoCIII GeneCluster in vitro and in Trangenic Mice:The Role of Nuclear Receptors

摘要

Apolipoprotein A-I is required for the biogenesis and the anti-atherogenic functions of high density lipoprotein HDL (Segrest et al., 2000; Segrest et al., 2000b). Existing epidemiological and genetic data suggest that decreased plasma apoA-I and HDL levels predispose to coronary heart disease, whereas increased plasma apoA-I and HDL levels protect from coronary heart disease and confer longevity to humans (Castelli et al., 1977). Similarly, overexpression of the apoA-1 gene in mice protects from diet-induced atherosclerosis (Rubin et al., 1991). Overexpression of the apoCIII gene induces hypertriglyceridemia in transgenic mice (Ito et al., 1990) and it has been suggested that the enrichment of lipoproteins with apoCIII generates atherogenic lipoprotein particles. The plasma levels of the apoA-I and apoCIII could in principle be altered by altering selectively the level of gene transcription. Ideally, one would like to be able to upregulate selectively the apoA-I and down regulate the apoCIII gene. A rational approach towards this objective would require a thorough understanding how eukaryiotic genes are regulated at the level of transcription.