triglyceride (TG) metabolism ( 1 ). When it is overexpressed in transgenic mice, apoA-V reduces plasma TG levels by 65%, whereas inactivation of the apoA-V gene increases plasma TG by 4-fold ( 2 ). The preponderance of current literature suggests that apoA-V affects plasma TG turnover by stimulating LPL-mediated lipolysis of TG-rich lipoproteins, either directly or indirectly ( 3-7 ). ApoA-V has also been found to serve as a ligand for LDL receptor family members and other potential lipoprotein receptors and may thus contribute to the clearance of TG-rich lipoproteins and their remnants ( 8-11 ). However, recent studies have revealed that the effects of apoA-V on plasma TG concentration are complex and variable. In humans, several loss-of-function and null apoA-V alleles are associated with both reduced plasma apoA-V levels and elevated plasma TG ( 12, 13 ), yet other studies have found both positive and negative associations between plasma apoA-V and TG concentrations ( 7,14,15 ). Moreover, recent studies in mice have found a positive correlation between plasma apoA-V and TG concentrations ( 16,17 ).Despite its apparent impact on intravascular TG-rich lipoprotein lipolysis and clearance, a peculiar characteristic of apoA-V is that its plasma concentration is in the range of 100-200 µg/l, which is ف 10,000-fold lower than apoA-I and ف 1,000-fold lower than apoA-IV and corresponds to ف 1 molecule of apoA-V for every 1,000 VLDL particles ( 18,19 ). This presents a conundrum as to how an apolipoprotein circulating at such low levels could exert such a potent effect on plasma TG metabolism and concentration. Although it is certainly possible that apoA-V could function in plasma at extreme substoichiometric concentrations relative to that of TG-rich lipoproteins, it has also been suggested that apoA-V might function within the hepatocyte to directly modulate Apolipoprotein A-V (apoA-V), a member of the exchangeable apolipoprotein family synthesized predominantly in the liver, is a potent regulator of intravascular and
This work was supported by National Institutes of Health Grants