ApoA-II maintains HDL levels in part by inhibition of hepatic lipase: studies in apoA-II and hepatic lipase double knockout mice

High density lipoprotein (HDL) cholesterol levels are inversely related to the risk of developing coronary heart disease. Apolipoprotein (apo) A-Il is the second most abundant HDL apolipoprotein and apoA-II knockout mice show a 70% reduction in HDL cholesterol levels. There is also evidence, using h uman apoA-II transgenic mice, that apoA-II can prevent hepatic lipase-media ted HDL triglyceride hydrolysis and reduction in HDL size. These observatio ns suggest the hypothesis that apo,S-II maintains HDL levels, at least in p art, by inhibiting hepatic lipase, To evaluate this, apoA-II knockout mice were crossbred With hepatic lipase knockout mice. Compared to apoA-II-defic ient mice, in double knockout mice there were increased HDL cholesterol lev els (57% in males and 60% in females), increased HDL size, and decreased HD L cholesteryl ester fractional catabolic rate. In vitro incubation studies of plasma from apoA-II knockout mice, which contains largely apoA-I HDL par ticles, showed, active lipolysis of HDL triglyceride, whereas similar studi es of plasma from apoA-I knockout mice, which contains largely apoA-II part icles, did not, j/r In summary these results strongly suggest that apoA-II is a physiological inhibitor of hepatic lipase and that this is at least pa rt of the mechanism whereby apoA-II maintains HDL cholesterol levels., ApoA -II maintains HDL levels in part by inhibition of hepatic lipase: studies i n apoA-II and hepatic Lipase double knockout mice.