Lipoprotein lipase (LPL) is a rate-limiting
enzyme that hydrolyzes circulating
triglyceride-rich
lipoprotein such as
very low density lipoproteins and
chylomicrons. A decrease in LPL activity is associated with an increase in plasma
triglycerides (TG) and decrease in
high density lipoprotein (
HDL) cholesterol. The increase in plasma TG and decrease in
HDL cholesterol are risk factors of
coronary heart disease. However, whether LPL directly or indirectly promotes or protects against
atherosclerosis remains unclear as two contrary views exist in this regard: one where LPL promotes
atherosclerosis and one where LPL protects against
atherosclerosis. Many studies have been carried out to investigate whether LPL is an anti-atherogenic or atherogenic
enzyme by using animals with genetic defects or with an excess of this
enzyme. From these studies, much evidence has been acquired showing that LPL is an anti-atherogenic
enzyme. We hypothesized that elevating LPL activity would cause a reduction of plasma TG and increase in
HDL cholesterol, resulting in protection against the development of
atherosclerosis. To test this hypothesis, we studied the effects of the LPL activator
NO-1886 in animals.
NO-1886 has been shown to increase LPL
mRNA in adipose tissue and myocardium, and increase LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats.
NO-1886 has also been shown to decrease plasma TG levels accompanied by a concomitant rise in
HDL cholesterol. Long-term administration of
NO-1886 to rats and rabbits with experimental
atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortae. The results of multiple regression analysis in these studies suggest that the increase in plasma
HDL cholesterol and the decrease in TG protect against
atherosclerosis. We have determined in our studies that the atherogenic
lipid profile is changed to an anti-atherogenic
lipid profile by increasing LPL activity, resulting in protection against the development of
atherosclerosis. Therefore, we believe that high activity of LPL is anti-atherogenic, whereas a low activity of LPL is atherogenic.