Lipoprotein lipase and atherosclerosis.
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.
Tsutsumi
K
K
Research and Development, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima 772-8601, Japan. tutumikz@otsukakj.co.jp
D000818:Animals; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D008076:Cholesterol, HDL / Q000097:blood; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D020536:Enzyme Activators / Q000494:pharmacology / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy / Q000201:enzymology; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008071:Lipoprotein Lipase / Q000097:blood / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
D001549:Benzamides; D008076:Cholesterol, HDL; D020536:Enzyme Activators; D000960:Hypolipidemic Agents; D009943:Organophosphorus Compounds; D014280:Triglycerides; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D008071:Lipoprotein Lipase