LIPOPROTEIN LIPASE

Lipoprotein Lipase



Lipoprotein Lipase

1.0 Introduction

Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride (TG)-rich lipoproteins such as very low-density lipoproteins (VLDL) and chylomicrons. A decrease in LPL activity is associated with an increase in plasma TG and a decrease in plasma high-density lipoprotein cholesterol (HDL-C). The increase in plasma TG and decrease in plasma HDL-C are risk factors for cardiovascular disease (CVD). Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction in plasma TG and an increase in plasma HDL-C, resulting in protection against the development of atherosclerosis.

To test this hypothesis, Otsuka synthesized the LPL activator NO-1886. The effects of NO-1886 in animals have been extensively studied. NO-1886 has been shown to increase LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of post-heparin plasma LPL activity and LPL mass in rats. NO-1886 has also been shown to decrease plasma TG concentration and to cause a concomitant rise in plasma HDL-C. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aorta. The results of multiple regression analysis in these studies suggested that the increase in plasma HDL-C and the decrease in plasma TG protected against atherosclerosis. These results show that the atherogenic lipid profile is changed to an antiatherogenic lipid profile by increasing LPL activity, resulting in protection against the development of atherosclerosis. Therefore, the LPL activator NO-1886 is potentially beneficial for the treatment of hypertriglyceridemia and hypo-HDL-cholesterolemia, and for protection against atherosclerosis.

Furthermore, we hypothesized that elevation of LPL activity in adipose tissue would cause an improvement in cachexia, and elevation of LPL activity in skeletal muscle would lead to an improvement in obesity, because the LPL in adipose tissue is related to fat storage and LPL in skeletal muscle is related to free fatty acid (FFA) oxidation. From the many published studies, we confirmed that NO-1886 improved cachexia by elevating LPL activity in adipose tissue and improved obesity by elevating LPL activity in skeletal muscle. It is concluded that NO-1886, and possibly other LPL-activating agents, protect against atherosclerosis, as well as cachexia and obesity.

2.0 Literature Review

Lipoprotein lipase (LPL) is a glycoprotein enzyme that is produced in several cells and tissues. LPL belongs to a large lipase gene family that includes, among others, hepatic lipase and pancreatic lipase. After secretion, LPL becomes anchored on the luminal surface of the capillary endothelial cells. There it hydrolyzes triglycerides in triglyceride-rich lipoproteins, generating free fatty acids that can serve either as a direct energy source or can be stored. Through this action LPL plays a pivotal role both in energy and in lipoprotein metabolism. LPL production is regulated in a tissue-specific fashion by developmental, hormonal, and nutritional factors. The recent availability of the regulatory sequences of the LPL gene will greatly facilitate these regulatory studies in the future. In man, several mutations resulting in familial LPL deficiency have been delineated at a molecular ...