In vitro remodelling of plasma lipoproteins in whole plasma by lipoprotein lipase in primary and secondary hypertriglyceridaemia

Abstract

In patients with familial lipoprotein lipase deficiency (FLPL-d) and glycogen storage disease type I (GSD-I), hypertriglyceridaemia (1445 +/- 247 and 1082 +/- 312 mg dl-1, n = 5 per group) was associated primarily with reduced extrahepatic lipoprotein lipase (LPL) activity (0.33 +/- 0.33 and 1.69 +/- 0.38 mumol FFA ml-1 h-1) when compared with controls (4.83 +/- 0.90). Hypercholesterolaemia was characterized by elevated LDL cholesterol (191 +/- 30 and 344 +/- 34 vs. 115 +/- 5 mg dl-1 in controls P less than 0.01) and low HDL cholesterol (12 +/- 2 and 22 +/- 2 vs. 56 +/- 3 in controls, P less than 0.001). In order to ascertain the role of LPL in the interconversion and remodelling of lipoproteins in these disorders, we analysed lipid and lipoprotein profiles before and following in vitro incubation of patient plasma with purified milk LPL (EC 3.1.1.34) for 6 h at 37 degrees C. The efficiency of exogenous LPL in vitro was demonstrated by the extent of hydrolysis of chylomicrons and of VLDL-TG in both groups. Concomitant with the disappearance of TG-rich lipoprotein particles, a consistent per cent increment of IDL (99.2 +/- 30.8 and 43.9 +/- 70.5), LDL (152.8 +/- 36.2 and 137.0 +/- 36.1) and of HDL2 (144.8 +/- 29.4 and 99.8 +/- 18.7) was observed in both groups of patients. The enhancement of the latter fractions contrasted with the decline of HDL3 mass concentration (25.4 +/- 7.7 and 51.4 +/- 5.8%), suggesting that a major shift of HDL3----HDL2 occurs following in vitro lipolysis by LDL. Simultaneous compositional and morphological changes of individual lipoprotein particles were noted, confirming the dynamic movement and exchange of neutral lipids and proteins. Specificity of LPL results was demonstrated by experiments in which incubation of the whole plasma at 37 degrees C without exogenous lipolytic enzyme did not cause any substantial changes. The present study, therefore, demonstrates a correction of the major lipoprotein abnormalities associated with FLPL-d and GSD-I by exogenous LPL. No substantial difference was noted between primary (FLPL-d) and secondary (GSD-I) hyperlipidaemias. These studies allow us to conclude that a simple in vitro system, utilizing an exogenous source of LPL and plasma from patients, may serve as a suitable model for the study of the metabolic relationships of lipoproteins. However, in view of the fact that the extent of lipolysis achieved in vitro did not differ between FLPL-d and GSD-I, it may not be able to separate primary from secondary hyperlipaemias.

Differential effects of activation of liver X receptor on plasma lipid homeostasis in wild-type and lipoprotein clearance-deficient mice

“…Rather these small VLDL particles are generated by the remodeling of nascent hepatic lipoproteins in the plasma under the influence of active lipoprotein lipase. This explanation is supported by a previous in vitro study in which exogenous lipoprotein lipase added to whole plasma hydrolyzed lipids in chylomicrons and VLDL leading to increases in IDL, LDL and HDL2 [33]. …”

Chylomicron- and VLDL-derived Lipids Enter the Heart through Different Pathways

“…Faster HDL turnover was associated with cholesteryl ester transfer protein modification of HDL and its subsequent hydrolysis by enzymes such as hepatic lipase (60) and endothelial lipase (61), and clearance in the kidney (62). Our data show that LpL-mediated lipolysis of CM and VLDL particles, a process that dissociates lipids and surface apoproteins that transfer to HDL (52,63), is a major pathway for HDL production. Thus, both creation of HDL as well as delivery of core lipids is likely to involve a similar LpL-dependent shedding of lipids.…”

Lipoprotein Abnormalities in Two Children with Minimal Biliary Excretion

“…It is also the site for the secretion of nascent very-low-density lipoproteins (VLDL) and high-density lipoproteins (HDL) and is involved in the uptake and degradation of chylomicron remnants, intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and HDL (4,5). Moreover, the liver constitutes the delivery system for regulatory enzymes and conversion factors, including hepatic lipase, lecithin:cholesterol acyltransferase, and cholesteryl ester transfer protein, which promote and control the metabolic relationships and remodeling of plasma lipoproteins (6,7). Finally, the pathways of biliary cholesterol secretion and bile acid synthesis by the liver are the main routes of cholesterol elimination from the body; thus, this organ plays an active role in sterol homeostasis (8,9) .…”