Plasma lipoproteins in familial hepatic lipase deficiency.

Abstract

We have studied the lipoproteins, apolipoproteins, and postheparin lipase activities In an extended pedigree with familial hepatic lipase deficiency. A deficiency of hepatic lipase was found In three of five brothers and In one of their children. Trlglycerlde enrichment of low density and high density lipoproteins was Identified as the constitutive phenotype. 0-very low density lipoproteln was observed In hepatic llpase-deflclent subjects, but It was absent when the plasma trlglycerlde concentration was less than 1 mM/l. The hepatic llpase-deflclent subjects had normal or elevated low density lipoproteln cholesterol and high density lipoproteln cholesterol concentrations. Hyperprebetalipoprotelnemla, hyperbetallpoprotelnemla, and hyperalphallpoproteinemla were observed In both affected and unaffected family members. Compared with the unaffected family members, the hepatic lipase-deflclent subjects had no significant differences In very low density lipoproteln cholesterol, very low density lipoproteln trlglycerlde, or low density lipoproteln cholesterol. These observations are consistent with the presence of additional genes causing hyperilpIdemla In this family, independent of the deficiency of hepatic lipase. The role of HL in lipoprotein metabolism is only partly understood. 1 -» Postheparin plasma HL activity has been reported to be positively correlated with VLDL concentration and negatively correlated with HDL cholesterol concentration.2 -5 It is known that in vitro HL will hydrolyze HDL triglyceride and phospholipid. 6 Intermediate density lipoproteins (IDL) and low density lipoproteins (LDL) with a density between 1.019 and 1.045 have also been shown to be in vitro substrates of HL. 78 The inhibition of HL in vivo by infusion of anti-HL antibody into rats 9 ' 1011 and cynomolgous monkeys 12 has been found to result in the increase of HDL and IDL. However, there is no agreement on the temporal relationships of these changes and no consistent changes in IDL between species. In the study on the primate model, 12 VLDL triglyceride concentrations increased 60% to 300% after infusion of anti-HL antibody. These authors did not report whether the VLDL contained particles of /3 electrophoretic mobility.The discovery of familial HL deficiency 13 has provided an opportunity to investigate the role of HL in lipoprotein metabolism in humans. The proband and his brother were markedly hvpertriglyceridemic, with hyperprebetalipoproteinemia, /3-VLDL, normal or elevated concentrations of LDL cholesterol and HDL cholesterol, and elevated concentrations of LDL and HDL triglyceride and phospholipid. Recently another family with HL deficiency and virtually identical qualitative lipoprotein abnormalities has been described.14 The brothers studied in our laboratory have significant ischemic vascular disease and plasma apolipoprotein (apo) B levels approximately twice the normal level, 13 in contrast to the Scandinavian subjects, 14 who had no apparent ischemic vascular disease and normal levels of plasma apo B. The turnover of ...

Dose-Dependent Acceleration of High-Density Lipoprotein Catabolism by Endothelial Lipase

“…In humans, high plasma HL activity is associated with reduced HDL-C levels and smaller HDL particles, 3 and genetic HL deficiency is associated with modestly elevated HDL-C levels and larger HDL particles. 4,5 A common single nucleotide polymorphism in the HL promoter has been associated with lower levels of HL activity and increased levels of HDL-C, especially HDL 2 . 6 -8 Overexpression of HL in transgenic mice, 9 -11 transgenic rabbits, 12 and mice after adenoviral-mediated gene transfer [13][14][15] resulted in reduced levels of HDL-C.…”

In Vivo Evidence for Both Lipolytic and Nonlipolytic Function of Hepatic Lipase in the Metabolism of HDL

“…Patients with a genetic deficiency of HL have increased plasma levels of HDL cholesterol and phospholipids. 3,4 Increased HDL is also a hallmark of HLdeficient states induced by infusion of anti-HL antibodies 5,6 or genetic manipulation 7 or naturally present in different animal models. 8 Conversely, increased expression of HL in transgenic mice 9,10 and rabbits 11 significantly decreases plasma HDL concentrations.…”

The T Allele of the Hepatic Lipase Promoter Variant C−480T Is Associated With Increased Fasting Lipids and HDL and Increased Preprandial and Postprandial LpCIII:B

“…A deficiency of HL often leads to a mild phenotype with elevation of HDL and/or an increase in LDL concentration and buoyancy. 13,19,20 In conjunction with other hyperlipidemia-causing genes, HL deficiency influences plasma lipoprotein levels more strongly, with tri-glyceride enrichment of lipoprotein fractions with a dϾ1.006 g/mL, the presence of ␤-VLDL, and impaired metabolism of postprandial triglyceride-rich lipoproteins. 19 Thus, because of the multiple effects of HL on lipoprotein metabolism, genetic variation in HL expression may influence atherosclerotic risk.…”

“…31 We carried out our investigation on subjects taking part in the European Atherosclerosis Research Study (EARS) II, a postprandial trial of young, male, university students from 11 European countries (L. Tiret et al, unpublished observations, 1998) whose fathers had documented CAD (designated as cases) and age-matched controls, thus enabling us to examine populations of different European regions. Moreover, because HL deficiency may result in impaired postprandial lipoprotein metabolism, 19 we studied whether the HL polymorphism influenced the lipid response to an oral fat load.…”