Overexpression of Hepatic Lipase in Transgenic Mice Decreases Apolipoprotein B-containing and High Density Lipoproteins

Abstract

To determine the mechanisms by which human hepatic lipase (HL) contributes to the metabolism of apolipoprotein (apo) B-containing lipoproteins and high density lipoproteins (HDL) in vivo, we developed and characterized HL transgenic mice. HL was localized by immunohistochemistry to the liver and to the adrenal cortex. In hemizygous (hHLTg ؉/0 ) and homozygous (hHLTg ؉/؉ ) mice, postheparin plasma HL activity increased by 25-and 50-fold and plasma cholesterol levels decreased by 80% and 85%, respectively. In mice fed a high fat, high cholesterol diet to increase endogenous apoB-containing lipoproteins, plasma cholesterol decreased 33% (hHLTg ؉/0 ) and 75% (hHLTg ؉/؉ ). Both apoBcontaining remnant lipoproteins and HDL were reduced. To extend this observation, the HL transgene was expressed in human apoB transgenic (huBTg) and apoEdeficient (apoE ؊/؊ ) mice, both of which have high plasma levels of apoB-containing lipoproteins. (Note that the huBTg mice that were used in these studies were all hemizygous for the human apoB gene.) In both the huBTg,hHLTg ؉/0 mice and the apoE ؊/؊ ,hHLTg mice. However, the HDL were only minimally reduced. Thus, the catalytic activity of HL is critical for its effects on HDL but not for its effects on apoB-containing lipoproteins. These results provide evidence that HL can act as a ligand to remove apoB-containing lipoproteins from plasma.

The Ligand-binding Function of Hepatic Lipase Modulates the Development of Atherosclerosis in Transgenic Mice

“…The altered lipid profile of HL-WT and HL-S145G mice was not due to changes in lipoprotein lipase activity since it was reduced by ϳ23% in both groups of mice compared with E-KO ϫ HL-KO mice; decreased lipolysis resulting from lower lipoprotein lipase activity would increase rather than decrease plasma TC, TG, and PL as well as apoB-Lp and HDL-C levels. These data are consistent with previous adenovirus and transgenic studies in E-KO mice (25,26) and indicate that whereas the lipolytic function of HL significantly contributes to plasma HDL metabolism, the ligand-binding function of HL accounts for most of the reduction in the cholesterol-rich remnant lipoproteins that accumulate in E-KO ϫ HL-KO mice.…”

“…The levels of HL overexpression (3-5-fold) achieved in our transgenic mice were within the physiological range reported previously for various metabolic states such as sex, dietary status, diabetes, and hormonal stimulation (6,10). This contrasts with previous studies in which HL-WT and catalytically inactive HL were overexpressed by either 10-fold (25) or 20-fold (26) in E-KO mice expressing endogenous HL. Thus, the transgenic mice used in this study express HL in liver at physiologically relevant levels compared with mice lacking endogenous HL.…”

“…Finally, adenoviral expression of HL-S145G in mice with no endogenous expression of HL (HL-KO) decreased the plasma concentrations of HDL-C by mechanisms independent of lipolysis (28). However, these in vivo reports are limited by the confounding effects of having fully active, endogenous mouse HL present along with HL-S145G in the adenovirus and transgenic studies in E-KO mice and by non-steady-state expression of catalytically inactive HL-S145G in the adenovirus studies (25,26,28). More recently, Dichek et al (29) reported that overexpression of catalytically inactive HL in LDLR-KO, LDLR-KO ϫ apoB-100, and LDLR-KO ϫ apoB-48 (HL-KO) mice facilitates the clearance of apoB-48-and apoB-100-containing lipoproteins.…”

“…These data were confirmed and extended by in vivo experiments that either infused the receptor-associated protein (RAP) and anti-HL/LDLR antibodies (24) or expressed a catalytically inactive form of HL, HL-S145G, in various mouse models. Adenoviral and transgenic overexpression of HL-S145G in apoE knockout (E-KO) mice demonstrated that the ligand-binding function of HL lowers the plasma concentrations of apoB-containing lipoproteins (apoB-Lp) in the absence of apoE (25,26). Decreased apoB-Lp levels are also observed in transgenic mice that overexpress catalytically inactive HL in LDLR knockout (KO) mice (27).…”

“…HL overexpression beneficially alters the plasma lipid profile of mice and rabbits by reducing the amount of cholesterol present in apoB-Lp (26,27,39). In addition, overexpression of human HL reduces the aortic cholesterol content in cholesterol-fed mice (40).…”