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

Helén L. Dichek, Walter Brecht, Jianglin Fan, Zhong-Sheng Ji, Sally P. A. McCormick, Hassibullah Akeefe, LoriAnna Conzo, David A. Sanan, Karl H. Weisgraber, Stephen G. Young, John M. Taylor, Robert W. Mahley
1998 Journal of Biological Chemistry  
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%,
more » ... 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 ؉/0 mice, plasma cholesterol decreased by 50%. This decrease was reflected in both the apoB-containing and the HDL fractions. To determine if HL catalytic activity is required for these decreases, we expressed catalytically inactive HL (HL-CAT) in apoE ؊/؊ mice. The postheparin plasma HL activities were similar in the apoE ؊/؊ and the apoE ؊/؊ ,HL-CAT ؉/0 mice, reflecting the activity of the endogenous mouse HL and confirming that the HL-CAT was catalytically inactive. However, the postheparin plasma HL activity was 20-fold higher in the apoE ؊/؊ ,hHLTg ؉/0 mice, indicating expression of the active human HL. Immunoblotting demonstrated high levels of human HL in postheparin plasma of both apoE ؊/؊ ,hHLTg ؉/0 and apoE ؊/؊ ,HL-CAT ؉/0 mice. Plasma cholesterol and apoB-containing lipoprotein levels were ϳ60% lower in apoE ؊/؊ ,HL-CAT ؉/0 mice than in apoE ؊/؊
doi:10.1074/jbc.273.4.1896 pmid:9442022 fatcat:qxku66czrvfl3psdpqvtcexnay