HUMAN HEPATIC TRIGLYCERIDE LIPASE EXPRESSION REDUCES HIGH-DENSITY-LIPOPROTEIN AND AORTIC CHOLESTEROL IN CHOLESTEROL-FED TRANSGENIC MICE

We have produced a line of transgenic mice expressing human hepatic tr iglyceride lipase (hH-TGL) to examine the in vivo effects of hepatic l ipase expression on high density lipoprotein catabolism. Activation of a metallothionine I promoter-hH-TGL cDNA transgene produced high leve ls of lipase mRNA in liver, heart, and kidney and elevated enzyme acti vity as assayed in post-heparin plasma. In a series of hyperlipidemic diet studies in which zinc was included in the diet to induce the tran sgene, hH-TGL expression was associated with a 34% lowering of plasma HDL-cholesterol levels (p < 0.01) when compared with animals on the sa me hyperlipidemic diet without zinc. This lowering of HDL cholesterol was paralleled by a decrease in total cholesterol and a decrease in HD L particle size. SDS-polyacrylamide gel electrophoresis analysis of th e smaller HDL particles revealed that apolipoprotein AI was still the major apoprotein associated with the HDL. Quantitative analysis of abd ominal aortic cholesterol content from the same animals suggests that the observed changes in plasma HDL by hH-TGL over-expression correlate d with a decrease in the accumulation of aortic cholesterol (42%, p < 0.01). These data support the hypothesis that hH-TGL mediates a non-re ceptor pathway for the clearance of cholesterol from the plasma compar tment.