Increased production of very-low-density lipoproteins in transgenic mice overexpressing human apolipoprotein A-II and fed with a high-fat diet

We investigated the mechanisms that lead to combined hyperlipidemia in tran sgenic mice that overexpress human apolipoprotein (apo) A-II (line 11.1). T he 11.1 transgenic mice develop pronounced hypertriglyceridemia, and a mode rate increase in free fatty acid (FFA) and plasma cholesterol, especially w hen fed a high-fat/high-cholesterol diet. Post-heparin plasma lipoprotein l ipase and hepatic lipase activities (using artificial or natural autologous substrates), the decay of plasma triglycerides with fasting, and the fract ional catabolic rate of the radiolabeled VLDL-triglyceride (both fasting an d postprandial) were similar in 11.1 transgenic mice and in control mice. I n contrast, a 2.5-fold increase in hepatic VLDL-triglyceride production was observed in 11.1 transgenic mice in a period of 2 h in which blood lipolys is was inhibited. This increased synthesis of hepatic VLDL-triglyceride use d preformed FFA rather than FFA of de novo hepatic synthesis. The 11.1 tran sgenic mice also presented reduced epididymal/parametrial white adipose tis sue weight (1.5-fold), increased rate of epididymal/parametrial hormone-sen sitive lipase-mediated lipolysis (1.2-fold) and an increase in cholesterol and, especially, in triglyceride liver content, suggesting an enhanced mobi lization of fat as the sourer of preformed FFA reaching the liver. Increase d plasma FFA was reverted by insulin, demonstrating that 11.1 transgenic mi ce are not insulin resistant. We conclude that the overexpression of human apoA-II in transgenic mice induces combined hyperlipidemia through an incre ase in VLDL production. These mice will be useful in the study of molecular mechanisms that regulate the overproduction of VLDL, a situation of major pathophysiological interest since it is the basic mechanism underlying fami lial combined hyperlipidemia. (C) 2000 Elsevier Science B.V. All rights res erved.