Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL

Transgenic mice that overexpress the nuclear form of sterol regulatory elem ent binding protein-1a (SREBP-1a) in liver (TgBP-1a mice) were shown previo usly to overproduce cholesterol and fatty acids and to accumulate massive a mounts of cholesterol and triglycerides in hepatocytes. Despite the hepatic overproduction of lipids, the plasma levels of cholesterol (similar to 45 mg/dl) and triglycerides (similar to 55 mg/dl) were not elevated, perhaps o wing to degradation of lipid-enriched particles by low-density lipoprotein (LDL) receptors. To test this hypothesis, in the current studies we bred Tg BP-1a mice with LDL receptor knockout mice. As reported previously, LDLR-/- mice manifested a moderate elevation in plasma cholesterol (similar to 215 mg/dl) and triglycerides (similar to 155 mg/dl). In contrast, the doubly m utant TgBP-1a;LDLR-/- mice exhibited marked increases in plasma cholesterol (similar to 1,050 mg/dl) and triglycerides (similar to 900 mg/dl). These li pids were contained predominantly within large very-low-density lipoprotein (VLDL) particles that were relatively enriched in cholesterol and apolipop rotein E. Freshly isolated hepatocytes from TgBP-1a and TgBP-1a; LDLR-/- mi ce overproduced cholesterol and fatty acids and secreted increased amounts of these lipids into the medium. Electron micrographs of livers from TgBP-1 a mice showed large amounts of enlarged lipoproteins within the secretory p athway. We conclude that the TgBP-1a mice produce large lipid-rich lipoprot eins, but these particles do not accumulate in plasma because they are degr aded through the action of LDL receptors.