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

JD Horton, H Shimano, RL Hamilton… - The Journal of …, 1999 - Am Soc Clin Investig
JD Horton, H Shimano, RL Hamilton, MS Brown, JL Goldstein
The Journal of clinical investigation, 1999Am Soc Clin Investig
Transgenic mice that overexpress the nuclear form of sterol regulatory element binding
protein-1a (SREBP-1a) in liver (TgBP-1a mice) were shown previously to overproduce
cholesterol and fatty acids and to accumulate massive amounts of cholesterol and
triglycerides in hepatocytes. Despite the hepatic overproduction of lipids, the plasma levels
of cholesterol (∼ 45 mg/dl) and triglycerides (∼ 55 mg/dl) were not elevated, perhaps owing
to degradation of lipid-enriched particles by low-density lipoprotein (LDL) receptors. To test …
Transgenic mice that overexpress the nuclear form of sterol regulatory element binding protein-1a (SREBP-1a) in liver (TgBP-1a mice) were shown previously to overproduce cholesterol and fatty acids and to accumulate massive amounts of cholesterol and triglycerides in hepatocytes. Despite the hepatic overproduction of lipids, the plasma levels of cholesterol (∼45 mg/dl) and triglycerides (∼55 mg/dl) were not elevated, perhaps owing to degradation of lipid-enriched particles by low-density lipoprotein (LDL) receptors. To test this hypothesis, in the current studies we bred TgBP-1a mice with LDL receptor knockout mice. As reported previously, LDLR–/– mice manifested a moderate elevation in plasma cholesterol (∼215 mg/dl) and triglycerides (∼155 mg/dl). In contrast, the doubly mutant TgBP-1a;LDLR–/– mice exhibited marked increases in plasma cholesterol (∼1,050 mg/dl) and triglycerides (∼900 mg/dl). These lipids were contained predominantly within large very-low-density lipoprotein (VLDL) particles that were relatively enriched in cholesterol and apolipoprotein E. Freshly isolated hepatocytes from TgBP-1a and TgBP-1a;LDLR–/– mice overproduced cholesterol and fatty acids and secreted increased amounts of these lipids into the medium. Electron micrographs of livers from TgBP-1a mice showed large amounts of enlarged lipoproteins within the secretory pathway. We conclude that the TgBP-1a mice produce large lipid-rich lipoproteins, but these particles do not accumulate in plasma because they are degraded through the action of LDL receptors.
J. Clin. Invest. 103:1067–1076 (1999).
The Journal of Clinical Investigation