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Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL
Jay D. Horton, … , Michael S. Brown, Joseph L. Goldstein
Jay D. Horton, … , Michael S. Brown, Joseph L. Goldstein
Published April 1, 1999
Citation Information: J Clin Invest. 1999;103(7):1067-1076. https://doi.org/10.1172/JCI6246.
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Article

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

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Abstract

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.

Authors

Jay D. Horton, Hitoshi Shimano, Robert L. Hamilton, Michael S. Brown, Joseph L. Goldstein

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Figure 1

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Amounts of various mRNAs in livers of (A) wild-type, (B) TgBP-1a, (C) LD...
Amounts of various mRNAs in livers of (A) wild-type, (B) TgBP-1a, (C) LDLR–/–, and (D) TgBP-1a;LDLR–/– mice, as measured by blot hybridization. Total RNA isolated from livers of mice described in experiment A of Table 1 was pooled, and 15-μg aliquots were subjected to electrophoresis and blot hybridization with the indicated 32P-labeled probe. The amount of radioactivity in each band was quantified as described in Methods. The probe used for SCD was a mouse SCD-1 cDNA fragment that detects both SCD-1 and SCD-2 mRNAs (see ref. 35). The increase for each mRNA relative to that of wild-type mice was calculated after correction for loading differences with GAPDH as described previously (12). These values are shown below each blot. GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MTP, microsomal triglyceride transfer protein; SCD, stearoyl CoA desaturase.

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