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

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

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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 TgBP1a;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 TgBP1a 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.

Original languageEnglish (US)
Pages (from-to)1067-1076
Number of pages10
JournalJournal of Clinical Investigation
Volume103
Issue number7
StatePublished - Apr 1999

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Sterol Regulatory Element Binding Protein 1
VLDL Lipoproteins
LDL Receptors
Hyperlipidemias
Cholesterol
Lipids
Triglycerides
Genes
Lipoproteins
Hepatocytes
Liver
Fatty Acids
Secretory Pathway
Apolipoproteins E
Knockout Mice
Transgenic Mice
Electrons

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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title = "Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL",
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 TgBP1a;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 TgBP1a 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.",
author = "Horton, {Jay D.} and Hitoshi Shimano and Hamilton, {Robert L.} and Brown, {Michael S.} and Goldstein, {Joseph L.}",
year = "1999",
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T1 - Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL

AU - Horton, Jay D.

AU - Shimano, Hitoshi

AU - Hamilton, Robert L.

AU - Brown, Michael S.

AU - Goldstein, Joseph L.

PY - 1999/4

Y1 - 1999/4

N2 - 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 TgBP1a;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 TgBP1a 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.

AB - 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 TgBP1a;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 TgBP1a 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.

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