LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size

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Abstract

Liver X receptors (LXRs) activate triglyceride synthesis in liver directly and indirectly by inducing sterol regulatory element-binding protein-1c (SREBP-1c). When administered to wild-type mice, the LXR activator T0901317 produces a mild and transient hypertriglyceridemia. Here, we show that T0901317 produces massive hypertriglyceridemia when given to mice lacking low density lipoprotein (LDL) receptors (Ldlr-/- mice). Triglycerides ranged from 4000 to 6000 mg/dl, and the plasma turned milky. The median diameter of VLDL particles, measured by electron microscopy, increased from 43 to 112 nm, 87% exceeding 80 nm, the size of chylomicrons. Hypertriglyceridemia was prevented in Ldlr-/- recipient mice that lacked SREBP-1c (Ldlr -/-;Srebp-1c-/- double knock-out mice). In Ldlr -/- mice, T0901317 increased mRNAs not only for enzymes of fatty acid and triglyceride synthesis, but also for phospholipid transfer protein (PLTP), which transfers phospholipids into nascent VLDL, allowing particle expansion. The PLTP increase was blunted in Ldlr-/-;Srebp-1c-/- animals. When Ldlr-/-;Srebp-1c-/- mice received an adenovirus encoding Pltp, the hypertriglyceridemic response to T0901317 was partially restored and the VLDL size increased. We conclude that LXR agonists activate triglyceride synthesis and Pltp transcription by activating Srebp-1c. In concert with the increase in TG synthesis, the increased PLTP permits triglyceride incorporation into abnormally large VLDL, which are removed from plasma by LDL receptors. In the absence of LDL receptors, the large VLDLs accumulate and produce massive hypertriglyceridemia.

Original languageEnglish (US)
Pages (from-to)6801-6810
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number9
DOIs
StatePublished - Feb 26 2010

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Phospholipid Transfer Proteins
Sterol Regulatory Element Binding Protein 1
VLDL Lipoproteins
Particle Size
Liver
Triglycerides
Hypertriglyceridemia
Particle size
LDL Receptors
Plasmas
Chylomicrons
Transcription
Electron microscopy
Phospholipids
Animals
Adenoviridae
Knockout Mice
Fatty Acids
Liver X Receptors
Electron Microscopy

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

@article{2850b9b5c04646668524eef3e7b1d46c,
title = "LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size",
abstract = "Liver X receptors (LXRs) activate triglyceride synthesis in liver directly and indirectly by inducing sterol regulatory element-binding protein-1c (SREBP-1c). When administered to wild-type mice, the LXR activator T0901317 produces a mild and transient hypertriglyceridemia. Here, we show that T0901317 produces massive hypertriglyceridemia when given to mice lacking low density lipoprotein (LDL) receptors (Ldlr-/- mice). Triglycerides ranged from 4000 to 6000 mg/dl, and the plasma turned milky. The median diameter of VLDL particles, measured by electron microscopy, increased from 43 to 112 nm, 87{\%} exceeding 80 nm, the size of chylomicrons. Hypertriglyceridemia was prevented in Ldlr-/- recipient mice that lacked SREBP-1c (Ldlr -/-;Srebp-1c-/- double knock-out mice). In Ldlr -/- mice, T0901317 increased mRNAs not only for enzymes of fatty acid and triglyceride synthesis, but also for phospholipid transfer protein (PLTP), which transfers phospholipids into nascent VLDL, allowing particle expansion. The PLTP increase was blunted in Ldlr-/-;Srebp-1c-/- animals. When Ldlr-/-;Srebp-1c-/- mice received an adenovirus encoding Pltp, the hypertriglyceridemic response to T0901317 was partially restored and the VLDL size increased. We conclude that LXR agonists activate triglyceride synthesis and Pltp transcription by activating Srebp-1c. In concert with the increase in TG synthesis, the increased PLTP permits triglyceride incorporation into abnormally large VLDL, which are removed from plasma by LDL receptors. In the absence of LDL receptors, the large VLDLs accumulate and produce massive hypertriglyceridemia.",
author = "Hiroaki Okazaki and Goldstein, {Joseph L.} and Brown, {Michael S.} and Guosheng Liang",
year = "2010",
month = "2",
day = "26",
doi = "10.1074/jbc.M109.079459",
language = "English (US)",
volume = "285",
pages = "6801--6810",
journal = "Journal of Biological Chemistry",
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publisher = "American Society for Biochemistry and Molecular Biology Inc.",
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TY - JOUR

T1 - LXR-SREBP-1c-phospholipid transfer protein axis controls very low density lipoprotein (VLDL) particle size

AU - Okazaki, Hiroaki

AU - Goldstein, Joseph L.

AU - Brown, Michael S.

AU - Liang, Guosheng

PY - 2010/2/26

Y1 - 2010/2/26

N2 - Liver X receptors (LXRs) activate triglyceride synthesis in liver directly and indirectly by inducing sterol regulatory element-binding protein-1c (SREBP-1c). When administered to wild-type mice, the LXR activator T0901317 produces a mild and transient hypertriglyceridemia. Here, we show that T0901317 produces massive hypertriglyceridemia when given to mice lacking low density lipoprotein (LDL) receptors (Ldlr-/- mice). Triglycerides ranged from 4000 to 6000 mg/dl, and the plasma turned milky. The median diameter of VLDL particles, measured by electron microscopy, increased from 43 to 112 nm, 87% exceeding 80 nm, the size of chylomicrons. Hypertriglyceridemia was prevented in Ldlr-/- recipient mice that lacked SREBP-1c (Ldlr -/-;Srebp-1c-/- double knock-out mice). In Ldlr -/- mice, T0901317 increased mRNAs not only for enzymes of fatty acid and triglyceride synthesis, but also for phospholipid transfer protein (PLTP), which transfers phospholipids into nascent VLDL, allowing particle expansion. The PLTP increase was blunted in Ldlr-/-;Srebp-1c-/- animals. When Ldlr-/-;Srebp-1c-/- mice received an adenovirus encoding Pltp, the hypertriglyceridemic response to T0901317 was partially restored and the VLDL size increased. We conclude that LXR agonists activate triglyceride synthesis and Pltp transcription by activating Srebp-1c. In concert with the increase in TG synthesis, the increased PLTP permits triglyceride incorporation into abnormally large VLDL, which are removed from plasma by LDL receptors. In the absence of LDL receptors, the large VLDLs accumulate and produce massive hypertriglyceridemia.

AB - Liver X receptors (LXRs) activate triglyceride synthesis in liver directly and indirectly by inducing sterol regulatory element-binding protein-1c (SREBP-1c). When administered to wild-type mice, the LXR activator T0901317 produces a mild and transient hypertriglyceridemia. Here, we show that T0901317 produces massive hypertriglyceridemia when given to mice lacking low density lipoprotein (LDL) receptors (Ldlr-/- mice). Triglycerides ranged from 4000 to 6000 mg/dl, and the plasma turned milky. The median diameter of VLDL particles, measured by electron microscopy, increased from 43 to 112 nm, 87% exceeding 80 nm, the size of chylomicrons. Hypertriglyceridemia was prevented in Ldlr-/- recipient mice that lacked SREBP-1c (Ldlr -/-;Srebp-1c-/- double knock-out mice). In Ldlr -/- mice, T0901317 increased mRNAs not only for enzymes of fatty acid and triglyceride synthesis, but also for phospholipid transfer protein (PLTP), which transfers phospholipids into nascent VLDL, allowing particle expansion. The PLTP increase was blunted in Ldlr-/-;Srebp-1c-/- animals. When Ldlr-/-;Srebp-1c-/- mice received an adenovirus encoding Pltp, the hypertriglyceridemic response to T0901317 was partially restored and the VLDL size increased. We conclude that LXR agonists activate triglyceride synthesis and Pltp transcription by activating Srebp-1c. In concert with the increase in TG synthesis, the increased PLTP permits triglyceride incorporation into abnormally large VLDL, which are removed from plasma by LDL receptors. In the absence of LDL receptors, the large VLDLs accumulate and produce massive hypertriglyceridemia.

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