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J Biol Chem. 2010 Feb 26;285(9):6801-10. doi: 10.1074/jbc.M109.079459. Epub 2009 Dec 27.

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

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Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046, USA.


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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