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.
Highlights
Duces prominent fatty liver and mild hypertriglyceridemia in mice (2)
Fractionation of the lipoproteins by fast performance liquid chromatography revealed that the elevated cholesterol and triglycerides were contained in large VLDL particles (Fig. 1, C and D; Table 1)
Previous studies have shown that activators of Liver X receptors (LXRs) increase fatty acid and triglyceride synthesis in liver in part by direct actions and in part by increasing SREBP-1c levels (1, 2)
Summary
Animals—C57BL/6J and LdlrϪ/Ϫ mice (B6.129S7-Ldlrtm1Her/J) were obtained from The Jackson Laboratory. Fast Performance Liquid Chromatography Analysis—Pooled plasma (1.7 ml) from 4 male mice of C57BL/6J and LdlrϪ/Ϫ fed a chow diet or a chow diet containing 0.025% (w/w) T0901317 for 10 days was subjected to ultracentrifugation at a density (d) of 1.215 g/ml. Triglyceride Synthesis in Primary Hepatocyte—Primary hepatocytes were isolated (12) from male C57BL/6J, LdlrϪ/Ϫ, and LdlrϪ/Ϫ;Srebp-1cϪ/Ϫ mice fed for 3 days with a chow diet with or without 0.015% T0901317. To isolate VLDL secreted from primary hepatocytes, male C57BL/6J, LdlrϪ/Ϫ, and LdlrϪ/Ϫ;Srebp-1cϪ/Ϫ mice were fed a chow diet with or without 0.015% T0901317 for 3 days prior to the study. Experiment A used a previously described data set in which the mRNA expression profiles were compared in livers from chow-fed wild-type (WT) mice, transgenic mice that overexpress the nuclear forms of SREBP-1a, and knock-out mice lacking Scap in the liver (L-ScapϪ/Ϫ) (15). Lipids and protein concentrations in the VLDL were measured as described under “Experimental Procedures.”
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