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Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice.

Abstract
The lipolysis-stimulated lipoprotein receptor, LSR, is a multimeric protein complex in the liver that undergoes conformational changes upon binding of free fatty acids, thereby revealing a binding site (s) that recognizes both apoB and apoE. Complete inactivation of the LSR gene is embryonic lethal in mice. Here we show that removal of a single LSR allele (LSR(-/+)) caused statistically significant increases in both plasma triglyceride and cholesterol levels, a 2-fold increase in plasma triglyceride changes during the post-prandial phase, and delayed clearance of lipid emulsions or a high fat meal. The longer postprandial lipoprotein clearance time observed in LSR(-/+) mice was further increased in LSR(-/+) mice lacking functional low density lipoprotein (LDL) receptors. LSR(-/+) mice placed on a Western-type diet displayed higher plasma triglycerides and cholesterol levels, increased triglyceride-rich lipoproteins and LDL, and increased aorta lipid content, as compared with control mice on the same diet. Furthermore, a direct correlation was observed between the hyperlipidemia and weight gain but only in the LSR(-/+) mice. Knockdown of LSR expression by small interfering RNA in mouse Hepa1-6 cells led to decreased internalization of both DiI-labeled cyclohexanedione-LDL and very low density lipoprotein in the presence of oleate. These data led us to conclude that LSR contributes to the physiological clearance of atherogenic triglyceride-rich lipoproteins and LDL. We propose that LSR cooperates with the LDL receptor in the final hepatic processing of apoB-containing lipoproteins and represents a novel therapeutic target for the treatment of hyperlipidemia associated with obesity and atherosclerosis.
AuthorsFrances T Yen, Olivier Roitel, Lionel Bonnard, Véronique Notet, Dagmar Pratte, Christophe Stenger, Erwan Magueur, Bernard E Bihain
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 37 Pg. 25650-25659 (Sep 12 2008) ISSN: 0021-9258 [Print] United States
PMID18644789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cyclohexanes
  • Lipoproteins, LDL
  • Receptors, Lipoprotein
Topics
  • Alleles
  • Animals
  • Atherosclerosis (metabolism)
  • Cyclohexanes (chemistry)
  • Heterozygote
  • Hyperlipidemias (metabolism)
  • Lipolysis
  • Lipoproteins, LDL (chemistry)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Biological
  • Obesity
  • Receptors, Lipoprotein (metabolism)
  • Weight Gain

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