Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice.
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.
Yen
Frances T
FT
Lipidomix (JE2482), Institut National Polytechnique de Lorraine, Nancy University. Electronic address: frances.yenpotin@mtm.nancy.inserm.fr.
Roitel
Olivier
O
Genclis SAS, 54500 Vandoeuvre-lès-Nancy, France.
Bonnard
Lionel
L
Genclis SAS, 54500 Vandoeuvre-lès-Nancy, France.
Notet
Véronique
V
Genclis SAS, 54500 Vandoeuvre-lès-Nancy, France.
Pratte
Dagmar
D
Genclis SAS, 54500 Vandoeuvre-lès-Nancy, France.
Stenger
Christophe
C
Lipidomix (JE2482), Institut National Polytechnique de Lorraine, Nancy University.
Magueur
Erwan
E
Genclis SAS, 54500 Vandoeuvre-lès-Nancy, France.
Bihain
Bernard E
BE
Genclis SAS, 54500 Vandoeuvre-lès-Nancy, France.
D000483:Alleles; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D003510:Cyclohexanes / Q000737:chemistry; D006579:Heterozygote; D006949:Hyperlipidemias / Q000378:metabolism*; D008066:Lipolysis; D008077:Lipoproteins, LDL / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009765:Obesity; D018110:Receptors, Lipoprotein / Q000378:metabolism*; D015430:Weight Gain
D003510:Cyclohexanes; D008077:Lipoproteins, LDL; D018110:Receptors, Lipoprotein