The low density lipoprotein receptor prevents secretion of dense apoB100-containing lipoproteins from the liver.
The assembly and secretion of very low density lipoproteins (VLDL) require microsomal triglyceride transfer protein (MTP). Recent evidence also suggests a role for the low density lipoprotein (LDL) receptor in this process. However, the relative importance of MTP in the two steps of VLDL assembly and the specific role of the LDL receptor still remain unclear. To further investigate the role of MTP and the LDL receptor in VLDL assembly, we bred mice harboring "floxed" Mttp alleles (Mttpflox/flox) and a Cre transgene on a low-density lipoprotein receptor-deficient background to generate mice with double deficiency in the liver (Ldlr-/- MttpDelta/Delta). In contrast to the plasma of Ldlr+/+ MttpDelta/Delta mice, the plasma of Ldlr-/- MttpDelta/Delta mice contained apoB100. Accordingly, Ldlr-/- MttpDelta/Delta but not Ldlr+/+ MttpDelta/Delta hepatocytes secreted apoB100-containing lipoprotein particles. The secreted lipoproteins were of LDL and HDL sizes but no VLDL-sized lipoproteins could be detected. These findings indicate that hepatic LDL receptors function as "gatekeepers" targeting dense apoB100-containing lipoproteins for degradation. In addition, these results suggest that very low levels of MTP are insufficient to mediate the second step but sufficient for the first step of VLDL assembly.
Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Karolinska Hospital, 17176 Stockholm, Sweden.
Sofia L
SL
Larsson
Josefin
J
Skogsberg
Johan
J
Björkegren
D000483:Alleles; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D002499:Centrifugation, Density Gradient; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005091:Exons; D006056:Golgi Apparatus / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D013997:Time Factors; D019076:Transgenes; D014280:Triglycerides / Q000378:metabolism
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; D011973:Receptors, LDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein