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J. Biol. Chem., Vol. 279, Issue 2, 831-836, January 9, 2004
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The Low Density Lipoprotein Receptor Prevents Secretion of Dense ApoB100-containing Lipoproteins from the Liver*
From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Karolinska Hospital, 171 76 Stockholm, Sweden
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–/– Mttp
/). In contrast to the plasma of Ldlr+/+ Mttp/ mice, the plasma of Ldlr–/– Mttp/ mice contained apoB100. Accordingly, Ldlr–/– Mttp/ but not Ldlr+/+ Mttp/ 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.
Received for publication, March 25, 2003 , and in revised form, October 28, 2003.
* This work was support by grants from the Swedish Research Council and the Swedish Heart-Lung Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Institutet, Karolinska Hospital, 171 76 Stockholm, Sweden. Tel.: 46-8-51770314; Fax: 46-8-311298; E-mail: johan.bjorkegren{at}ks.se.
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