Hepatic secretion of small lipoprotein particles in apobec-1-/- mice is regulated by the LDL receptor.
Recent studies have examined the role of the LDL receptor (LDLR) in regulating murine hepatic lipoprotein production and apolipoprotein B (apoB) secretion, with divergent conclusions from in vivo versus in vitro approaches. We have re-examined this question, both in vivo and in vitro, using apobec-1-/- mice to model the pattern of human hepatic apoB-100 secretion. Hepatic triglyceride production in vivo (using Triton WR-1339) was unchanged in wild-type (WT) C57BL/6, apobec-1-/-, ldlr-/-, and [apobec-1-/-, ldlr-/-] mice, while apoB-100 production (using [35S]methionine incorporation) was increased > 2-fold in [apobec-1-/-, ldlr-/-] mice. Although > 90% of newly synthesized apoB floated within the d < 1.006 fraction of serum from all genotypes, fast-performance liquid chromatography separation revealed that nascent triglyceride-rich particles from [apobec-1-/-, ldlr-/-] mice, but not WT, apobec-1-/-, or ldlr-/- mice, distributed into smaller (intermediate and LDL-sized) particles. Studies in isolated hepatocytes from these different genotypes confirmed secretion of smaller particles exclusively from [apobec-1-/-, ldlr-/-] mice, and pulse-chase analysis demonstrated increased secretion of apoB-100 with virtual elimination of posttranslational degradation. These results directly support the suggestion that the LDLR regulates hepatic apoB-100 production and modulates secretion of small, triglyceride-rich particles, both in vivo and in vitro.
Nassir
Fatiha
F
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Xie
Yan
Y
Patterson
Bruce W
BW
Luo
Jianyang
J
Davidson
Nicholas O
NO
D000071479:APOBEC-1 Deaminase; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics*; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010316:Particle Size; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D001055:Apolipoproteins B; D008074:Lipoproteins; D011973:Receptors, LDL; D014280:Triglycerides; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase