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1 Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
2 Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: nod{at}im.wustl.edu.
Mammalian enterocytes express apolipoprotein B48 (apoB48), which is produced following post-transcriptional RNA editing of the nuclear apoB100 transcript by the catalytic deaminase, apobec-1. Earlier studies in apobec-1-/- mice revealed an apoB100-only lipoprotein profile, but no gross defects in triglyceride absorption. However, subtle defects may have been obscured by the mixed genetic background. In addition, the intrinsic susceptibility to proteolytic degradation of intestinal apoB100 and apoB48 has been questioned. Accordingly, we examined triglyceride absorption, intestinal apoB expression and lipoprotein secretion in apobec-1-/- mice backcrossed into a C57/BL6 background. Inbred apobec-1-/- mice absorb triglyceride normally, yet secrete triglyceride-rich lipoproteins more slowly than wild type congenic controls. There was comparable induction of apoB synthesis in response to fat feeding in both genotypes, but apoB100 was preferentially retained and more extensively degraded than apoB48. By contrast, synthesis, secretion and content of apoA-IV was indistinguishable in apobec-1-/- and wild-type mice with 100% recovery, suggesting no degradation of this apoprotein in either genotype. Newly secreted lipoproteins from isolated enterocytes of wild-type mice revealed apoB48 in both high density (HDL) and very low density (VLDL) lipoproteins. By contrast, apobec-1-/- mice secreted apoB100-containing particles that were almost exclusively in the low and VLDL range with no apoB100-containing HDL. These studies establish the existence of preferential degradation of intestinal apoB100 and subtle defects in triglyceride secretion in apobec-1/- mice, coupled with a shift to the production of larger particles, findings that suggest an important divergence in intestinal lipoprotein assembly pathways with the different isoforms of apoB.
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