A targeted apolipoprotein B-38.9-producing mutation causes fatty livers inmice due to the reduced ability of apolipoprotein B-38.9 to transport triglycerides
Zj. Chen et al., A targeted apolipoprotein B-38.9-producing mutation causes fatty livers inmice due to the reduced ability of apolipoprotein B-38.9 to transport triglycerides, J BIOL CHEM, 275(42), 2000, pp. 32807-32815
Nonphysiological truncations of apolipoprotein (apo) B-100 cause familial h
ypobetalipoproteinemia (FHBL) in humans and mice. An elucidation of the mec
hanisms underlying the FHBL phenotypes may provide valuable information on
the metabolism of apo B-containing lipoproteins and the structure-function
relationship of apo B. To generate a faithful mouse model of human FHBL, a
subtle mutation was introduced into the mouse apo B gene by targeting embry
onic stem cells using homologous recombination followed by removal of the s
election marker gene by Cre-loxP-mediated site-specific recombination. The
engineered mice bear a premature stop codon at residue 1767 and a 42-base p
air loxP inserted into intron 24 of the apo B gene, thus closely resembling
the apo B-38.9-producing mutation in humans. Apo B-38.9 was the sole apo B
protein in homozygote (apob(38.9/38.9)) plasma. In heterozygotes (apob(+/3
8.9)), apo B-100 and apo B-48 were reduced by 75 and 40%, respectively, and
apo B-38.9 represented 20% of total circulating apo B. Hepatic apo B-38.9
mRNA levels were reduced by 40%. In cultured apob(+/38.9) hepatocytes, apo
B-100 was produced in trace quantities, and the synthesis rate of apo B-38.
9 relative to apo B-48 was reduced by 40%. However, almost equimolar amount
s of apo B-38.9 and apo B-48 were secreted into the media, Pulse-chase stud
ies revealed that apo B-38.9 was secreted at a faster rate and more efficie
ntly than apoB-48. Nevertheless, both apob(+/38.9) and apob(38.9/38.9) mice
had reduced hepatic triglyceride secretion rates and fatty livers. Thus, l
ow mRNA levels or defective secretion of apo B-38.9 may not be responsible
for the FHBL phenotypes caused by the apo B-38.9 mutation. Rather, a reduce
d capacity of apo B-38.9 for triglyceride transport may account for the fat
ty livers in these mice.