Targeted disruption of the apolipoprotein C-III gene in mice results in hypotriglyceridemia and protection from postprandial hypertriglyceridemia.
Using gene targeting in embryonic stem cells, we have generated mice lacking apolipoprotein C-III (ApoC-III). Homozygous mutant animals show absence of ApoC-III protein and no expression of ApoC-III mRNA in the liver or in the intestine. Expression of the neighboring genes, coding for apolipoprotein A-I and apolipoprotein A-IV, are not altered in the liver but are reduced in the intestine. This suggests that these three genes share a tissue-specific element for intestinal expression and that insertion of an additional promoter for the neomycin-resistant gene into the locus affects interaction between the tissue-specific element and the promoter of the individual gene. Fasted plasma triglyceride levels in the homozygous mutants are reduced to about 70% of normal, while heterozygotes have values intermediate between those of the homozygous mutants and wild types. Plasma levels of total cholesterol and of high density lipoprotein cholesterol in homozygotes are consistently lower than those in normal mices but the reduction does not reach statistical significance. A fat meal test showed that postprandial hypertriglyceridemia is abolished in homozygotes lacking ApoC-III. The homozygous mutants also clear chylomicrons faster than wild type controls. These data indicate that ApoC-III modulates the catabolism of triglyceride-rich lipoproteins and plays a role in the postprandial management of triglycerides.
Maeda
N
N
Department of Pathology, University of North Carolina, Chapel Hill 27599-7525.
Li
H
H
Lee
D
D
Oliver
P
P
Quarfordt
S H
SH
Osada
J
J
D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000378:metabolism*; D002914:Chylomicrons / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D004435:Eating; D015870:Gene Expression; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D012333:RNA, Messenger / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D002914:Chylomicrons; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D012333:RNA, Messenger; D014280:Triglycerides