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 l acking 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, codin g for apolipoprotein A-I and apolipoprotein A-IV, are not altered in t he liver but are reduced in the intestine. This suggests that these th ree genes share a tissue-specific element for intestinal expression an d that insertion of an additional promoter for the neomycin-resistant gene into the locus affects interaction between the tissue-specific el ement and the promoter of the individual gene. Fasted plasma triglycer ide levels in the homozygous mutants are reduced to about 70% of norma l, while heterozygotes have values intermediate between those of the h omozygous mutants and wild types. Plasma levels of total cholesterol a nd of high density lipoprotein cholesterol in homozygotes are consiste ntly lower than those in normal mices but the reduction does not reach statistical significance. A fat meal test showed that postprandial hy pertriglyceridemia is abolished in homozygotes lacking ApoC-III. The h omozygous mutants also clear chylomicrons faster than wild type contro ls. These data indicate that ApoC-III modulates the catabolism of trig lyceride-rich lipoproteins and plays a role in the postprandial manage ment of triglycerides.