Epidemiologic studies have demonstrated correlations of dietary intake of total and saturated fats with the incidence of atherosclerosis both within and between populations. However, only a small fraction of the population appear to be susceptible to diet-induced atherosclerosis. We have undertaken the investigation of human intestinal apolipoprotein gene expression to evaluate one potential molecular mechanism for this phenomenon. There is one human apolipoprotein B gene present on chromosome 2. Two distinct proteins are derived from this gene by a novel posttranscriptional modification. After transcription, the cytosine at residue 6666 is converted to a uridine. This changes the codon from that of a glutamine to a stop codon. Thus, the mRNA can code for a full length protein termed apoB-100 as well as the prematurely terminated apoB-48. The human liver produces only apoB-100 and the human intestine synthesizes primarily apoB-48. We have previously established that 7% of the apoB synthesized by the human intestine is apoB-100. Since the plasma half-life of apoB-48 is less than 15 minutes and apoB- 100 more than 2 days, production of enterocytically-derived apoB-100 could lead to a triglyceride-rich, long-lived, atherogenic lipoprotein particles that could be influenced by diet. Utilizing intestinal biopsies obtained by endoscopy both before and after a fat meal, we evaluated the effect of a fat meal on human intestinal apoB synthesis. Pulse-chase labeling, immunoprecipitation, and sequential radioautography-Western blotting indicated that fat feeding did not change the relative amounts of apoB-100 synthesized in normolipidemic subjects. In contrast, patients with atherosclerosis, hypertriglyceridemia, and a family history of coronary artery disease showed some changes. One patient was identified who synthesized 3 fold more apoB-100 than normals postprandially. We have further investigated the impact that the loss of this editing has on this patient's plasma lipoprotein metabolism. After a 3 kg weight loss and dietary modification, this patient with premature cardiovascular disease normalized his plasma lipoprotein concentrations with concomitant normalization of apoB mRNA editing. hypertriglyceridemia, thThis was correlated with the relative abundance of apoB-100 mRNA detected utilizing a reverse transcriptase-polymerase chain reaction on intestinal RNA. These findings suggest that diet-induced atherosclerosis can be due to defective intestinal apoB in some patients with premature coronary artery disease.
