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Cardiovascular disease (CVD) is the leading cause of mortality in the United States. Both postprandial triglycerides and inflammation are well-established mediators of CVD. Of particular importance are macrophages, which are potent contributors to the development of atherosclerotic lesions. Therefore, factors that influence both plasma triglycerides and macrophage activation are particularly important targets. Apolipoprotein C-III (apoC-III) is one such target. It is an exchangeable apolipoprotein expressed in both liver and intestine; in humans, apoC-III levels in plasma are an independent predictor of CVD risk. ApoC-III is a potent regulator of plasma triglycerides through effects on lipoprotein lipase, hepatic lipoprotein uptake, and VLDL secretion. ApoC-III also acts as a signaling molecule modulating vascular function. Though much is known about hepatic apoC-III, little is known about intestinal apoC-III (including the primary stimulus for its expression and its ability to influence macrophage activation). We have found that apoC-III is secreted from the intestine in response to dietary lipid, and that a fish oil-enriched diet lowers intestinal apoC-III RNA expression, as compared a butterfat diet. These findings are the first to link intestinal apoC-III expression with a dietary stimulus. The purpose of this proposal, therefore, is to: 1) define the role of dietary fat in regulating intestinal apoC-III and 2) determine how this regulation impacts macrophage activation. The goal is to determine how apoC-III expression in the intestine can be exploited by dietary strategies to prevent inflammation and CVD. We propose to accomplish these goals through the following objectives:1) Evaluate the role of dietary fat in modulating apoC-III expression, and subsequent impact on lipoprotein secretion.2) Determine how apoC-III expression changes impact macrophage activation and inflammatory cytokine secretion in response to LPS.
Cardiovascular disease is a leading cause death in the United States. Though much is known about how to reduce the risk for developing this disease, there are still a large number of people who die from the disease despite taking advantages of all the suggested dietary and pharmaceutical approaches. Therefore, it is necessary to find new targets and approaches to treating and preventing cardiovascular disease. Apolipoprotein C-III (apoC-III) is one such target. It is a known regulator of cardiovascular disease risk, yet little is known how it is regulated in the intestine, where it is expressed. We propose to determine how apoC-III is regulated in the intestine and whether diet can positively impact apoC-III in that tissue. We hypothesize that modulation of apoC-III in the intestine may be preferential to the reduction of cardiovascular disease risk.