April 2013

Tomatoes with mimic of good-cholesterol peptide benefit mice

Cover of the April 2013 issue of the Journal of Lipid ResearchResearchers have come up with genetically engineered tomatoes that could stave off heart attacks and strokes. In a recent paper in the Journal of Lipid Research, a team led by Srinivasa Reddy and Alan Fogelman at the University of California, Los Angeles, described fruit that contained a protein that helps to halt atherosclerosis, the buildup of arterial plaques that leads to heart attacks and strokes.
One way to treat atherosclerosis is to give patients apoA-I mimetic therapy. The 243-amino-acid apolipoprotein A-I is the main component in high-density lipoprotein, also known as good cholesterol. In animal models and humans, infusions of apoA-I have been associated with improvements in atherosclerosis. But its length makes it an expensive protein to manufacture, and it has to be given intravenously.
Mimics of apoA-I of 18 to 26 amino acids have been produced. They don’t have sequence similarities with apoA-I, but they bind lipids in the same way. Reddy, Fogelman and their colleagues have been studying an apoA-I mimetic peptide called 4F, which has been demonstrated in animal models to reduce atherosclerosis and disease processes associated with inflammation. The animal studies spawned two clinical trials; data from these trials indicated that 4F was most effective at preventing atherosclerosis when taken orally and processed in the digestive system.
But the problem was that the oral dose was too high to be cost-effective. “The 4F peptide can only be made by chemical synthesis,” explains Reddy. “The cost of producing enough 4F peptide by chemical synthesis to achieve efficacy prevented this from being pursued as a therapy in humans.”
The investigators searched for a peptide that could be synthesized in a biological rather than chemical manner. The apoA-I mimetic peptide 6F seemed to fit the bill, so the investigators decided to see if they could produce it in tomatoes. “We wanted to produce the peptide in a plant that could be eaten without cooking, because we felt that cooking the peptide might denature it,” says Fogelman. “The tomato was a convenient and tasty choice.”
The investigators genetically engineered tomatoes to produce 6F, freeze-dried them and ground them into a powder. They then added the powder to a high-fat, high-cholesterol Western diet for mice. “We found that, some hours after feeding the peptide, it was still intact in the small intestine,” says Reddy. “Markers of inflammation in the blood were significantly reduced, HDL-cholesterol and HDL function were significantly improved, and atherosclerosis of the aorta was significantly reduced.”
The investigators say the work demonstrates that tomatoes engineered to produce an apoA-I mimic could potentially reduce inflammation and atherosclerosis when eaten. Because the engineered tomatoes can be eaten whole, there is no need to extract and purify the peptide from the fruit.

Rajendrani MukhopadhyayRajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer and blogger for ASBMB. Follow her on Twitter (www.twitter.com/rajmukhop), and read her ASBMB Today blog, Wild Types.

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