Scripps scientists create cholesterol-like molecule that reduces atherosclerosis15 October 2014 Scientists at The Scripps Research Institute (TSRI) in the US have synthesised a molecule that mimics high-density cholesterol and shown it can reduce plaque build-up in arteries even when taken orally. The molecule, taken orally, improved blood cholesterol levels and reduced plaque in just two weeks in mice strains that were prone to atherosclerosis. This research, published in the October issue of Journal of Lipid Research, could lead to a new method for treating atherosclerosis, which can cause heart attacks and strokes. Good & bad cholesterol To combat atherosclerosis, researchers are looking for new ways to target and remove low-density lipoprotein (LDL) cholesterol (commonly known as bad cholesterol) from the body. Though the body needs some LDL to stay healthy, high levels lead to dangerous plaque buildups. In contrast, high-density lipoprotein (HDL) cholesterol (good cholesterol) is known for its protective effects. “HDL is like a taxi in the bloodstream; it takes the LDL cholesterol out of the blood and delivers it to the liver,” said Yannan Zhao, a postdoctoral researcher and first author of the new study. From the liver, the LDL is packaged for elimination from the body. Using a method reported by the researchers last year in the Journal of the American Chemical Society, the team created a 'nanopeptide' to have three arm-like structures that can wrap around cholesterol and fats in the blood. Once the synthetic peptide wraps around LDL cholesterol, it removes it by mimicking the behaviour of apoA-1, a protein of HDL, and carrying it to the liver for elimination. A surprising finding The researchers tested this synthetic peptide in a mouse strain bred to be prone to atherosclerosis. The team originally used the synthetic peptide in an experiment they thought would be a gamble. They gave it to mice in their drinking water, but assumed their digestive acids might break down the peptide before it got a chance to interact with its target and modify LDL cholesterol. To their surprise, it worked. After 10 weeks of treatment, the mice had a 40% reduction in LDL cholesterol in their blood and a 50% reduction in the size of plaque lesions in their hearts. Similar results were obtained using nanolipids of the corresponding monomeric peptide. “We were definitely surprised at the results in the oral feeding studies,” said Assistant Professor of Chemistry Luke Leman. “We’ve repeated it many times.” Many cholesterol treatments currently in development rely on an injection, not a pill. With the option of an orally effective peptide, Ghadiri believes researchers are closer to developing an accessible new therapy for atherosclerosis. The researchers also reported no signs of increased inflammation in the blood or toxicity after 10 weeks of the peptide treatment. Gut feeling Ghadiri and his team are now investigating exactly how the synthetic peptide works in the intestines and the possibility that it interacts with beneficial microbes. The researchers believe that finding new targets in the gastrointestinal tract could lead to new therapies for many more diseases. Reference Yannan Zhao et al. Journal of Lipid Research, Published, JLR Papers in Press,
June 29, 2014, DOI 10.1194/jlr.M049262.
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