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| Xiuchun Li is the first author of the research paper. Photo Credit: UCR/Zhou lab |
A team of researchers led by University of California, Riverside biomedical scientists has identified a small, previously overlooked small RNA molecule that plays a major role in controlling the body’s cholesterol production and the development of heart disease. The molecule, named tsRNA-Glu-CTC, could be a potential new target for future therapies aimed at lowering high cholesterol.
Using PANDORA-seq, a sequencing technology developed at UC Riverside, the scientists were able to detect hidden types of small RNAs in the liver, the organ central to cholesterol metabolism. They found that tsRNA-Glu-CTC is highly abundant in the liver (more than 65% of all detectable tsRNAs or tRNA-derived small RNAs) and responds directly to changes in cholesterol levels. The study was done in mice.
The research established a direct link between tsRNA-Glu-CTC and SREBP2 (Sterol Regulatory Element-Binding Protein 2), a key protein known as the “master regulator” of cholesterol production.
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| Changcheng Zhou Professor of biomedical sciences Photo Credit: Courtesy of University of California, Riverside |
“We found that when tsRNA-Glu-CTC levels rise, it boosts SREBP2 activity, which switches on the genes that synthesize cholesterol,” said Changcheng Zhou, a professor of biomedical sciences in the UCR School of Medicine and the lead author of the study that appears in Nature Communications. “This mechanism directly contributes to higher cholesterol levels and increases the risk of atherosclerosis, or the clogging of arteries.”
Atherosclerosis is a common and serious disease caused by the slow accumulation of sticky plaque — made of cholesterol, fat, and other substances — in the arteries. This buildup narrows the arteries, reducing the flow of oxygen-rich blood to the body’s tissues and organs. According to the National Institutes of Health, approximately 50% of Americans between the ages of 45 and 84 are living with undiagnosed atherosclerosis.
In their mouse models, the researchers successfully used an antisense oligonucleotide (ASO) — genetic material designed to block RNA — to lower tsRNA-Glu-CTC levels. This resulted in a reduction in cholesterol and less severe atherosclerosis in the mice.
Zhou explained that this approach offers an “upstream” advantage over existing cholesterol medications like statins, which act further down the metabolic pathway.
“By targeting the molecule that initiates the cholesterol production boost, it may be possible to achieve a more fundamental and earlier regulation of the process,” he said.
Zhou’s team also found that the naturally occurring, chemically modified form of tsRNA-Glu-CTC was more effective at regulating cholesterol than synthetic versions, a finding that could guide the development of future targeted drugs.
While much of the initial work was conducted in mouse models, the relevance to humans is strong. The researchers analyzed human blood samples and observed that individuals with elevated levels of tsRNA-Glu-CTC tended to have higher circulating cholesterol, suggesting the newly discovered regulatory mechanism is active in human physiology.
“Our study marks the first evidence that a tsRNA can directly influence cholesterol metabolism and heart disease, pointing to a new direction for preventing cardiovascular events,” Zhou said.
Published in journal: Nature Communications
Authors: Xiuchun Li, Rebecca Hernandez, Xudong Zhang, Sijie Tang, Xiaohong Yuan, Jing Wu, Kathy Pham, Hukam C. Rawal, Erica C. Heinrich, Shenglong Zhang, Qi Chen, Tong Zhou, and Changcheng Zhou
Source/Credit: University of California, Riverside | Iqbal Pittalwala
Reference Number: bmed121525_01
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