Researchers have identified a microRNA liver gene, miR-27b, which regulates lipid (cholesterol or fat) levels in the blood. This regulator gene controls multiple genes involved in dyslipidemia-abnormal blood cholesterol levels that can contribute to heart disease. Study details published in the February issue of Hepatology, a journal of the American Association for the Study of Liver Diseases (AASLD), describe a new in silico approach to identify the significance of microRNAs in regulating disease-related gene pathways.
The Human Genome Project (HGP) was completed in April, 2003 and the world had a map of the 3 billion DNA letters making up the human genome. One of the HGP leaders was Dr. Francis Collins, currently NIH Director and contributor to the present study. "The HGP provided the basic instruction book for human biology," explains Dr. Collins. "Further genomic studies, such as the investigation of microRNAs, have built upon the efforts of the HGP to explain how the genome carries out its functions, and helps identify genes involved in the development of disease."
For the present study, lead author Dr. Kasey Vickers from the NIH/NHLBI Lipoprotein Metabolism Section (presently at Vanderbilt University School of Medicine) and colleagues performed high-throughput small RNA sequencing of mouse liver and detected roughly 150 microRNAs. The team used a novel in silico approach to identify microRNA regulatory hub genes involved in lipid metabolism. In human and mouse livers miR-27b was determined to be the strongest hub with 27 predicted targets.
"We found liver miR-27b levels to be sensitive to high triglycerides (hyperlipidemia) in the blood and liver," said Dr. Vickers. The team reported a nearly 3-fold increase in miR-27b levels in the liver of mice on a high-fat diet, with 42% of calories from fat. In human liver tissue cells, researchers determined that miR-27b regulates mRNA and protein expression of key lipid-metabolism genes (Angptl3 and Gpam). Vickers added, "Using a mouse model of dyslipidemia and atherosclerosis, we found hepatic miR-27b and its target genes to be inversely altered, and thus contributing to risk for cardiovascular disease."