UT Southwestern researchers have discovered a molecular pathway that allows cells to sense when their lipid stores are depleted, causing a flurry of activity that prevents starvation. The findings are reported in Naturemay one day lead to new ways to deal with metabolic disorders and many other diseases.
“Lipids are critical to providing energy and serving components to membranes and other cellular structures,” said study leader Peter Douglas, Ph.D., an associate professor of molecular biology at UT Southwestern. “The mechanism we’ve found seems to be a way for cells to universally measure lipid levels without having to distinguish a huge variety of different types of lipids.”
Dr Douglas, a member of the Hamon Center for Regenerative Science and Medicine at UT Southwestern, explained that mammalian cells possess tens of thousands of different types of chemically different lipids, a class of molecules made up of the most energy-rich hydrocarbon chains. chemicals in the body. In the 1990s, UT Southwestern Nobel laureates Michael Brown, MD, and Joseph Goldstein, MD, both professors of molecular genetics and internal medicine, discovered the first way to detect lipids: the SREBP pathway, which helps cells regulate their cells. a type of lipid called sterols.
Components in the SREBP pathway accomplish this feat by directly binding sterol molecules. However, to cater to a large number of different types of lipids, Dr. Douglas said the cell is likely to have additional sensory mechanisms.
In search of a mechanism that cells could normally use to sense lipid levels, researchers starved Caenorhabditis elegans, a species of roundworm that serves as a conventional laboratory model and shares many genes with humans. When these animals were deprived of food for 24 hours, the researchers found that a protein known as the nuclear hormone receptor 49 (NHR-49) moved from the cytosol – a liquid component of cells – to the nucleus, where it triggered a cascade of gene activity that caused transport of others. proteins on the cell surface to collect extracellular nutrients.
Researchers have found that if C. elegans were well fed, NHR-49 held in place by a protein known as RAB-11.1. This protein belongs to a class known as small G proteins, which were discovered by the late Alfred G. Gilman, MD, PhD, Nobel Prize winner and longtime UTSW Department of Pharmacology, who later served as dean of medical school. Vice President for Academic Affairs and Vice-Rector. But in the face of starvation RAB-11.1 released NHR-49, which allowed it to enter the nuclear system.
Further experiments showed that this release was caused by a lack of a lipid known as geranylgeranylpyrophosphate. Because cells can use virtually any lipid as a starting material for geranylgeranylpyrophosphate, its presence served as a universal signal for acceptable levels of lipids in cells, Dr. Douglas explained.
He added that previous studies by other laboratories have shown that components of this pathway are active in a number of diseases and health problems, including metabolic diseases, cardiovascular disease, viral infections, neurological aging and some cancers. Manipulating this new way of sensing lipids could eventually lead to new treatments for these diseases, Dr. Douglas said.
Dr. Douglas is a researcher at the Southwest Medical Foundation in biomedical research and a researcher at the Cancer Prevention Institute and the Texas Research Institute (CPRIT).
Other Southwestern UT researchers who contributed to this study include Abigail Watterson, Lexus Tage, Naryn Wajahat, Sonya L.B. Arno, Rene S. Fonseca, Chagay T. Beheshti, Patrick Metang, Melina Michelakis, Kielen R. Zurbier, Chase D. Degan and Jeffrey G. MacDonald.
This work was funded by the Clayton Foundation, the Welch Foundation (I-2061-20210327), the National Institutes of Health (R00AG042495, R01AG061338 and R56AG070167) and the CPRIT (RR150089).
Dr. Brown and Dr. Goldstein are Regent Professors at UTSW. Dr. Goldstein is the Department of Molecular Genetics, and Dr. Brown is the Director of the Eric Johnson Center for Molecular Genetics and Human Disease Research. Dr. Brown holds the outstanding WA (Monti) Montcriff Chair in Cholesterol and Arteriosclerosis Research and the Paul J. Department of Medicine. Thomas. Dr. Goldstein holds the Honored Department of Biomedical Research of Julie and Louis A. Beecherl Jr., and the Department of Medicine Paul J. Thomas.