In lipotoxic cardiomyopathy, for example, heart function is disrupted by fat accumulation in heart cells. Obesity and high-fat diets are major risk factors for lipotoxic cardiomyopathy. A team led by Rolf Bodmer, Ph.D. at Sanford-Burnham Medical Research Institute (Sanford-Burnham) recently unraveled an alternative pathway to lipotoxic cardiomyopathy in fruit flies – a genetic mechanism that occurs independently of a diet high in fat. Their study, published in the January 15 issue of Genes & Development, lays the foundation for the development of new ways to combat lipotoxic cardiomyopathy and other types of heart disease.
“It’s a well-accepted notion that if you eat too much fatty food and your body can’t metabolize it properly, you can become obese and this can lead to lipotoxic cardiomyopathy. Our study shows that there is also an alternative cause of obesity and associated heart problems – an imbalance in the fats that normally make up the basic structure of our cells,” explained Hui-Ying Lim, Ph.D., post-doctoral researcher and lead author of the study.
In this study, the researchers analyzed mutant fruit flies (called easily shocked mutants) that have abnormally low levels of phosphatidylethanolamine (PE), a type of fat that makes up a major component of cellular membranes in both flies and mammals. They found that these flies compensate for low PE levels by initiating a mechanism for synthesizing fat. In this mechanism, a protein called sterol regulatory element-binding protein (SREBP) turns on genes encoding metabolic enzymes that synthesize more fat.
As a consequence of high SREBP, these PE-deficient mutant flies also had high levels of triglycerides, heart-damaging fats commonly associated with obesity and type 2 diabetes in humans. The disruption in cell membrane fat synthesis and consequent triglyceride fat accumulation added up to heart problems for flies short on PE-producing enzymes. Compared to their genetically normal counterparts, they were especially prone to cardiac arrest under stress and other heart problems.
Since overactive SREBP seems to be the cause of heart disease in this system, can it be targeted to reduce heart disease? The researchers addressed this question by inhibiting SREBP or its fat-synthesizing target genes through genetic manipulation. In doing so, they were able to restore fat balance and rescue PE-deficient flies from heart malfunction. These beneficial effects were also achieved by reducing SREBP in just the heart, rather than the whole fly. As a result, the flies were still obese, but their hearts functioned normally. These findings further underscore the importance of SREBP in excess fat-related heart diseases, like lipotoxic cardiomyopathy.
“Here we identified a new metabolic pathway that exhibits striking similarities to obesity- and diabetes-related heart failure in humans,” explained Dr. Bodmer, professor and director of the development and aging program at Sanford-Burnham and senior author of the study. “This information might now allow us to interfere with the toxic effects of high fat in the heart by directly manipulating these genes in the heart muscle.”
This study was funded by the American Heart Association (AHA), the Ellison Medical Foundation and the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH). For more information about Sanford-Burnham research, visit http://beaker.sanfordburnham.org.
Lim H-Y, Wang W, Wessells RJ, Ocorr K, Bodmer R. Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila. Genes & Development. January 15, 2011.
About Sanford-Burnham Medical Research Institute
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham, with operations in California and Florida, is one of the fastest-growing research institutes in the country. The Institute ranks among the top independent research institutions nationally for NIH grant funding and among the top organizations worldwide for its research impact. From 1999 – 2009, Sanford-Burnham ranked #1 worldwide among all types of organizations in the fields of biology and biochemistry for the impact of its research publications, defined by citations per publication, according to the Institute for Scientific Information. According to government statistics, Sanford-Burnham ranks #2 nationally among all organizations in capital efficiency of generating patents, defined by the number of patents issued per grant dollars awarded.
Sanford-Burnham utilizes a unique, collaborative approach to medical research and has established major research programs in cancer, neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is especially known for its world-class capabilities in stem cell research and drug discovery technologies. anford-Burnham is a nonprofit public benefit corporation. For more information, please visit www.sanfordburnham.org.