Researchers at the Karolinska Institutet, University of Oxford and University of Copenhagen have shown that elevated levels of lipids known as ceramides can be associated with a ten-fold higher risk of death from cardiovascular disease. However, they noted that treatment with liraglutide could keep the ceramide levels in check, compared with placebo. The results have been revealed in the paper, ‘Fat-Secreted Ceramides Regulate Vascular Redox State and Influence Outcomes in Patients With Cardiovascular Disease’, published in the Journal of the American College of Cardiology.
Obesity is associated with increased cardiovascular risk; however, the potential role of dysregulations in the adipose tissue (AT) metabolome is unknown. The aim of this study was to explore the role of dysregulation in the AT metabolome on vascular redox signalling and cardiovascular outcomes.
"Understanding the link between obesity and cardiovascular diseases is important and can lead the way to the development of new therapies," explained principal investigator docent, Dr Craig Wheelock at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
Fat has traditionally been seen as simply storage tissue, but in recent years it has been shown to be a "biochemical laboratory" capable of producing signalling molecules that exert potent biological functions. Understanding how adipocytes produce and release these molecules opens the possibility of reprogramming them with the aim of preventing future incidence of cardiovascular disease.
Applying a mass-spectrometry method called metabolomics, the Wheelock Laboratory was able to measure levels of multiple metabolites secreted by two kinds of human fat tissue.
The fat that accumulated around the heart in people with obesity secreted different metabolites relative to subcutaneous fat. Notably, thoracic adipose tissue secreted higher levels of ceramides, a kind of lipid that belongs to the sphingolipid family. In particular, elevated levels were observed of a lipid variant called C16:0-ceramide, which is based on palmitic acid - a saturated fat consisting of 16 carbon atoms. Ceramides are found in high levels in cell membranes and are also important signalling molecules.
The researchers were also able to show that ceramides secreted from adipose tissue damaged human blood vessels by initiating a process called oxidative stress, which can eventually lead to heart attacks and stroke.
"These results show emphatically that fat is not just energy-storage tissue but also a source of important bioactive molecules that can have powerful immunomodulatory functions," added Wheelock. "In addition, all tissue is not equal, and the type of fat is clearly important in determining the observed biological function."
To understand the significance of the cardiovascular effects of the ceramides, the researchers studied 633 patients with atherosclerosis, who were monitored for more than five years. They found that elevated levels of both C16:0-ceramide and its glycosylated variant could be linked to a ten-fold increase in the risk of fatal cardiovascular disease, even after controlling for other risk factors including age and weight. The results were consistent with earlier studies by other research groups.
"The results suggest that it could be worth incorporating the measurement of different kinds of sphingolipids, both in their original form as well as the glycosylated variants, to better gauge the risk of the occurrence of a fatal cardiovascular event," said co-author, Dr Antonio Checa, researcher at Karolinska Institutet who developed the sphingolipid platform and conducted the analyses.
The results also gave the researchers reason to examine if high ceramide levels in the blood can be effectively reduced. In the last part of the study, 32 volunteers were placed on a low-calorie diet for eight weeks before being split into two groups, one that received a placebo and one that received liraglutide, a GLP 1-analog drug that is approved for the treatment of obesity and type 2 diabetes. Both groups continued the low-calorie diet for another 44 weeks. One year after the study onset, ceramide levels in the blood had increased significantly in the control group, while levels remained stable in the liraglutide group.
"The most important findings are that we add to the evidence that there is a direct correlation between risk of fatal cardiovascular disease and ceramide levels in the blood, and that this can be treated with an existing medication," said Wheelock.
"We reveal for the first time the role that the ceramides play as messengers that bring about the damaging effect on blood vessels that we see in obesity," said Professor Charalambos Antoniades at the University of Oxford, who led and coordinated the study. "This presents unique opportunities for the improved diagnosis and treatment of cardiovascular disease.
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