Liraglutide prevents accumulation of lipid linked to cardiac mortality

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. Treatment with liraglutide
could keep the ceramide levels in check, compared with placebo. The results
have been published in the Journal of the American College of Cardiology.

Approximately 16 percent of
the Swedish population suffers from obesity (BMI over 30), which is one of the
greatest risk factors for cardiovascular diseases such as myocardial infarction
and stroke. The World Health Organisation (WHO) estimates that cardiovascular
diseases are the main cause of mortality worldwide, with more than 17 million
deaths a year.

“Understanding the link
between obesity and cardiovascular diseases is important and can lead the way
to the development of new therapies,” says principal investigator docent
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 accumulates
around the heart in obese individuals secreted different metabolites relative
to subcutaneous fat. Notably, thoracic adipose tissue (which surrounds the
heart) from obese individuals 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,”
Wheelock says. “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,” says co-author 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-analogue
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,” Wheelock says.

The study was led and
coordinated by Professor Charalambos Antoniades at the University of Oxford.

“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,” Charalambos Antoniades says. “This presents unique opportunities for the improved diagnosis and treatment of cardiovascular disease.”

IMAGE: PROFESSOR CHARALAMBOS
ANTONIADES AT THE UNIVERSITY OF OXFORD. view more 

CREDIT: OXFORD MEDICAL ILLUSTRATIONS AT
THE JOHN RADCLIFFE HOSPITAL