- Lipotoxic cardiomyopathy (LCM) is caused due to the accumulation of ceramides.
- The main function of the ceramide is to form cell membranes.
- A balanced level of ceramide should be maintained for a robust cardiac function.
Lipotoxic cardiomyopathy (LCM) is a heart condition that usually occurs in patients with diabetes and obesity due to the accumulation of a type of fat known as ceramides, finds a study conducted at Sanford Burnham Prebys Medical Discovery Institute (SBP). The findings of the study are published in the journal Cell Reports
. The study was also helpful to identify various therapeutic drugs that could prevent or reverse the effects of LCM.
"We have used Drosophila as a model to show that elevated levels of ceramide --driven by genetic or dietary manipulation-- is sufficient to induce LCM," says Rolf Bodmer, Ph.D., professor and director of the Development, Aging and Regeneration Program at SBP and senior author of the paper. The research gives direct evidence of the association between ceramides and heart dysfunction and also helps to decrease LCM symptoms by inhibiting ceramide synthesis.
‘Lipotoxic cardiomyopathy (LCM) is caused by the accumulation of ceramides, which occurs due to the consumption of a diet high in fat or high in calories.’
Ceramides play a complicated role in the heart. The main function of the fat is to form cellular membranes, but it gets accumulated when consumed in excess and leads to cardiovascular problems like ventricular thickening, weakened contractility and heart failure.
The scientists used various methods to manipulate the level of ceramide in the Drosophila heart. The studies showed that feeding the flies with ceramides and lowering the gene expression that break down lipids have similar, negative effects. They also found that reducing the level of ceramide caused a condition known as 'restrictive cardiomyopathy.'
According to Bodmer, the reduction and elevation of ceramide levels cause a specific form of lipotoxic cardiomyopathy. He also said that excess or limited quantity of ceramides affect the heart function. Hence, the levels have to be well balanced to ensure robust cardiac function.
The results of the study were based on various genetic and pharmacological methods that were used to increase and decrease ceramide levels. It proved that ceramides play a central role in LCM. Drosophila (fruit flies) was used as a genetic model because their metabolic control systems were similar to mammals.
The study was helpful to identify therapies that control the ceramides and treat LCM. The researchers identified a dozen ceramide-interacting proteins (CIPs) out of which ten of them were tested. These ceramides affect the molecules through various mechanisms and ultimately lead to apoptosis (programmed cell death) and heart muscle protein instability.
Bodmers says that promising results were shown on analyzing a protein called dIAP1. Overexpression of this protein by inhibiting caspases (a protein breakdown enzyme) led to the increase in LCM symptoms. Unc45, a muscle protein maintenance factor is turned down by the ceramides.
Another scientist Stanley Walls says that it is very important to identify protein interaction as they represent new targets to treat lipotoxic cardiomyopathies.
"For example, if this interaction between Unc45 and ceramide is preventing Unc45 from performing its normal maintenance, then screening for small molecules that block that interaction could be an avenue to find therapeutics that help Unc45 maintain its role in optimizing muscle protein function."
These findings may lead to research in various areas like diabetic cardiomyopathy and cancer. The scientists are currently studying on how these lipids influence breast cancer in patients where obesity is a risk factor. Certain cancer cells have shown an increased level of ceramides and with the help of these protein interactions, the progression and establishment of cancer can be analyzed.
Cardiomyopathy is a disease of the heart muscle, which makes it harder to pump the blood to the rest of the body. There are different types of cardiomyopathy some of them are: dilated, hypertrophic and restrictive cardiomyopathy. The common symptoms of the condition are swelling of the legs, fatigue, breathlessness, rapid heartbeat, cough, chest discomfort and dizziness. The condition can be prevented by avoiding alcohol, reducing stress, enough sleep and by eating a healthy diet.
- Stanley M. Walls, Anthony Cammarato, Dale A. Chatfield, Karen Ocorr, Greg L. Harris, Rolf Bodmer. Ceramide-Protein Interactions Modulate Ceramide-Associated Lipotoxic Cardiomyopathy. Cell Reports (2018)