The Rev-erbα/β gene in cardiac cells regulates a normal metabolic rhythm that allows the cell to prefer lipids as an energy source during rest time in animals, during the day in mice.
Removal of Rev-erbα/β disrupts this rhythm, reduces the ability of cardiomyocytes to utilize lipids during resting, and leads to progressive dilated cardiomyopathy and lethal heart failure.
“We investigated how the Rev-erbα/β gene affects heart metabolism by removing it specifically in mouse cardiomyocytes,” said co-author Dr. Zheng Sun, associate professor medicine, endocrinology, diabetes, and metabolism and cell and molecular biology at Baylor.
To find out how Rev-erbα/β mediates its effects, the team analyzed gene and protein expression as well as a panel of metabolites and lipids, during both awake and sleeping hours.
They found that The Rev-erbα/β gene is highly expressed only during sleep hours and its activity is related to fat and sugar metabolism..
During the resting phase, in humans it is at night, and in rats during the day, the heart uses fatty acids secreted from fat as its main source of energy.
During the active phase, which is during the day for humans and at night for mice, the heart has some resistance to dietary carbohydrates.
The researchers found that without Rev-erbα/β, the heart has metabolic defects that limit the utilization of fatty acids at rest and there is an overuse of sugar during the active phase.
To test this hypothesis, the researchers determined whether restoring the defect in fatty acid utilization would improve the condition.
They fed Rev-erbα/β knockout mice one of two high-fat diets. A diet that is mostly high in fat. The other is a high-fat/sucrose diet, much like the human diet that promotes obesity and insulin resistance. A high-fat/sucrose-rich diet partially alleviated heart defects, but a high-fat diet did not.
These findings support that a metabolic defect that prevents heart cells from using fatty acids for fuel causes the majority of cardiac dysfunction.
The researchers then analyzed molecular clock function in the heart tissue of patients with dilated cardiomyopathy who had received heart transplants to find out if clock function was associated with severity. of cardiac dilatation in humans.
Tissue samples were obtained at different times of day and gene expression ratios of the circadian genes Rev-erbα/β and Bmal1 were calculated to provide a temporal pattern. They found that the chronological order of the heart correlated with the severity of cardiac dilation.
Finally, the researchers explore the possibility of pharmacologically manipulating fatty acid and sugar metabolism to improve disease status.
They found that while drugs can help restore altered metabolic pathways, it is important to give the drugs a match with the internal circadian rhythms of metabolic pathways. corresponding.
If the drugs used are out of sync with the pathway they are intended to restore, treatment does not improve the heart condition..
These findings highlight the importance of chronotherapy, circadian rhythmic dosing, not only in this study but also for many other drugs.