A research team at Baylor College of Medicine and collaborating institutions investigated the function of the protein Rev-erbα/β, a key component of the circadian clock, on heart disease development in animal models and human patients.

The team reports in the journal Circulation that Rev-erbα/β in cardiomyocytes mediates a normal metabolic rhythm that enables the cells to prefer lipids as a source of energy during the animal’s resting time, daytime for mice. Removing Rev-erbα/β disrupts this rhythm, reduces the cardiomyocytes’ ability to use lipids in the resting time and leads to progressive dilated cardiomyopathy and lethal heart failure.

“We studied how the Rev-erbα/β gene influenced the metabolism of the heart by knocking it out specifically in mouse cardiomyocytes,” says co-corresponding author Zheng Sun, PhD, associate professor of medicine, section of endocrinology, diabetes and metabolism and of molecular and cellular biology at Baylor, in a statement. “Lacking the gene resulted in progressive heart damage that led to heart failure.”

To learn how Rev-erbα/β mediated its effects, the team analyzed gene and protein expression and a comprehensive panel of metabolites and lipids, during both the awake and sleep hours. They found that the Rev-erbα/β gene is highly expressed only during sleep hours, and its activity is associated with fat and sugar metabolisms.

“The heart responds differently to different sources of energy, depending on the time of the day,” says co-corresponding author Lilei Zhang, MD, PhD, assistant professor of molecular and human genetics and of molecular physiology and biophysics at Baylor. “In the resting phase, which for humans is at night and for mice in the day, the heart uses fatty acids that are released from fats as the main source of energy. In the active phase, which is during the day for people and at night for mice, the heart has some resistance to dietary carbohydrates. We found that without Rev-erbα/β, hearts have metabolic defects that limit the use of fatty acids when resting, and there is overuse of sugar in the active phase.”

“We suspected that when Rev-erbα/β knockout hearts cannot burn fatty acids efficiently in the resting phase, then they don’t have enough energy to beat. That energy deficiency would probably lead to changes in the heart that resulted in progressive dilated cardiomyopathy,” says Sun, a member of Dan L Duncan Comprehensive Cancer Center.

To test this hypothesis, the researchers determined whether restoring the defect in fatty acid use would improve the condition.

“We know that fatty acid use can be controlled by lipid-sensing metabolic pathways. We hypothesized that if we fed the Rev-erbα/β knockout mice more lipids, maybe the lipid-sensing pathways would be activated, override the defect and consequently the heart would be able to derive energy from lipids,” Sun says.

The researchers fed Rev-erbα/β knockout mice one of two high-fat diets. One diet was mostly high-fat. The other was a high-fat/high-sucrose diet, resembling human diets that promote obesity and insulin resistance. “The high-fat/high-sucrose diet partially alleviated the cardiac defects, but the high-fat diet did not,” Sun says.

“These findings support that the metabolic defect that prevents the heart cells from using fatty acids as fuel is causing the majority of the cardiac dysfunction we see in the Rev-erbα/β knockout mice. Importantly, we also show that correcting the metabolic defect can help improve the condition,” Zhang says.

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