ACBP protein links cortisol to Cushing’s symptoms: Mouse study
Suppressing protein activity abolished Cushing's syndrome signs in mice
A protein called ACBP mediates the relationship between elevated levels of cortisol, the hallmark feature of Cushing’s syndrome, and the development of associated symptoms, according to a mouse study led by researchers in France.
Using several methods to suppress ACBP activity, the researchers abolished Cushing’s signs in the mice — eliminating increased appetite, weight gain, fat buildup, and type 2 diabetes.
Each of these is a known risk factor for cardiovascular disease, which is the leading cause of death in Cushing’s, the team noted.
“It appears that [ACBP] constitutes an actionable target that is causally involved in the development of Cushing’s syndrome,” the researchers wrote, noting that blood ACBP “concentrations were elevated in … mice with Cushing’s syndrome.”
Their study, “Pathogenic role of acyl coenzyme A binding protein (ACBP) in Cushing’s syndrome,” was published in the journal Nature Metabolism.
The researchers noted that these findings “importantly provide new insights into the molecular pathways mediating increased cardiometabolic risk in the presence of glucocorticoid excess,” according to an editorial comment published in the same journal, alongside the study.
Investigating the links between ACBP and Cushing’s symptoms
Cushing’s syndrome is marked by prolonged exposure to high levels of the hormone cortisol. It can be caused by the long-term use of immune-suppressing glucocorticoid medications, which activate cortisol receptors, or by problems within the body itself. Such problems can include Cushing’s disease, in which tumors in the brain’s pituitary gland ultimately lead to excessive cortisol production.
Characteristic symptoms of Cushing’s include a round face, skin changes, obesity, muscle weakness and loss, fatigue, and mood disorders. The condition also is typically accompanied by metabolic disturbances, such as abnormal levels of fat molecules in the blood, known as dyslipidemia, insulin resistance, type 2 diabetes, and high blood pressure. Altogether, these effects increase the risk of cardiovascular disease and mortality.
ACBP, fully called acyl coenzyme A binding protein, is responsible for transporting fats, or lipids, within cells as part of lipid metabolism. However, it’s also been found to modulate certain receptors in the nervous system. Among its many functions, ACBP plays a major role in the body’s response to low nutrient intake — such as starvation, where it’s released from cells to stimulate feeding.
Overall, sustained elevations of ACBP are associated with old age, obesity, metabolic disturbances, chronic inflammation, and kidney failure. Moreover, studies have shown that deleting ACBP in animal models reduced inflammation, scarring (fibrosis), and cell death in several organs, and extended their survival.
“Although these associations have led to the suggestion that ACBP could serve as a biomarker for metabolic dysfunction, more recent studies have pointed to the potential of ACBP as a therapeutic target for obesity-related comorbidities,” or co-occurring conditions, the editorial comment noted.
In their first set of experiments using mice, the researchers showed that exposure to corticosteroids reduced ACBP within cells in a dose-dependent manner. This was accompanied by a significant increase in ACBP in the bloodstream.
In line with these data, the team found that patients with active Cushing’s and people receiving glucocorticoid therapy had elevated levels of ACBP in their bloodstream. In Cushing’s patients, such levels significantly correlated with a high body mass index, a measure of body fat content based on weight and height.
Findings now must be validated in the clinic, researchers note
To assess the impact of reducing ACBP activity, the team induced Cushing’s syndrome in mice by exposing the animals to high doses of corticosterone, a rodent glucocorticoid.
The researchers then used several methods to lower ACBP levels or inhibit its effects in the animals. These methods included treating the mice with antibodies against ACBP, deleting the gene that encodes for the protein, chemically reducing the gene’s activity, or selectively mutating ACBP’s receptor in the nervous system.
“These … approaches abolished manifestations of Cushing’s syndrome” in the mice, the researchers reported. Specifically, Cushing’s symptoms such as increased food intake, weight gain, excessive fat buildup known as adiposity, liver damage, high levels of fats in the blood, and type 2 diabetes, all were eliminated.
Importantly, according to the researchers, ACBP inhibition did not affect corticosterone levels, and its benefits were independent of reduced feeding.
Approaches [that lowered ACBP levels or inhibited its effects in mice] abolished manifestations of Cushing’s syndrome. … The effects of ACBP inhibition on immune cell function and inflammation will be crucial to investigate further.
Lastly, an analysis of gene activity in liver tissue found that blocking ACBP reduced lipid-building pathways induced by corticosterone, while reactivating immune-related genes suppressed by the steroid.
“Given the widespread use of glucocorticoids as an anti-inflammatory therapy, the effects of ACBP inhibition on immune cell function and inflammation will be crucial to investigate further,” authors wrote in the editorial comment.
In the main study, the team noted that “it appears that a glucocorticoid-induced increase in extracellular [ACBP] levels is mechanistically involved in the … manifestation of several signs of Cushing’s syndrome.”
However, the scientists noted that these are early data, and further research is needed.
“These results obtained in [this mouse] model of Cushing’s syndrome require future clinical validation,” they wrote.
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