Mesenchymal stem cells reduce LDL cholesterol in Cushing’s mice
Treatment may be novel strategy for lowering bad cholesterol: Study
Treatment with mesenchymal stem cells, a type of adult stem cell, was shown to reduce the levels of low-density lipoprotein (LDL) cholesterol — known as bad cholesterol — in a mouse model of exogenous Cushing’s syndrome, according to a study conducted in South Korea.
The researchers noted that exogenous Cushing’s, in which high levels of cortisol in the body result from prolonged treatment with glucocorticoids, is linked to metabolic abnormalities. In this study, the team tested the therapeutic efficacy of treatment with mesenchymal stem cells in a mouse model of the condition, which is marked in humans by obesity and high levels of fatty molecules in the blood.
“These results suggest that [mesenchymal stem cells] may offer a novel therapeutic strategy for managing exogenous Cushing’s syndrome by regulating cholesterol metabolism,” the researchers wrote.
The study, “Reduction of Low-Density Lipoprotein Cholesterol by Mesenchymal Stem Cells in a Mouse Model of Exogenous Cushing’s Syndrome,” was published in the journal Tissue Engineering and Regenerative Medicine.
Seeking ways to reduce LDL cholesterol in exogenous Cushing’s model
Cushing’s syndrome refers to a cluster of health problems caused by high levels of cortisol, a hormone that regulates a wide range of biological processes, including energy use and fat storage. Too much cortisol leads to metabolic complications, which manifest as obesity, insulin resistance, high blood pressure, known as hypertension, and dyslipidemia — abnormal levels of fatty molecules in the blood.
Endogenous Cushing’s arises from an underlying medical condition that causes the body to produce excessive amounts of cortisol. Cushing’s disease, the most common type of endogenous Cushing’s syndrome, is caused by tumors in the brain’s pituitary gland that produce large amounts of a signaling molecule that stimulates the production of cortisol.
Exogenous Cushing’s, meanwhile, is caused by the long-term use of immune-suppressing steroid medications.
Mesenchymal stem cells, known as MSCs, are adult stem cells that can differentiate into many other cell types. MSCs respond to injury by secreting and recruiting a range of biological molecules and can also modulate inflammatory responses to promote tissue repair.
Here, a research team from the Ewha Womans University Seoul Hospital in Seouel sought to evaluate the therapeutic effect of MSCs derived from tonsils in a mouse model of exogenous Cushing’s syndrome.
To induce exogenous Cushing’s, healthy male and female mice drank water containing the steroid corticosterone for five weeks. During the third week, MSCs were injected into the abdomen twice.
Over 21 days of corticosterone treatment, both male and female mice gained significant weight. By day 32, female mice had gained more weight than males (150.5% vs. 134.5%). After MSC administration, female mice lost a significant amount of weight, but the male mice did not.
Treatment with stem cells significantly lowered blood sugar in mice
MSC treatment significantly decreased blood sugar, or glucose, levels in both male and female mice. However, blood sugar levels only normalized in male mice.
In female mice, the stem cells attenuated the high levels of triglyceride fats associated with exogenous Cushing’s. Likewise, treatment reduced total cholesterol, primarily due to a decrease in LDL cholesterol. Treatment did not affect the levels of fatty molecules in the blood of male mice, the researchers noted.
The team then explored the underlying mechanisms by which MSCs reduce LDL cholesterol in the bloodstream using a liver cell line.
Liver cells exposed to the steroid dexamethasone for two days showed a transient boost in the expression, or activity, of a gene encoding LXR-alpha, a protein that indirectly promotes the degradation of the LDL receptor by activating another protein called IDOL. When liver cells were cultured alongside MSCs, the expression of genes encoding LXR-alpha and IDOL was significantly reduced. The uptake of LDL into liver cells was also enhanced.
In line with these findings, an examination of mouse livers showed less production of the LDL receptor after chronic corticosterone treatment, which was elevated after MSC administration.
[Treatment with mesenchymal stem cells was found to] reduce circulating LDL cholesterol levels.
“The LDL cholesterol-lowering effect of MSC administration was due to decreased [LXR-alpha] and IDOL expression, which in turn stabilized [LDL receptors] in the liver,” the researchers wrote, noting that, overall, treatment with mesenchymal stem cells was found to “reduce circulating LDL cholesterol levels.”
Given these findings, “further study is warranted,” according to the team.
The scientists called for additional research “to identify the effector molecules of MSCs that reduce weight gain and improve dyslipidemia in exogenous Cushing’s syndrome.” Such studies “will provide insight into the therapeutic potential of MSCs for the treatment of metabolic complications associated with Cushing’s syndrome,” the researchers wrote.
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