By reducing high levels of circulating cholesterol with a bacterial protein, researchers at Houston Methodist demonstrated another link between high cholesterol and female infertility in sterile mice. One in five American women of reproductive age cannot conceive after a year of trying, so this is an encouraging development.
“We’re working with a protein called serum opacity factor that has unique properties,” said Corina Rosales, PhD, assistant research professor of molecular biology in medicine with the Houston Methodist Research Institute and lead author of the study. “In our experiments, serum opacity factor reduced cholesterol levels by 40 percent in three hours. So, this protein is very powerful.”
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The results are published in the American Society for Biochemistry and Molecular Biology Journal of Lipid Research.
While this protein’s primary function is to increase bacterial colonization, it also changes the structure of cholesterol-carrying high-density lipoprotein, or HDL, making it easier for the liver to dispose of excess cholesterol that prevents pregnancy. The researchers also noted that the dramatic action of serum opacity factor on HDL could be used as a potential alternative to statins, which are the current gold standard for lowering cholesterol in people with atherosclerosis.
HDL, known as “good cholesterol,” carries excess cholesterol from various tissues to the liver for breakdown, thereby lowering cholesterol levels. However, if HDL is dysfunctional, lipid metabolism changes, which can be harmful, as can its counterpart LDL, or low-density lipoprotein. Often called “bad cholesterol,” LDL carries cholesterol from the liver to other tissues, with high levels leading to accumulation and disease.
Henry J., professor of biochemistry in medicine at Houston Methodist Research Institute. “Both HDLs and LDLs contain a mixture of free and esterified cholesterol, and free cholesterol is known to be toxic to many tissues,” said Pownall, PhD and corresponding author. Study. “So, any dysfunction in HDL can be a risk factor for many diseases.”
To study HDL dysfunction, the researchers worked with preclinical mouse models that had abnormally high levels of HDL cholesterol circulating in their bloodstreams. Although this made them ideal for studying atherosclerosis, Rosales observed that these mice were also completely sterile.
“Cholesterol is the backbone of all steroidal hormones, and an orchestra of hormones is essential for a reproductive animal,” Rosales said. “We know that the ovaries are loaded with receptors for HDL, so the metabolism of HDL must therefore play a very important role in fertility.”
As predicted, when the researchers fed the infertile mice a lipid-lowering drug, LDL and HDL cholesterol levels dropped, and the animals were temporarily protected from infertility. Motivated by these results, they turned to the bacterial protein serum opacity factor, known to be highly selective for HDL.
“Serum opacity factor is known primarily in the context of bacterial strep infections where it acts as a virulence factor. But it was also discovered that this protein only reacts with HDL and not with LDL or other lipoproteins,” Rosales said. “We hypothesized that administering serum opacity factor to these mice might help restore their fertility as well.”
For their next set of experiments, the team engineered an adeno-associated virus to deliver the gene for serum opacity factor to mice lacking HDL receptors with high blood cholesterol. When the gene was expressed and the bacterial protein produced, the animals’ HDL cholesterol dropped significantly, and their fertility was restored.
Based on these promising preclinical results, the researchers next plan to conduct a clinical study to investigate lipid levels in women undergoing treatment for idiopathic infertility, where the underlying causes are not fully known. If these patients have high HDL levels, the researchers say that serum opacity factor may be a future line of treatment.
“If we could help the 1 percent of women who are struggling to conceive, that would change their lives, and I think that’s where we can have the most impact with our research,” Rosales said.
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