Houston Methodist scientists reversed infertility in sterile mice by reducing high circulating cholesterol with a bacterial protein, providing further evidence that high cholesterol is associated with female infertility. This is a promising development: one in five women of childbearing age in the US cannot conceive after a year of trying.
The results have been published in the American Society for Biochemistry and Molecular Biology’s Journal of Lipid Research.
While this protein’s primary function is to increase bacterial colonization, it also changes the structure of high-density cholesterol-carrying lipoproteins, or HDLs, making it easier for the liver to dispose of the excess cholesterol that prevents fertilization. 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 the “good cholesterol,” carries excess cholesterol from various tissues to the liver for breakdown, lowering cholesterol levels. However, if there is HDL dysfunction, lipid metabolism is altered, which can then be harmful, like its counterpart LDL or low-density lipoprotein. LDL, often referred to as “bad cholesterol,” transports cholesterol from the liver to other tissues, with high levels of it causing accumulation and disease.
“Both HDLs and LDLs contain a mixture of free and esterified cholesterol, and free cholesterol is known to be toxic to many tissues,” said Henry J. Pownall, Ph.D., a biochemistry professor of medicine at the Houston Methodist Research Institute. and corresponding author of the study. “So any dysfunction in HDL could also be a risk factor for several diseases.”
To study HDL dysfunction, the researchers worked with preclinical mouse models that had unnaturally high levels of HDL cholesterol in their bloodstream. While this made them ideal for studying atherosclerosis, Rosales noted that these mice were also completely sterile.
“Cholesterol is the backbone of all steroid hormones, and an orchestra of hormones is needed to have a fertile animal,” Rosales said. “We know that the ovaries are studded with receptors for HDL, so HDL metabolism had to play a very important role in fertility for that reason.”
As predicted, when the researchers fed the sterile mice with a lipid-lowering drug, both LDL and HDL cholesterol levels dropped and the animals were temporarily saved from infertility. Motivated by these results, they turned to the bacterial protein serum opacity factor, which is known to be highly selective for HDL.
“Serum opacity factor is best known in the context of bacterial streptococcal infections where it serves as a virulence factor. But it was also discovered that this protein only responds to HDL and not to LDL or other lipoproteins,” said Rosales. “We hypothesized that administering the serum opacity factor to these mice might also help restore their fertility.”
For their next set of experiments, the team engineered an adeno-associated virus to deliver the serum opacity factor gene to the mice lacking HDL receptors that had 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 plan to next conduct a clinical study to investigate lipid levels in women undergoing treatments for idiopathic infertility, the underlying causes of which are not fully known. If these patients have high HDL levels, the researchers say serum opacity factor could be a future line of treatment.
“Even if we helped 1% of women who are struggling to conceive, it would change their lives, and I think that’s where we can make the most impact with our research,” Rosales said.
Rosales and Pownall’s collaborators on this study were Dedipya Yelamanchili, Baiba K. Gillard, and Jing Liu with the Center for Bioenergetics and Department of Medicine at the Houston Methodist Research Institute; and Antonio M. Gotto Jr. with Weill Cornell Medicine’s Department of Medicine.
This research is funded by the National Institutes of Health (HL149804) and the Bass Endowment.