TY - JOUR
T1 - Serum opacity factor rescues fertility among female Scarb1−/− mice by reducing HDL-free cholesterol bioavailability
AU - Rosales, Corina
AU - Yelamanchili, Dedipya
AU - Gillard, Baiba K.
AU - Liu, Jing
AU - Gotto, Antonio M.
AU - Pownall, Henry J.
N1 - Funding Information:
This work was supported by the National Institutes of Health (HL149804) and the Bass Endowment.
Publisher Copyright:
© 2023 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.
PY - 2023/2
Y1 - 2023/2
N2 - Human female infertility, 20% of which is idiopathic, is a public health problem for which better diagnostics and therapeutics are needed. A novel cause of infertility emerged from studies of female mice deficient in the HDL receptor gene (Scarb1). These mice are infertile and have high plasma HDL cholesterol (C) concentrations, due to elevated HDL-free cholesterol (FC), which transfers from HDL to all tissues. Previous studies have indicated that oral delivery of probucol, an HDL-lowering drug, to female Scarb1¡/¡ mice reduces plasma HDL-C concentrations and rescues fertility. Additionally, serum opacity factor (SOF), a bacterial virulence factor, disrupts HDL structure, and bolus SOF injection into mice reduces plasma HDL-C concentrations. Here, we discovered that delivering SOF to female Scarb1¡/¡ mice with an adeno-associated virus (AAVSOF) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAVSOF did not alter ovary-FC content, the ovary-mol% FC correlated with plasma HDL-mol% FC in a fertility-dependent way. Therefore, reversing the abnormal plasma microenvironment of high plasma HDL-mol% FC in female Scarb1-/- mice rescues fertility. These data provide the rationale to search for similar mechanistic links between HDL-mol% FC and infertility and the rescue of fertility in women by reducing plasma HDL-mol% FC.
AB - Human female infertility, 20% of which is idiopathic, is a public health problem for which better diagnostics and therapeutics are needed. A novel cause of infertility emerged from studies of female mice deficient in the HDL receptor gene (Scarb1). These mice are infertile and have high plasma HDL cholesterol (C) concentrations, due to elevated HDL-free cholesterol (FC), which transfers from HDL to all tissues. Previous studies have indicated that oral delivery of probucol, an HDL-lowering drug, to female Scarb1¡/¡ mice reduces plasma HDL-C concentrations and rescues fertility. Additionally, serum opacity factor (SOF), a bacterial virulence factor, disrupts HDL structure, and bolus SOF injection into mice reduces plasma HDL-C concentrations. Here, we discovered that delivering SOF to female Scarb1¡/¡ mice with an adeno-associated virus (AAVSOF) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAVSOF did not alter ovary-FC content, the ovary-mol% FC correlated with plasma HDL-mol% FC in a fertility-dependent way. Therefore, reversing the abnormal plasma microenvironment of high plasma HDL-mol% FC in female Scarb1-/- mice rescues fertility. These data provide the rationale to search for similar mechanistic links between HDL-mol% FC and infertility and the rescue of fertility in women by reducing plasma HDL-mol% FC.
KW - HDL receptor gene
KW - Infertility
KW - bacterial virulence factor
KW - cholesterol transport
KW - gene therapy
KW - high-density lipoproteins
KW - ovary morphology
KW - ovary-free cholesterol content
KW - plasma HDL cholesterol
KW - serum opacity factor delivery
KW - Humans
KW - Cholesterol/metabolism
KW - Biological Availability
KW - Scavenger Receptors, Class B/genetics
KW - Animals
KW - Cholesterol, HDL
KW - Fertility
KW - Female
KW - Mice
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U2 - 10.1016/j.jlr.2022.100327
DO - 10.1016/j.jlr.2022.100327
M3 - Article
C2 - 36596339
AN - SCOPUS:85148772668
SN - 0022-2275
VL - 64
SP - 100327
JO - Journal of lipid research
JF - Journal of lipid research
IS - 2
M1 - 100327
ER -