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Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability

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 c...

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Autores principales: Rosales, Corina, Yelamanchili, Dedipya, Gillard, Baiba K., Liu, Jing, Gotto, Antonio M., Pownall, Henry J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932678/
https://www.ncbi.nlm.nih.gov/pubmed/36596339
http://dx.doi.org/10.1016/j.jlr.2022.100327
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author Rosales, Corina
Yelamanchili, Dedipya
Gillard, Baiba K.
Liu, Jing
Gotto, Antonio M.
Pownall, Henry J.
author_facet Rosales, Corina
Yelamanchili, Dedipya
Gillard, Baiba K.
Liu, Jing
Gotto, Antonio M.
Pownall, Henry J.
author_sort Rosales, Corina
collection PubMed
description 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 (AAV(SOF)) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAV(SOF) 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.
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spelling pubmed-99326782023-02-17 Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability Rosales, Corina Yelamanchili, Dedipya Gillard, Baiba K. Liu, Jing Gotto, Antonio M. Pownall, Henry J. J Lipid Res Research Article 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 (AAV(SOF)) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAV(SOF) 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. American Society for Biochemistry and Molecular Biology 2022-12-31 /pmc/articles/PMC9932678/ /pubmed/36596339 http://dx.doi.org/10.1016/j.jlr.2022.100327 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Rosales, Corina
Yelamanchili, Dedipya
Gillard, Baiba K.
Liu, Jing
Gotto, Antonio M.
Pownall, Henry J.
Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability
title Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability
title_full Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability
title_fullStr Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability
title_full_unstemmed Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability
title_short Serum opacity factor rescues fertility among female Scarb1(−/−) mice by reducing HDL-free cholesterol bioavailability
title_sort serum opacity factor rescues fertility among female scarb1(−/−) mice by reducing hdl-free cholesterol bioavailability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932678/
https://www.ncbi.nlm.nih.gov/pubmed/36596339
http://dx.doi.org/10.1016/j.jlr.2022.100327
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