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Despite its prominence in autoimmunity, its role in lipid metabolism and potential sex-specific effects remain poorly understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We investigated \u03b22GPI\u2019s influence on lipoprotein profiles using \u03b22GPI knockout (KO) and wild-type (WT) mice subjected to normal chow (NC) and high-fat (HF) diets, as well as plasma from \u03b22GPI-deficient patients and aged and sex matched controls. Lipoprotein fractions were analyzed for cholesterol and apolipoprotein content, and protein interactions were assessed by co-immunoprecipitation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In animal studies, female \u03b22GPI KO mice\u2014but not males\u2014displayed significantly increased total plasma cholesterol on a HF diet and greater cholesterol content within HDL fractions. Apo E was enriched in HDL fractions from female KO mice under both NC and HF diets, and plasma Apo E was elevated in HF-fed female KOs. In WT females on HF diet, \u03b22GPI was enriched in HDL fractions, and \u03b22GPI co-immunoprecipitated with Apo E. In human studies, the \u03b22GPI-deficient female patient exhibited increased HDL cholesterol, a shift toward larger HDL particles, and enriched Apo E in HDL fractions relative to controls. Co-immunoprecipitation confirmed \u03b22GPI\u2013Apo E interaction in human plasma, with binding requiring Domain V of \u03b22GPI.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our findings identify \u03b22GPI as a sex-specific regulator of HDL metabolism. In females, \u03b22GPI modulates Apo E-containing HDL particles, influencing cholesterol distribution and lipoprotein composition. These results reveal a novel mechanism linking \u03b22GPI to lipid homeostasis, with potential implications for cardiovascular risk in women with autoimmune disease. Targeting \u03b22GPI\u2013Apo E interactions may represent a therapeutic avenue for correcting dysregulated HDL metabolism in female-specific cardiometabolic and autoimmune contexts.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13293-025-00766-9","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T12:54:28Z","timestamp":1760705668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["\u03b2eta-2 glycoprotein I is a novel regulator of Apolipoprotein E containing HDL particles in females"],"prefix":"10.1186","volume":"16","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liming","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maaike","family":"Kockx","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Weaver","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonard","family":"Kritharides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Krilis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bill","family":"Giannakopoulos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"766_CR1","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/S0889-8529(05)70023-2","volume":"27","author":"HN Ginsberg","year":"1998","unstructured":"Ginsberg HN. 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