βeta-2 glycoprotein I is a novel regulator of Apolipoprotein E containing HDL particles in females.

BACKGROUND

βeta-2 glycoprotein I (β2GPI, Apolipoprotein H) is a plasma glycoprotein best known as a major autoantigen in autoimmune disorders such as antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE), both of which confer elevated cardiovascular risk. Despite its prominence in autoimmunity, its role in lipid metabolism and potential sex-specific effects remain poorly understood.

METHODS

We investigated β2GPI's influence on lipoprotein profiles using β2GPI knockout (KO) and wild-type (WT) mice subjected to normal chow (NC) and high-fat (HF) diets, as well as plasma from β2GPI-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.

RESULTS

In animal studies, female β2GPI KO mice-but not males-displayed 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, β2GPI was enriched in HDL fractions, and β2GPI co-immunoprecipitated with Apo E. In human studies, the β2GPI-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 β2GPI-Apo E interaction in human plasma, with binding requiring Domain V of β2GPI.

CONCLUSIONS

Our findings identify β2GPI as a sex-specific regulator of HDL metabolism. In females, β2GPI modulates Apo E-containing HDL particles, influencing cholesterol distribution and lipoprotein composition. These results reveal a novel mechanism linking β2GPI to lipid homeostasis, with potential implications for cardiovascular risk in women with autoimmune disease. Targeting β2GPI-Apo E interactions may represent a therapeutic avenue for correcting dysregulated HDL metabolism in female-specific cardiometabolic and autoimmune contexts.