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

## TL;DR

A blood protein called β2-glycoprotein I helps regulate HDL cholesterol in females, with its absence leading to changes in HDL particles and cholesterol levels, especially under high-fat diets.

## Contribution

The study reveals β2-glycoprotein I as a novel, sex-specific regulator of ApoE-containing HDL particles in females.

## Key findings

- Female β2GPI knockout mice showed increased total cholesterol and ApoE enrichment in HDL under high-fat diets.
- β2GPI interacts with ApoE via Domain V in both mice and humans, influencing HDL composition.
- A β2GPI-deficient female patient had larger HDL particles and elevated HDL cholesterol, similar to the mouse model.

## Abstract

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.

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.

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.

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.

β2GPI (Apolipoprotein H) regulates HDL cholesterol levels in a sex-specific manner, significantly impacting lipid metabolism in females but not males.Female β2GPI knockout mice exhibit elevated total cholesterol and enrichment of ApoE in HDL particles, especially under high-fat diet conditions.β2GPI directly interacts with ApoE, with domain V of β2GPI mediating this binding in both mouse and human plasma. A rare β2GPI-deficient female patient showed larger HDL particle size, mirroring the murine phenotype.Findings suggest β2GPI is a novel modulator of ApoE-containing HDL particles in females, with potential relevance to cardiovascular and autoimmune diseases, and possibly Alzheimer’s disease risk.

β2GPI (Apolipoprotein H) regulates HDL cholesterol levels in a sex-specific manner, significantly impacting lipid metabolism in females but not males.

Female β2GPI knockout mice exhibit elevated total cholesterol and enrichment of ApoE in HDL particles, especially under high-fat diet conditions.

β2GPI directly interacts with ApoE, with domain V of β2GPI mediating this binding in both mouse and human plasma.

A rare β2GPI-deficient female patient showed larger HDL particle size, mirroring the murine phenotype.

Findings suggest β2GPI is a novel modulator of ApoE-containing HDL particles in females, with potential relevance to cardiovascular and autoimmune diseases, and possibly Alzheimer’s disease risk.

This study uncovers a new role for a blood protein called β2-glycoprotein I (also known as Apolipoprotein H) in cholesterol metabolism, specifically in females. β2-glycoprotein I is best known for its involvement in autoimmune diseases such as lupus and antiphospholipid syndrome — conditions that mostly affect women and increase cardiovascular risk. Using both mouse models and rare human samples, we found that the absence of β2-glycoprotein I leads to increased levels of certain high-density lipoprotein (HDL) particles in females, but not in males. These HDL particles also showed higher levels of another key protein called Apolipoprotein E (ApoE), which is involved in cholesterol transport and linked to diseases like Alzheimer’s. However, not all HDL particles have the same biological effects — some may be protective, while others could contribute to disease. Our findings suggest that β2-glycoprotein I may play an important role in maintaining the balance of HDL particle types in females. Disrupting this balance could affect how cholesterol is processed in the body, with implications for heart and brain health. This research helps explain important sex differences in disease risk and opens new paths for targeted treatment strategies, particularly for women.