# Enhanced lymphocyte infiltration in the liver of LDL receptor and Myeloid Differentiation 1 double knockout mice on high fat diet

## TL;DR

This study shows that MD-1 deficiency in mice with LDL receptor deficiency leads to increased fat levels and more lymphocytes in the liver when on a high-fat diet.

## Contribution

The study reveals a novel role of MD-1 deficiency in enhancing lymphocyte infiltration and lipid levels in LDL receptor-deficient mice on a high-fat diet.

## Key findings

- MD-1 deficiency did not affect atherosclerosis development but increased serum lipid levels in LDLr−/− mice.
- LDLr−/−/MD-1−/− mice showed a Th2 antibody shift and increased B-cell percentage after 24 weeks of HFD.
- Lymphocyte infiltration, mainly B2B cells and CD4+T cells, was observed in the liver of LDLr−/−/MD-1−/− mice.

## Abstract

Myeloid differentiation 1 (MD-1; gene name: ly86), a glycoprotein that forms a complex with radioprotective protein 105 (RP105), is involved in the regulation of inflammation, obesity, and insulin resistance. Previous reports have shown an exacerbation of cardiac pathology in MD-1 deficient mice, including pressure overload-induced cardiac remodeling and high fat diet (HFD) -induced inflammatory atrial fibrosis. Furthermore, MD-1 expression is upregulated in atherosclerosis, as indicated by DEG database analysis, and is present in human atherosclerotic plaques. However, its involvement in atherosclerosis is unclear. In this study, we analyzed the effect of MD-1 deficiency on the development of HFD-induced atherosclerosis in littermates of low-density lipoprotein (LDL) receptor-deficient mice (LDLr−/−/MD-1+/− and LDLr−/−/MD-1−/−). In contrast to RP105 deficient mice in previous reports, MD-1 deficiency did not clearly influence atherosclerosis development. However, LDLr−/−/MD-1−/− mice exhibited significantly higher serum levels of total protein, triglycerides, cholesterol, LC/MS-detected lipophilic compounds, and an increased peripheral B-cell percentage with a Th2 antibody shift after 24 weeks of HFD. Furthermore, lymphocyte infiltration, predominantly of B2B cells and CD4+T cells, was visible in random cross-sectional liver sections from LDLr−/−/MD-1−/− mice. Our results indicated that MD-1 deficiency leads to further hyperlipidemia, Th2 shift, and enhances lymphocyte infiltration in the LDLr−/− liver.

The online version contains supplementary material available at 10.1038/s41598-025-21070-x.