ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver
Low expression level of low-density lipoprotein receptor (LDLR) in hepatocytes leads to hypercholesterolemia and eventually contributes to atherosclerotic cardiovascular disease (ASCVD). Here, we report that inhibition of hepatocyte ABCC4, identified as a top hit from large-scale CRISPR/Cas9 screens, significantly increases hepatic LDLR abundance and enhances LDL cholesterol clearance. As a hepatic transporter for cAMP efflux, ABCC4 silencing alters its intracellular distribution and activates the downstream Epac2/Rap1a signaling pathway, which ultimately blocks PCSK9 protein expression, thereby preventing lysosomal degradation of LDLR. Furthermore, in both male mice and cell models, we demonstrate that liver-specific disruption and pharmacological inhibition of ABCC4 elevate hepatic plasma membrane LDLR levels and reduce plasma LDL cholesterol through ABCC4-cAMP-PCSK9 pathway. Collectively, our genome-wide CRISPR screening offers a valuable resource for identifying LDLR modifiers, providing potential insights for therapeutic strategies in hypercholesterolemia and atherosclerosis.
Authors
- Guofang Xia (ORCID: https://orcid.org/0000-0002-4345-2491)
- Peng Wei (ORCID: https://orcid.org/0000-0001-7483-5236)
- Lu Li (ORCID: https://orcid.org/0000-0003-4274-9426)
- Jingsong Li (ORCID: https://orcid.org/0000-0002-1064-637X)
- Chunyan Ji (ORCID: https://orcid.org/0000-0003-4438-1768)
- Chengxing Shen (ORCID: https://orcid.org/0000-0002-3882-7586)
- Hao Huang (ORCID: https://orcid.org/0000-0003-1748-1245)
- Guangre Xu
- Liang Wen (ORCID: https://orcid.org/0000-0001-5967-5596)
- Wenjie Tian (ORCID: https://orcid.org/0000-0002-4328-0255)
- Yan Xiong (ORCID: https://orcid.org/0009-0000-1252-3085)
- Jiaxin Chen (ORCID: https://orcid.org/0000-0002-7375-0182)
- Yu Chen (ORCID: https://orcid.org/0000-0001-9682-7894)
- Chi Chen
- Xiaoqing Wang (ORCID: https://orcid.org/0000-0001-7476-8889)
- Hui Huang (ORCID: https://orcid.org/0000-0001-6104-7660)
- Jin Zhou (ORCID: https://orcid.org/0000-0001-6535-9426)
- Peng Luo (ORCID: https://orcid.org/0009-0008-5488-7483)
Institutions
- University of Electronic Science and Technology of China (CN)
- Shanghai Jiao Tong University (CN)
- Sichuan University (CN)
- Shanghai Innovative Research Center of Traditional Chinese Medicine (CN)
- West China Hospital of Sichuan University (CN)
- Shanghai Sixth People's Hospital (CN)
Publication Details
- Journal
- Communications Biology
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1038/s42003-025-08818-x
- Citations
- 1
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- National Natural Science Foundation of China