ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Low hepatic low-density lipoprotein receptor (LDLR) expression causes hypercholesterolemia, a risk factor for atherosclerotic cardiovascular disease (ASCVD).
• Identifying novel regulators of hepatic LDLR is crucial for developing effective hypercholesterolemia treatments.

Purpose of the Study:

• To identify novel genetic modifiers of hepatic LDLR expression using genome-wide CRISPR screening.
• To investigate the therapeutic potential of targeting ABCC4 for managing hypercholesterolemia and ASCVD.

Main Methods:

• Genome-wide CRISPR/Cas9 screening in hepatocytes to identify genes regulating LDLR.
• Inhibition of ABCC4 in cell models and male mice (liver-specific disruption and pharmacological inhibition).
• Analysis of intracellular signaling pathways (Epac2/Rap1a) and protein expression (PCSK9, LDLR).

Main Results:

• ABCC4 was identified as a key regulator of hepatic LDLR abundance.
• ABCC4 inhibition significantly increased hepatic LDLR levels and enhanced LDL cholesterol clearance.
• ABCC4 silencing activated the Epac2/Rap1a pathway, suppressed PCSK9, and prevented LDLR lysosomal degradation.
• Liver-specific ABCC4 disruption and pharmacological inhibition reduced plasma LDL cholesterol in mice.

Conclusions:

• Targeting hepatocyte ABCC4 represents a promising therapeutic strategy for hypercholesterolemia.
• The ABCC4-cAMP-PCSK9-LDLR pathway provides novel insights into cholesterol metabolism regulation.
• Genome-wide CRISPR screening is a powerful tool for discovering therapeutic targets for metabolic diseases.