Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Hepatic low-density lipoprotein receptor (LDLR) metabolism is vital for cholesterol homeostasis.
• Molecular mechanisms coordinating LDLR trafficking and turnover in response to dietary cholesterol are not fully understood.

Purpose of the Study:

• To identify molecular pathways linking dietary cholesterol signals to LDLR turnover.
• To elucidate the role of Ral GTPases in regulating LDLR metabolism.

Main Methods:

• Investigated Ral GTPase activation by dietary cholesterol in hepatocytes.
• Utilized genetic manipulation (RalGAPB deletion, active Ral mutants) and biochemical assays.
• Examined LDLR trafficking, lysosomal degradation, and cathepsin A (CTSA) activity.

Main Results:

• Chronic dietary cholesterol activates Ral GTPases, promoting LDLR lysosomal degradation and inhibiting recycling.
• Ral activation routes LDLR via the RalBP1-REPS1 complex for internalization and lysosomal degradation by CTSA.
• Ral pathway activation enhances lysosomal CTSA maturation and limits its secretion, increasing LDLR breakdown.

Conclusions:

• A novel Ral GTPase pathway regulates hepatic LDLR turnover independently of transcriptional control or PCSK9.
• Genetic variants in this pathway correlate with human cholesterol levels.
• CTSA inhibition presents a potential therapeutic strategy for hypercholesterolaemia by enhancing LDLR function and cholesterol clearance.