Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Lipoprotein biogenesis and transport are crucial for systemic homeostasis and cardiometabolic health.
• The specialization of the secretory pathway for high-capacity lipoprotein export remains incompletely understood.

Purpose of the Study:

• To identify and characterize novel regulators of lipoprotein export.
• To elucidate the role of SEC16B in the secretory pathway and its impact on cardiometabolic health.

Main Methods:

• Integrative bioinformatic analyses to identify co-emerging genes.
• Functional studies and AI-driven prediction to determine SEC16B's mechanism.
• UK Biobank data analysis for human metabolic associations.
• In vivo studies involving hepatic deletion of SEC16B in mice.

Main Results:

• SEC16B was identified as a tissue-selective modulator of the COPII machinery, essential for APOB-lipoprotein secretion.
• SEC16B acts as a molecular brake, fine-tuning COPII condensation for efficient lipoprotein export.
• SEC16B links to human metabolic traits and HNF4A-dependent regulation.
• Hepatic SEC16B deletion in mice reduced circulating APOB, triglycerides, and cholesterol, conferring protection against atherosclerosis and cardiac dysfunction.

Conclusions:

• SEC16B is a specialized modulator of hepatic lipoprotein export via the general secretory pathway.
• SEC16B plays a critical role in regulating lipid metabolism and preventing cardiometabolic diseases.
• Targeting SEC16B may offer novel therapeutic strategies for cardiometabolic disorders.