Abstract The biogenesis and transport of lipoproteins are essential for systemic homeostasis and cardiometabolic health, yet how the secretory pathway acquires specialization to support high-capacity lipoprotein export remains unclear. Here, we report SEC16B as a tissue-selective modulator of the COPII machinery, critical for the efficient secretion of APOB-containing lipoproteins. Integrative bioinformatic analyses identify that SEC16B co-emerges with core genes involved in lipoprotein biogenes