ANGPTL4 induces allosteric changes in lipoprotein lipase that progress to irreversible unfolding and collapse of its catalytic site, an effect mitigated by GPIHBP1 binding.
The study defines the molecular mechanism by which ANGPTL4 inactivates lipoprotein lipase through unfolding, and how GPIHBP1 protects against this, providing crucial insights into intravascular triglyceride metabolism.
Significance Dietary lipids are packaged into triglyceride-rich lipoprotein particles and delivered to many tissues via the bloodstream. A complex of lipoprotein lipase (LPL) and its endothelial cell receptor, GPIHBP1, hydrolyzes lipoprotein triglycerides, releasing fatty acids for uptake by surrounding cells. The efficiency of triglyceride hydrolysis is regulated by physiologic LPL inhibitors: ANGPTL-3, -4, and -8. We defined the binding site for ANGPTL4 on LPL and showed that ANGPTL4 induces allosteric changes in LPL that progress to irreversible unfolding and collapse of LPL’s catalytic site. The binding of GPIHBP1 to LPL augments LPL stability and renders LPL less susceptible to inactivation by ANGPTL4. Our studies provide crucial insights into molecular mechanisms that regulate intravascular triglyceride metabolism.
Leth-Espensen et al. (2021) studied Intravascular triglyceride metabolism. ANGPTL4 vs. GPIHBP1 binding was evaluated on Lipoprotein lipase (LPL) stability and inactivation. ANGPTL4 induces allosteric changes in lipoprotein lipase that progress to irreversible unfolding and collapse of its catalytic site, an effect mitigated by GPIHBP1 binding.