Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Abstract

Background: Lipoprotein lipase (LPL) clears triglycerides from the blood, and angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. Results: Inhibited LPL is in a complex with ANGPTL4, and upon dissociation LPL regains activity. Conclusion: ANGPTL4 is a reversible, noncompetitive inhibitor of LPL, not an unfolding molecular chaperone as reported previously. Significance: Understanding the mechanism of LPL inhibition supports efforts to develop new therapies for hypertriglyceridemia. Elevated triglycerides are associated with an increased risk of cardiovascular disease, and lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides from circulating lipoproteins. The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. ANGPTL4 was previously described as an unfolding molecular chaperone of LPL that catalytically converts active LPL dimers into inactive monomers. Our studies show that ANGPTL4 is more accurately described as a reversible, noncompetitive inhibitor of LPL. We find that inhibited LPL is in a complex with ANGPTL4, and upon dissociation, LPL regains lipase activity. Furthermore, we have generated a variant of ANGPTL4 that is dependent on divalent cations for its ability to inhibit LPL. We show that LPL inactivation by this regulatable variant of ANGPTL4 is fully reversible after treatment with a chelator.