Angiopoietin-like protein 4 converts lipoprotein lipase to inactive monomers and modulates lipase activity in adipose tissue

Abstract

Lipoprotein lipase (LPL) has a central role in lipoprotein metabolism to maintain normal lipoprotein levels in blood and, through tissue specific regulation of its activity, to determine when and in what tissues triglycerides are unloaded. Recent data indicate that angiopoietin-like protein (Angptl)-4 inhibits LPL and retards lipoprotein catabolism. We demonstrate here that the N-terminal coiledcoil domain of Angptl-4 binds transiently to LPL and that the interaction results in conversion of the enzyme from catalytically active dimers to inactive, but still folded, monomers with decreased affinity for heparin. Inactivation occurred with less than equimolar ratios of Angptl-4 to LPL, was strongly temperaturedependent, and did not consume the Angptl-4. Furthermore, we show that Angptl-4 mRNA in rat adipose tissue turns over rapidly and that changes in the Angptl-4 mRNA abundance are inversely correlated to LPL activity, both during the fed-to-fasted and fastedto-fed transitions. We conclude that Angptl-4 is a fasting-induced controller of LPL in adipose tissue, acting extracellularly on the native conformation in an unusual fashion, like an unfolding molecular chaperone.chaperone ͉ heparin affinity ͉ protein folding ͉ surface plasmon resonance

Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise

“…Surprisingly, the most significantly induced gene in the nonexercising leg was angiopoietin-like 4 (ANGPTL4) (Fig. 1A), a sensitive target of the peroxisome proliferator-activated receptor (PPAR) transcription factors that encodes a secreted inhibitor of the enzyme lipoprotein lipase (LPL) (11)(12)(13). LPL catalyzes hydrolysis of circulating triglycerides (TG) and therefore plays a key role in uptake of fatty acids in skeletal muscle (14).…”

Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

“…The dried product was dissolved in 10 mM Tris, pH 8.5, containing 5 M urea. Murine N-terminal angptl4 was expressed in HEK293 cells as described previously (25). Protein concentrations were determined by the bicinchoninic acid assay (Pierce).…”

“…Unlike the apolipoproteins, angptl4 causes irreversible inactivation of LPL by binding to the enzyme and converting active LPL dimers to inactive monomers (25). LPL is known to be stabilized by binding to detergents, emulsion particles, and lipoproteins.…”

Angiopoietin‐Like Protein 4 Is a High‐Density Lipoprotein (HDL) Component for HDL Metabolism and Function in Nondiabetic Participants and Type‐2 Diabetic Patients

“…As a potent LPL inhibitor, ANGPTL4 disrupts LPL dimerization, converting this enzyme into inactive form 9, 10. Because of increased LPL activity, ANGPTL4‐null mice are featured as having lower triglycerides in the blood 11.…”