Angiopoietin-like 4 deficiency upregulates macrophage function through the dysregulation of cell-intrinsic fatty acid metabolism.

Angiopoietin-like 4 (ANGPLT4) regulates lipid metabolism by inhibiting lipoprotein lipase. Abnormal ANGTPL4 levels are associated with metabolic syndrome, atherosclerosis, inflammation, and cancer. We show here that ANGPTL4-deficient mice have abnormally large numbers of macrophages in the spleen, and that these macrophages produce large amounts of TNF-α, CD86, and inducible nitric oxide synthase. However, recombinant ANGPTL4 protein did not inhibit macrophage function ex vivo. Glycolysis and fatty-acid synthesis were upregulated in ANGPTL4-/- macrophages, whereas fatty-acid oxidation was decreased. Elevated levels of free fatty acids in the cytoplasm of ANGPTL4-/- macrophages were confirmed. ANGPTL4-/- macrophages also displayed endoplasmic reticulum (ER) stress after stimulation with LPS. Protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling was activated, but no major change in liver kinase B1 (LKB1)/adenosine 5'-monophosphate (AMP)- activated protein kinase (AMPK) phosphorylation was observed in ANGPTL4-/- macrophages. The modulation of fatty-acid metabolism prevented ER stress and the expression of inflammatory molecules, but the activation of ANGPTL4-/- macrophages was not restored by the inhibition of glycolysis. Thus, ANGPTL4 deficiency in macrophages results in ER stress due to the cell-intrinsic reprogramming of fatty-acid metabolism. Intracellular ANGPLT4 expression could thus be manipulated to modulate macrophage function.