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 . 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.