Angiopoietin-like 4 (ANGPTL4) regulates plasma
triglyceride levels by inhibiting LPL. Inactivation of ANGPTL4 decreases plasma
triglycerides and reduces the risk of
coronary artery disease. Unfortunately, targeting ANGPTL4 for the therapeutic management of
dyslipidemia and
atherosclerosis is hampered by the observation that mice and monkeys in which ANGPTL4 is inactivated exhibit
lipid accumulation in the mesenteric lymph nodes (MLNs). In mice these pathological events exclusively unfold upon feeding a high saturated FA diet and are followed by an ultimately lethal pro-inflammatory response and
chylous ascites. Here, we show that Angptl4-/- mice fed a diet rich in trans FAs develop numerous
lipid-filled giant cells in their MLNs, yet do not have elevated serum
amyloid and
haptoglobin, do not exhibit
ascites, and survive, unlike Angptl4-/- mice fed a saturated FA-rich diet. In RAW264.7 macrophages, the saturated FA,
palmitate, markedly increased markers of
inflammation and the unfolded protein response, whereas the trans-unsaturated
elaidate and the cis-unsaturated
oleate had the opposite effect. In conclusion, trans and saturated FAs have very distinct
biological effects in macrophages. Furthermore,
lipid accumulation in MLNs is uncoupled from activation of an
acute-phase response and
chylous ascites, suggesting that ANGPTL4 should not be fully dismissed as target for
dyslipidemia.