Abstract
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.
Highlights
Angiopoietin-like 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting LPL
We have previously demonstrated that the development of chylous ascites in Angptl4 / mice fed a saturated fat diet is accompanied by mesenteric lymphadenopathy, as shown by enlarged mesenteric lymph node (MLN) and the appearance of Touton giant cells
To verify that the behavior of elaidate was representative of a broader group of trans-unsaturated FAs, we studied the effect of trans-vaccenate, palmitelaidate, 9Z,11E conjugated linoleate, and 10E,12Z conjugated linoleate in RAW264.7 macrophages
Summary
Angiopoietin-like 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting LPL. 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 lethal pro-inflammatory response and chylous ascites. The activity of LPL is under tight regulation by several proteins to ensure the homeostatic balance in triglyceride disposal under different nutritional and physiological states [6, 7] One of these proteins is angiopoietin-like 4 (ANGPTL4). The pronounced lipid lowering caused by loss of ANGPTL4 in Gpihbp1 / mice may be due to enhanced entry of LPL into the bloodstream via the lymph [10]
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