| First Author | Ding S | Year | 2020 |
| Journal | Am J Cancer Res | Volume | 10 |
| Issue | 2 | Pages | 595-609 |
| PubMed ID | 32195030 | Mgi Jnum | J:308320 |
| Mgi Id | MGI:6728149 | Citation | Ding S, et al. (2020) Angiopoietin-like 4 deficiency upregulates macrophage function through the dysregulation of cell-intrinsic fatty acid metabolism. Am J Cancer Res 10(2):595-609 |
| abstractText | 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-alpha, 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. |
