Stressed About Atherosclerosis?

Science Signaling  15 Dec 2009:
Vol. 2, Issue 101, pp. ec399
DOI: 10.1126/scisignal.2101ec399

Macrophages that have accumulated toxic blood lipids accumulate in blood vessel walls, contributing to the genesis of atherosclerotic plaques (see Liu and Ntambi). Noting that the lipid-filled macrophages in atherosclerotic plaques show activation of the endoplasmic reticulum (ER) stress response, Erbay et al. explored the development of lipotoxic ER stress and its role in atherosclerosis. Treatment of cultured macrophages with palmitate elicited ER stress, as assessed by phosphorylation of PERK (pancreatic ER kinase) and of eIF2-α (eukaryotic translation initiation factor 2α), a response that was blocked by concurrent treatment with the chemical chaperone 4-phenyl butyric acid (PBA). PBA also inhibited palmitate-dependent induction of the ER stress–dependent unfolded protein response, apoptosis, and accumulation of macrophage fatty acid–binding protein-4 (aP2, a cytosolic lipid chaperone, loss of which protects against atherosclerosis). PBA reduced atherosclerotic lesions, and macrophage ER stress and apoptosis—as well as aP2 content—therein, in apolipoprotein E–deficient mice (Apoe–/– mice) fed a Western diet. Palmitate failed to elicit ER stress in macrophages lacking Tcfap2, which encodes aP2; introduction of wild-type (WT) aP2 restored palmitate sensitivity, whereas a lipid-binding mutant form did not. ER stress was attenuated in macrophage-rich regions of early-stage atherosclerotic lesions in Tcfap2–/–;Apoe–/– mice (unlike those in Apoe–/– mice) and in mice treated with an aP2 inhibitor. Lipidomics analysis revealed that, compared with macrophages with aP2, Tcfap2–/– macrophages showed increased abundance of monounsaturated fatty acids (MUFAs), enhanced de novo lipogenesis, and increased stearoyl CoA desaturase (SCD, an enzyme that converts saturated fatty acids to MUFAs) activity; furthermore, Tcfap2–/– macrophages had increased phospholipid content compared with WT macrophages and decreased abundance of cholesterol esters. C16:1n7-palmitate, which was more abundant in Tcfap2–/– than in WT macrophages, protected WT macrophages from palmitate-induced ER stress and apoptosis, whereas knockdown of SCD-1 (more abundant in Tcfap2–/– than in WT macrophages) restored palmitate sensitivity to Tcfap2–/– macrophages. Tcfap2–/– macrophages showed increased ligand-stimulated activity of nuclear receptor LXR, a transcriptional activator of Scd1, and LXR-α knockdown decreased Scd1 mRNA abundance and restored palmitate sensitivity to Tcfap2–/– macrophages, whereas an LXR antagonist mimicked the effects of aP2 deficiency in WT macrophages. The authors thus conclude that aP2 plays a key role in mediating lipotoxic ER stress in macrophages; loss or inhibition of aP2 leads to increased production of LXR and thereby MUFAs, reducing ER stress and protecting against atherosclerosis.

E. Erbay, V. R. Babaev, J. R. Mayers, L. Makowski, K. N. Charles, M. E. Snitow, S. Fazio, M. M. Wiest, S. M. Watkins, M. F. Linton, G. S. Hotamisligil, Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat. Med. 15, 1383–1391 (2009). [PubMed]

X. Liu, J. M. Ntambi, Atherosclerosis: Keep your macrophages in shape. Nat. Med. 15, 1357–1358 (2009). [PubMed]