Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis

Abstract

Macrophages exhibit endoplasmic reticulum (ER) stress when exposed to lipotoxic signals associated with atherosclerosis, although the pathophysiological significance and the underlying mechanisms remain unknown. Here, we demonstrate that mitigation of ER stress with a chemical chaperone results in marked protection against lipotoxic death in macrophages and prevents macrophage fatty acid binding protein-4 (aP2) expression. Utilizing genetic and chemical models, we show that aP2 is the predominant regulator of lipid-induced macrophage ER stress. Lipid chaperone effects are mediated by the production of phospholipids rich in monounsaturated fatty acids and bioactive lipids that render macrophages resistant to lipid-induced ER stress. Furthermore, aP2’s impact on macrophage lipid metabolism and ER stress response is mediated by upregulation of key lipogenic enzymes by the liver X receptor. Our results demonstrate the central role for lipid chaperones in regulating ER homeostasis in macrophages in atherosclerosis and that ER responses can be modified, genetically or chemically, to protect the organism against the deleterious effects of hyperlipidemia.

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

“…The evidence presented above in conjunction with previous results showing that restoring or improving ER function alleviates atherosclerosis (14,17,47) suggest that inhibiting IRE1 may impair atherosclerosis progression. Therefore, we postulated that administration of IRE1 modulators might have beneficial effects by limiting the inflammatory signaling associated with elevated ER stress in a mouse model of atherosclerosis.…”

“…Our finding that IRE1 maintains the expression of several important proatherogenic genes in macrophages suggests that, when induced by metabolic stress, heightened IRE1 activity could drive the atherosclerotic process. One important activating signal for the UPR in macrophages is exposure to excessive amounts of lipids, which elicits toxicity (14,28,41). This lipotoxicity results in increased production of reactive oxygen species (ROS), ER stress, and inflammation, and it can result in apoptosis (41).…”

“…Therefore, pharmacological manipulation of the UPR-the network of signaling pathways that respond to ER stress-represents a promising therapeutic approach to manage atherosclerosis (7,14,53). The recent discovery of highly selective UPR modulators provides unique opportunities to investigate the contribution of individual UPR branches to the pathogenesis of this disease.…”

“…For example, inhibiting the apoptotic signaling downstream of ER stress through genetic deletion of the proapoptotic transcription factor CCAAT box binding enhancer homologous protein (CHOP) or the signal transducer c-jun N-terminal kinase (JNK) blocks atherosclerosis progression (5,(11)(12)(13). Moreover, modulation of ER stress by using chemical chaperones alleviates atherosclerosis, further supporting the idea that therapeutic modulation of ER function is a promising avenue to combat atherosclerosis (14)(15)(16). Precedence for this notion is provided by pharmacological approaches to improve ER function-and thereby, limit ER stress-that include autophagy inducers, antioxidants, and regulators of ER calcium homeostasis (17)(18)(19).…”

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

“…Besides TLR4-agonistic LPS, the TLR2 ligand zymosan and the TLR3 ligand polyinosine:polycytidylic acid significantly upregulate AFABP in murine macrophages [47]. Furthermore, saturated fatty acids including palmitate induce AFABP production in macrophages [50]. Most interestingly, AFABP is an obligatory mediator coupling toxic lipids (i.e.…”