Saturated, but Not Unsaturated, Fatty Acids Induce Apoptosis of Human Coronary Artery Endothelial Cells via Nuclear Factor-κB Activation

Abstract

High nonesterified fatty acid (NEFA) concentrations, as observed in the metabolic syndrome, trigger apoptosis of human umbilical vein endothelial cells. Since endothelial apoptosis may contribute to atherothrombosis, we studied the apoptotic susceptibility of human coronary artery endothelial cells (HCAECs) toward selected NEFAs and the underlying mechanisms. HCAECs were treated with single or combined NEFAs. Apoptosis was quantified by flow cytometry, nuclear factor B (NFB) activation by electrophoretic mobility shift assay, and secreted cytokines by enzyme-linked immunosorbent assay. Treatment of HCAECs with saturated NEFAs (palmitate and stearate) increased apoptosis up to fivefold (P < 0.05; n ‫؍‬ 4). Unsaturated NEFAs (palmitoleate, oleate, and linoleate) did not promote apoptosis but prevented stearate-induced apoptosis (P < 0.05; n ‫؍‬ 4). Saturated NEFA-induced apoptosis neither depended on ceramide formation nor on oxidative NEFA catabolism. However, NEFA activation via acyl-CoA formation was essential. Stearate activated NFB and linoleate impaired stearate-induced NFB activation. Pharmacological inhibition of NFB and inhibitor of B kinase (IKK) also blocked stearate-induced apoptosis. Finally, the saturated NEFA effect on NFB was not attributable to NEFA-induced cytokine production. In conclusion, NEFAs display differential effects on HCAEC survival; saturated NEFAs (palmitate and stearate) are proapoptotic, and unsaturated NEFAs (palmitoleate, oleate, and linoleate) are antilipoapoptotic. Mechanistically, promotion of HCAEC apoptosis by saturated NEFA requires acyl-CoA formation, IKK, and NFB activation.

Fatty acids from fat cell lipolysis do not activate an inflammatory response but are stored as triacylglycerols in adipose tissue macrophages

“…Unsaturated FAs have been shown to inhibit the LPS-induced NF-κB signalling pathway in macrophages [25,34]. Moreover, monounsaturated FAs, such as oleate, protect against various lipotoxic effects of palmitate [35][36][37][38][39]. The protective effects of oleate are reported at concentrations lower or equimolar to that of palmitate.…”

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders?

“…[52] Palmitoleic acid supplementation seems to promote important effects to control obesity. For example, Yang et al [49] showed that palmitoleic acid induces satiety in mice, while studies with obese high-fat diet fed mice have shown that daily administration of palmitoleic acid (300 mg kg −1 ) for 10 d increased whole body insulin sensitivity [4,51] and enhanced glucose uptake into adipose tissue by modulation of GLUT-4 content and AMPK phosphorylation.…”

“…Cell culture/animal model Effect of palmitoleic acid [8] Rat pancreatic cells exposed to glucose β Cell proliferation and function [9] Rat islets of Langerhans exposed to several glucose levels Counteracted effect of high glucose [7] Human islet cells exposed to several glucose levels β Cell proliferation; counteracted effect of high glucose [76] Rat L6 skeletal muscle cells Glucose uptake, glucose oxidation, glycogen synthesis not attributed to insulin, GLUT 1 and 4 [52] Endothelial cells treated with single or combined fatty acids Stearate-induced apoptosis [3] Mice deficient in adipose tissue lipid chaperones aP2 and mal1, showing a high production of palmitoleic acid in adipose tissue, fed on HFD Mouse resistant to the deleterious effects of high fat, AKT and IRS (muscle), insulin action (muscle), SCD-1, FAS, ELOV6 (liver), NAFLD [94] F1 hamster, 12 weeks diet with 10% (wt:wt) of macadamia, palm, coconut or sunflower oil (n = 8)…”

“…[12,87,88] In particular, elevated plasma levels of NEFAs are frequently observed in patients with MetS and visceral obesity [52] ; NEFAs may promote endothelial dysfunction, the first step of atherosclerosis, by immune activation and upstream regulation of the nuclear transcription factor kappa B (NFκB). [87] By triggering NFκB, [89] saturated fatty acids such as palmitate (16:0) and stearate (18:0), promote crucial events in the initial steps of atherogenesis.…”

“…In endothelial cells, Staiger et al [52] showed that palmitoleic acid reduced the proapoptotic effects of palmitate and stearate. We observed that palmitoleic acid reduced the production of cytokines and chemokines (IL-6, IL-8, MCP-1) and the cell-surface content of ICAM-1 Intercellular Adhesion Molecule in endothelial cells stimulated with TNF-α (Souza et al, in press) ( Figure 2).…”