Role of free fatty acids in endothelial dysfunction

Abstract

Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.

Keywords: Endothelial dysfunction; Free fatty acids; Inflammation; Insulin resistance; Nitric oxide; Oxidative stress.

Fig. 1

Potential mechanisms by which FFAs induce ED. FFAs mediate ED by means of several mechanisms, which might have direct/indirect effects on NO production. For example, FFAs can mediate oxidative stress and inflammation in the endothelium which can affect insulin signaling and contribute to dysregulated NO production. Activation of the RAS by FFAs can elevate the level of ET-1, which can lead to vasoconstriction. Furthermore, FFAs can also activate the apoptotic pathways which can induces apoptosis in ECs and EPCs. Several dietary/therapeutic agents can be beneficial against FFA-induced ED through activation of the eNOS or via the inhibition of NF-κB-mediated inflammatory signaling (has been listed in Table 1)

Fig. 2

Possible targets against FFAs-induced ED. The level of FFAs is elevated in obesity/T2DM which contributes to ED. For a healthy endothelium, a balance in the relative pathways should be maintained. Here, we highlight some targets that may serve as important therapeutic avenue against FFAs-induced ED. These targets include Irisin and Exendin-4, which can increase eNOS activity by several means, but their role in ED, specifically induced by FFAs, should be studied. The Nrf2/HO-1 axis, which is a modulator of oxidative stress, might also have great impact to overcome FFAs-induced ED