Free fatty acid can induce cardiac dysfunction and alter insulin signaling pathways in the heart

Abstract

BackgroundInsulin resistance has been independently related to heart failure. However, the specific mechanisms of high FFA levels in the pathophysiology of heart failure in insulin-resistant states are remain largely unclear. This study investigated whether elevated circulating free fatty acids (FFA) levels result in impaired cardiac structure and function in vivo via insulin-related signaling pathways in myocardium.MethodsMale Wistar rats were randomly divided into the intralipid group (20% intralipid plus heparin infusion) and the control group (glycerol infusion). Blood samples were collected before and after 6-, 12-, and 24-h infusions. Cardiac structure and function were measured using echocardiography. Maximum velocity of myocardial contraction (+dP/dt max) and diastole (−dP/dt max) were measured using a physiological polygraph in vivo. Heart tissues were collected for western blotting.ResultsCompared with the control group, plasma FFA, plasma glucose, and serum insulin levels increased significantly in the intralipid group. With increasing infusion time, cardiac function in the intralipid group decreased gradually compared with the control group. After a 24-h infusion, early (E’, cm/s) diastolic peak velocities and (−dP/dt max) decreased significantly. Protein expression of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and phosphorylated Akt in myocardium increased after a 6-h infusion and decreased significantly after a 24-h infusion in the intralipid group. Protein expression of glucose transporter type 4 (GLUT4), Adenosine 5′-monophosphate -activated protein kinase (AMPK), phosphorylated AMPK(p-AMPK), and endothelial nitric oxide synthase (eNOS) in myocardium gradually decreased in the intralipid group.ConclusionsElevated FFA levels may impair cardiac function and cardiac dysfunction might result from myocardial insulin resistance with significant changes to PI3K-Akt-GLUT4 and AMPK-eNOS signaling pathways with increasing FFA levels.

Effect of the ketogenic diet on glycemic control, insulin resistance, and lipid metabolism in patients with T2DM: a systematic review and meta-analysis

“…Its typical manifestation is the increase of TG and free fatty acid (FFA) [44][45][46][47] . Increased FFA is an independent pathogenic factor for insulin resistance and can possibly increase the risk for cardiovascular diseases 48,49 . Therefore, the improvement of dyslipidemia is beneficial for not only regulating insulin sensitivity but also controlling the occurrence and progression of diabetic complications 50,51 .…”

A high serum-free fatty acid level is associated with cancer

“…Free fatty acids (FFAs) are intermediate products of lipid mobilization that result principally from lipolysis and the breakdown of triglycerides (TGs) (Stich and Berlan 2004). Previous studies have reported that FFA levels are associated with unfavorable functional outcomes in stroke and cardiovascular disease and may play a role in the process of disease progression (Choi et al 2014;Sun et al 2015;Xiong et al 2015;Duan et al 2017;Han et al 2018). In clinical work, we found that in some cancer patients, the FFA level was elevated even when TGs and total cholesterol (TCHO) were normal, and a high FFA level may be the only abnormality in biochemical tests.…”

Short high‐fat diet interferes with the physiological maturation of the late adolescent mouse heart

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