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Free Fatty Acid-Induced Cellular Stress Response and Protective Role of Palmitoleate
Maternal obesity has emerged as a significant health challenge in the 21st century and has been shown to influence the health of the fetus in utero and later in life. The prevalence of obesity during pregnancy or maternal obesity is increasing in the US and is associated with increased white adipose tissue and enhanced saturated free fatty acids in the circulation. Fatty acids are essential for optimal cell functions, but excess fatty acid can perturb cellular functions leading to pathological conditions. A recent study from our lab has shown that saturated free fatty acids (FFAs) can induce trophoblast lipoapoptosis. However, there is a gap in knowledge on the mechanisms of FFA-induced trophoblast lipoapoptosis. Our central hypotheses are 1) FFA induces integrated stress response and trophoblast lipoapoptosis via the activation of mitogen activated protein kinases (MAPKs); and 2) palmitoleate, a monounsaturated fatty acid protects against LPS or LPS and FFA-induced inflammation. First, we demonstrated the molecular mechanism underlying PA-induced trophoblast lipoapoptosis using JEG-3 and JAR trophoblasts, in vitro. Trophoblasts were exposed to pathophysiological concentrations of PA and apoptosis was analyzed using various approaches. We further showed PA-induced caspase activation is critical for trophoblast lipoapoptosis using pan-caspase inhibitor ZVAD-Fmk. Next, we observed that treatment of PA resulted in the induction of MAPKs and Endoplasmic Reticulum (ER) stress as evidenced by increased phosphorylation of crucial ER stress protein mediators. Further analysis also revealed that PA-induced formation of stress granules in trophoblasts. Second, we explored the role of an omega-7 monounsaturated fatty acid, palmitoleate (PO), as a potential anti-inflammatory molecule in macrophages and trophoblasts. Our data showed that palmitoleate was able to protect against lipopolysaccharide (LPS) induced inflammatory signal in both macrophages and trophoblasts. Further, palmitoleate was shown to be protective against LPS and FFA induced inflammatory cell death in macrophages. A better understanding of the molecular mechanisms of fatty acid impact on cells could provide information to better understand disease pathology and help develop new therapeutic strategies.
Sahoo, Prakash Kumar, "Free Fatty Acid-Induced Cellular Stress Response and Protective Role of Palmitoleate" (2023). ETD collection for University of Nebraska - Lincoln. AAI30576006.