游离脂肪酸是细胞的主要能量来源，其能够经过酯化后以甘油三酯的形式储存在脂肪组织中。脂肪细胞通过脂水解释放游离脂肪酸到血液中为外周组织所利用。肥胖是由于能量摄入与能量消耗不平衡所导致的脂肪异常增加，与其相关的代谢疾病和癌症严重威胁人类健康。肥胖引起的脂肪组织扩张通过促进脂水解最终导致血液循环中游离脂肪酸浓度的提高。目前，游离脂肪酸和代谢疾病的关系研究比较清楚，但是其与癌症发生和发展的关系所知甚少。PI3K-AKT信号通路包括代谢、生长、增殖和存活等诸多细胞过程中起到关键作用，其是人类癌症中最常被发现异常激活的通路之一。游离脂肪酸能否通过信号转导的方式激活PI3K-AKT信号通路目前并不清楚。通过实验我们发现游离脂肪酸油酸（OA）能够磷酸化并激活AKT。并且使用油酸（OA）衍生物SSO证明其引起的AKT磷酸化并不依赖于甘油三酯的合成。接着我们使用小分子抑制剂以及基因敲除的方式证明油酸（OA）和SSO通过经典的PI3K通路磷酸化并激活AKT。并且我们在分离的原代肝细胞中证明油酸（OA）和SSO引起的AKT激活，通过磷酸化GSK3β促进糖原合成以及磷酸化FOXO1下调糖异生相关基因。进一步研究我们发现钙离子和钙调蛋白参与油酸（OA）或SSO引起的AKT磷酸化。综上所述，本研究发现油酸（OA）可以通过激活PI3K-AKT信号通路并行使下游功能，为游离脂肪酸通过信号转导的方式调控细胞过程提供了依据。本研究还为揭示游离脂肪酸以及其受体参与的PI3K-AKT激活在癌症中的作用提供初步的线索。
Free fatty acids (FFA) are the main cellular energy source, and esterified and stored in adipose tissue as triglycerides. Adipocytes release FFA into the blood by lipolysis for peripheral tissues usage. Obesity results in an abnormal increase in fat tissue caused by an imbalance between energy intake and energy expenditure, and related metabolic diseases and cancers seriously threaten human health. Adipose tissue expansion caused by obesity via increasing lipolysis leads to an increase of FFA concentration in the blood circulation. At present, the relationship between FFA and metabolic diseases is relatively clear, but little is known about its connection with cancer development and progression. The PI3K-AKT signaling pathway plays a key role in many cellular processes including metabolism, growth, proliferation and survival, and is one of the most frequently found aberrantly activated pathways in human cancers. Whether FFA can activate the PI3K-AKT signaling pathway through signal transduction is unclear.We found that OA activates AKT by phosphorylation. Furthermore, the OA derivative SSO is used to demonstrate that the AKT phosphorylation it caused is not dependent on the synthesis of triglycerides. We then demonstrated that OA and SSO phosphorylate and activate AKT via the classical PI3K pathway using small molecule inhibitors and gene knockout. Furthermore, OA and SSO-induced AKT activation in isolated primary hepatocytes, promote glycogen synthesis by phosphorylation of GSK3β, and down-regulate gluconeogenesis-related genes by phosphorylation of FOXO1. Further studies revealed that calcium and calmodulin are involved in AKT phosphorylation induced by OA or SSO.In summary, this study found that OA can activate the PI3K-AKT signaling pathway and execute downstream functions, providing a basis for the regulation of cellular processes by FFA through signal transduction. This study also provides preliminary clues to reveal the role of FFA and their receptors involved PI3K-AKT activation in cancer.
