Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Equipe 11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale, U1138 Paris, France; Université Pierre et Marie Curie, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
Rutgers, New Jersey Medical High School, Newark, NJ, USA.
EBioMedicine. 2018 Apr;30:261-272. doi: 10.1016/j.ebiom.2018.03.028. Epub 2018 Mar 27.
Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis-unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans-unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well-established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids.
根据其碳链长度和饱和度状态，天然脂肪酸具有相当独特的生物学效应。因此，通过额外供应最丰富的天然顺式不饱和脂肪酸——油酸，而不是最丰富的饱和脂肪酸——棕榈酸，可以延长模式生物的寿命。在这里，我们系统地比较了不同饱和、顺式不饱和和异类（工业或反刍动物）反式不饱和脂肪酸在体外引起细胞应激的能力，在培养的人类细胞中表达一系列不同的生物传感器，这些传感器可以检测自噬、高尔基体应激和未折叠蛋白反应的迹象。与顺式不饱和脂肪酸不同，反式不饱和脂肪酸未能刺激自噬迹象，包括 GFP-LC3B 阳性斑点的形成、磷酸肌醇-3-磷酸的产生和转录因子 TFEB 的激活。当评估联合效应时，几种反式不饱和脂肪酸，包括油酸的反式异构体——反式油酸、亚油酸、反式vaccenic 酸和棕榈油酸，在抑制由棕榈酸引起的自噬和内质网应激方面非常有效，但对油酸无效。反式油酸还抑制了体内由棕榈酸引起的自噬诱导，在小鼠肝脏和心脏中也是如此。我们得出结论，尽管反式不饱和脂肪酸的毒性机制尚未完全阐明，但它们能够消除饱和脂肪酸引起的细胞保护应激反应，这可能是其毒性的原因之一。
