Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-Ku, Sendai, 980-8578, Japan.
Division of Clinical Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Sci Rep. 2023 Apr 11;13(1):5883. doi: 10.1038/s41598-023-32083-9.
trans-Fatty acids (TFAs) are unsaturated fatty acids containing at least one carbon-carbon double bond in trans configuration, which are classified into two groups according to their food source: industrial TFAs (iTFAs) and ruminant TFAs (rTFAs). Previous epidemiological evidence has demonstrated a preferential association of iTFAs, rather than rTFAs, with various diseases including cardiovascular diseases. However, it is still unknown how iTFAs exert their specific toxicity and what effective treatments are available to mitigate their toxicity. Here, we performed a comprehensive toxicological assessment of TFAs based on the toxicity mechanism that we established previously. We found that iTFAs including elaidic acid (EA), but not other types of fatty acids including rTFAs, had a strong pro-apoptotic effect upon treatment of extracellular ATP, a damage-associated molecular pattern that induces apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway. We also found that polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid (DHA), potently suppressed EA-dependent increase in ASK1 activation and apoptosis. These results demonstrate that iTFAs specifically exert toxicity by targeting ASK1, and that PUFAs serve as their effective suppressor. Our study provides a molecular basis for risk assessment of foods, and for new prevention and treatment strategies for TFA-related diseases.
反式脂肪酸（TFAs）是指至少含有一个碳-碳双键的不饱和脂肪酸，其空间构型呈反式，根据其食物来源可分为工业 TFAs（iTFAs）和反刍动物 TFAs（rTFAs）两类。先前的流行病学证据表明，iTFAs 与各种疾病（包括心血管疾病）的相关性强于 rTFAs。然而，iTFAs 如何发挥其特有的毒性，以及有哪些有效的治疗方法可以减轻其毒性，目前尚不清楚。在这里，我们根据我们之前建立的毒性机制，对 TFAs 进行了全面的毒理学评估。我们发现，包括油酸（EA）在内的 iTFAs，但不包括 rTFAs 等其他类型的脂肪酸，在处理细胞外 ATP 时具有很强的促凋亡作用，细胞外 ATP 是一种损伤相关分子模式，通过凋亡信号调节激酶 1（ASK1）-p38 MAP 激酶途径诱导细胞凋亡。我们还发现，多不饱和脂肪酸（PUFAs），如二十二碳六烯酸（DHA），能强烈抑制 EA 依赖性的 ASK1 激活和细胞凋亡增加。这些结果表明，iTFAs 通过靶向 ASK1 特异性发挥毒性，而 PUFAs 则是其有效的抑制剂。我们的研究为食品风险评估以及与 TFA 相关疾病的新的预防和治疗策略提供了分子基础。
