Zeng Mengqi, Xu Jie, Zhang Zhengyi, Zou Xuan, Wang Xueqiang, Cao Ke, Lv Weiqiang, Cui Yuting, Long Jiangang, Feng Zhihui, Liu Jiankang
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.
National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shannxi, 710004, China.
Redox Biol. 2021 May;41:101948. doi: 10.1016/j.redox.2021.101948. Epub 2021 Mar 19.
Mitochondria harbor a unique fatty acid synthesis pathway (mtFAS) with mysterious functions gaining increasing interest, while its involvement in metabolic regulation is essentially unknown. Here we show that 3-Hydroxyacyl-ACP dehydratase (HTD2), a key enzyme in mtFAS pathway was primarily downregulated in adipocytes of mice under metabolic disorders, accompanied by decreased de novo production of lipoic acid, which is the byproduct of mtFAS pathway. Knockdown of Htd2 in 3T3-L1 preadipocytes or differentiated 3T3-L1 mature adipocytes impaired mitochondrial function via suppression of complex I activity, resulting in enhanced oxidative stress and impaired insulin sensitivity, which were all attenuated by supplement of lipoic acid. Moreover, lipidomic study revealed limited lipid alterations in mtFAS deficient cells which primarily presenting accumulation of triglycerides, attributed to mitochondrial dysfunction. Collectively, the present study highlighted the pivotal role of mtFAS pathway in regulating mitochondrial function and adipocytes insulin sensitivity, demonstrating supportive evidence for lipoic acid being potential effective nutrient for improving insulin resistance and related metabolic disorders.
线粒体拥有一条独特的脂肪酸合成途径（线粒体脂肪酸合成途径，mtFAS），其神秘功能日益受到关注，但其在代谢调节中的作用基本上仍不清楚。在这里，我们表明，mtFAS途径中的关键酶3-羟基酰基-ACP脱水酶（HTD2）在代谢紊乱的小鼠脂肪细胞中主要下调，同时伴随着作为mtFAS途径副产物的硫辛酸从头合成减少。在3T3-L1前脂肪细胞或分化的3T3-L1成熟脂肪细胞中敲低Htd2会通过抑制复合体I的活性损害线粒体功能，导致氧化应激增强和胰岛素敏感性受损，而补充硫辛酸可减轻所有这些影响。此外，脂质组学研究揭示了mtFAS缺陷细胞中有限的脂质变化，主要表现为甘油三酯的积累，这归因于线粒体功能障碍。总的来说，本研究强调了mtFAS途径在调节线粒体功能和脂肪细胞胰岛素敏感性方面的关键作用，为硫辛酸作为改善胰岛素抵抗和相关代谢紊乱的潜在有效营养素提供了支持性证据。
