Rajan Sujith, Hofer Peter, Christiano Amanda, Stevenson Matthew, Ragolia Louis, Villa-Cuesta Eugenia, Fried Susan K, Lau Raymond, Braithwaite Collin, Zechner Rudolf, Schwartz Gary J, Hussain M Mahmood
Department of Foundations of Medicine, New York University Long Island School of Medicine, Mineola, NY 11501, United States of America.
Institute of Molecular Biosciences, University of Graz, Graz, Austria.
Metabolism. 2022 Dec;137:155331. doi: 10.1016/j.metabol.2022.155331. Epub 2022 Oct 10.
The triglyceride (TG) transfer activity of microsomal triglyceride transfer protein (MTP) is essential for lipoprotein assembly in the liver and intestine; however, its function in adipose tissue, which does not assemble lipoproteins, is unknown. Here we have elucidated the function of MTP in adipocytes.
We demonstrated that MTP is present on lipid droplets in human adipocytes. Adipose-specific MTP deficient (A-Mttp) male and female mice fed an obesogenic diet gained less weight than Mttp mice, had less fat mass, smaller adipocytes and were insulin sensitive. A-Mttp mice showed higher energy expenditure than Mttp mice. During a cold challenge, A-Mttp mice maintained higher body temperature by mobilizing more fatty acids. Biochemical studies indicated that MTP deficiency de-repressed adipose triglyceride lipase (ATGL) activity and increased TG lipolysis. Both wild type MTP and mutant MTP deficient in TG transfer activity interacted with and inhibited ATGL activity. Thus, the TG transfer activity of MTP is not required for ATGL inhibition. C-terminally truncated ATGL that retains its lipase activity interacted less efficiently than full-length ATGL.
Our findings demonstrate that adipose-specific MTP deficiency increases ATGL-mediated TG lipolysis and enhances energy expenditure, thereby resisting diet-induced obesity. We speculate that the regulatory function of MTP involving protein-protein interactions might have evolved before the acquisition of TG transfer activity in vertebrates. Adipose-specific inhibition of MTP-ATGL interactions may ameliorate obesity while avoiding the adverse effects associated with inhibition of the lipid transfer activity of MTP.
微粒体甘油三酯转移蛋白（MTP）的甘油三酯（TG）转移活性对于肝脏和肠道中的脂蛋白组装至关重要；然而，其在不组装脂蛋白的脂肪组织中的功能尚不清楚。在此，我们阐明了MTP在脂肪细胞中的功能。
我们证明MTP存在于人类脂肪细胞的脂滴上。喂食致肥胖饮食的脂肪特异性MTP缺陷（A-Mttp）雄性和雌性小鼠比Mttp小鼠体重增加更少，脂肪量更少，脂肪细胞更小且对胰岛素敏感。A-Mttp小鼠的能量消耗高于Mttp小鼠。在冷刺激期间，A-Mttp小鼠通过动员更多脂肪酸来维持更高的体温。生化研究表明，MTP缺陷解除了对脂肪甘油三酯脂肪酶（ATGL）活性的抑制并增加了TG脂解作用。野生型MTP和缺乏TG转移活性的突变型MTP均与ATGL相互作用并抑制其活性。因此，MTP的TG转移活性对于抑制ATGL并非必需。保留其脂肪酶活性的C末端截短的ATGL与全长ATGL的相互作用效率较低。
我们的研究结果表明，脂肪特异性MTP缺陷增加了ATGL介导的TG脂解作用并增强了能量消耗，从而抵抗饮食诱导的肥胖。我们推测，涉及蛋白质-蛋白质相互作用的MTP调节功能可能在脊椎动物获得TG转移活性之前就已经进化。脂肪特异性抑制MTP-ATGL相互作用可能改善肥胖，同时避免与抑制MTP的脂质转移活性相关的不良反应。
