Charcot-Marie Tooth type 2B (CMT2B) is a rare inherited peripheral neuropathy caused by five missense mutations in the RAB7A gene, which encodes a small GTPase of the RAB family. Currently, no cure is available for this disease. In this study, we approached the disease by comparing the lipid metabolism of CMT2B-derived fibroblasts to that of healthy controls. We found that CMT2B cells showed increased monounsaturated fatty acid level and increased expression of key enzymes of monounsaturated and polyunsaturated fatty acid synthesis. Moreover, in CMT2B cells a higher expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), key enzymes of de novo fatty acid synthesis, with a concomitantly increased [1-¹⁴C]acetate incorporation into fatty acids, was observed. The expression of diacylglycerol acyltransferase 2, a rate-limiting enzyme in triacylglycerol synthesis, as well as triacylglycerol levels were increased in CMT2B compared to control cells. In addition, as RAB7A controls lipid droplet breakdown and lipid droplet dynamics have been linked to diseases, we analyzed these organelles and showed that in CMT2B cells there is a strong accumulation of lipid droplets compared to control cells, thus reinforcing our data on abnormal lipid metabolism in CMT2B. Furthermore, we demonstrated that ACC and FAS expression levels changed upon RAB7 silencing or overexpression in HeLa cells, thus suggesting that metabolic modifications observed in CMT2B-derived fibroblasts can be, at least in part, related to RAB7 mutations.

Charcot-Marie牙2B型（CMT2B）是由RAB7A基因中的五个错义突变引起的罕见的遗传性周围神经病，该基因编码RAB家族的一个小GTPase。目前，尚无可治愈该疾病的方法。在这项研究中，我们通过比较CMT2B衍生的成纤维细胞的脂类代谢与健康对照组的脂类代谢来解决该疾病。我们发现CMT2B细胞显示增加单不饱和脂肪酸水平和增加单不饱和和多不饱和脂肪酸合成的关键酶的表达。此外，在CMT2B细胞中，乙酰辅酶A羧化酶（ACC）和脂肪酸合酶（FAS）是从头脂肪酸合成的关键酶，其表达较高，并随之增加[1- ¹⁴观察到乙酸C]乙酸酯掺入脂肪酸。与对照细胞相比，CMT2B中三酰基甘油合成中的限速酶二酰基甘油酰基转移酶2的表达以及三酰基甘油水平均增加。此外，由于RAB7A控制了脂质滴的分解，并且脂质滴的动力学与疾病有关，因此我们分析了这些细胞器，结果显示，与对照细胞相比，CMT2B细胞中脂质滴的积聚很多，从而加强了异常脂质代谢的数据在CMT2B中。此外，我们证明了在HeLa细胞中RAB7沉默或过表达后，ACC和FAS表达水平发生了变化，因此表明在CMT2B衍生的成纤维细胞中观察到的代谢修饰可能至少部分与RAB7突变有关。