转铁蛋白受体水平及其罕见变体与人类肥胖有关。
Transferrin receptor levels and its rare variant are associated with human obesity.
作者信息
Qiu Jin, Zhang Zhiyin, Hu Yepeng, Guo Yuhan, Liu Caizhi, Chen Yanru, Wang Dongmei, Su Junlei, Wang Sainan, Ni Mengshan, Xu Sainan, Yu Jian, Hu Tianhui, Song Gaojie, Ma Xinran, Gu Xuejiang, Wang Jiqiu, Xu Lingyan
机构信息
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Department of Endocrinology and Metabolism, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
出版信息
J Diabetes. 2024 Jan;16(1):e13467. doi: 10.1111/1753-0407.13467. Epub 2023 Aug 30.
AIM
Iron homeostasis is critical for functional respiratory chain complex of mitochondrial, thus potentially contributing to fat biology and energy homeostasis. Transferrin receptor (Tfrc) binds to transferrin for extracellular iron uptake and is recently reported to be involved in brown fat development and functionality. However, whether TFRC levels and variants are associated with human obesity is unknown.
METHODS
To investigate the association of TFRC levels and variants with human obesity, fat biopsies were obtained from surgery. Exon-sequencing and genetic assessments were conducted of a case-control study. For TFRC levels assessment in fat biopsy, 9 overweight and 12 lean subjects were involved. For genetic study, obese (n = 1271) and lean subjects (n = 1455) were involved. TFRC levels were compared in abdominal mesenteric fat of pheochromocytoma patients versus control subjects, and overweight versus lean subjects. For genetic study, whole-exome sequencing of obese and matched control subjects were conducted and analyzed. In addition, the possible disruption in protein stability of TFRC variant was assessed by structural and molecular analysis.
RESULTS
TFRC levels are increased in human browning adipose tissue and decreased in fat of overweight patients. Besides, TFRC levels are negatively correlated with body mass index and positively correlated with uncoupling protein 1 levels. Furthermore, a rare heterozygous missense variant p.I337V in TFRC shows a tendency to enrich in obese subjects. Structural and functional study reveals impaired protein stability of the TFRC variant compared to wild-type.
CONCLUSIONS
Reduced TFRC levels and its rare variant p.I337V with protein instability are associated with human obesity.
目的
铁稳态对于线粒体功能性呼吸链复合体至关重要，因此可能对脂肪生物学和能量稳态有影响。转铁蛋白受体（Tfrc）与转铁蛋白结合以摄取细胞外铁，最近有报道称其参与棕色脂肪的发育和功能。然而，TFRC水平和变体是否与人类肥胖相关尚不清楚。
方法
为了研究TFRC水平和变体与人类肥胖的关联，通过手术获取脂肪活检样本。进行了一项病例对照研究的外显子测序和基因评估。对于脂肪活检中TFRC水平的评估，纳入了9名超重和12名瘦受试者。对于基因研究，纳入了肥胖受试者（n = 1271）和瘦受试者（n = 1455）。比较了嗜铬细胞瘤患者与对照受试者、超重与瘦受试者腹部肠系膜脂肪中的TFRC水平。对于基因研究，对肥胖和匹配的对照受试者进行了全外显子测序并分析。此外，通过结构和分子分析评估了TFRC变体蛋白质稳定性的可能破坏情况。
结果
人类棕色脂肪组织中TFRC水平升高，超重患者的脂肪中TFRC水平降低。此外，TFRC水平与体重指数呈负相关，与解偶联蛋白1水平呈正相关。此外，TFRC中一种罕见的杂合错义变体p.I337V在肥胖受试者中有富集趋势。结构和功能研究表明，与野生型相比，TFRC变体的蛋白质稳定性受损。
结论
TFRC水平降低及其具有蛋白质不稳定性的罕见变体p.I337V与人类肥胖相关。
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