Ministry of Education Key Laboratory of Model Animal for Disease Study, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School, Nanjing University, 12 Xuefu Road, Pukou Area, Nanjing 210061, China.
Department of Oral Surgery, Shanghai Jiao Tong University, 639 Zhizaoju Road, Huangpu District, Shanghai 200240, China.
Int J Mol Sci. 2022 Aug 3;23(15):8634. doi: 10.3390/ijms23158634.
Deficiency in scavenger receptor class B, member 2 (SCARB2) is related to both Gaucher disease (GD) and Parkinson's disease (PD), which are both neurodegenerative-related diseases without cure. Although both diseases lead to weight loss, which affects the quality of life and the progress of diseases, the underlying molecular mechanism is still unclear. In this study, we found that mice showed significantly reduced lipid storage in white fat tissues (WAT) compared to WT mice on a regular chow diet. However, the phenotype is independent of heat production, activity, food intake or energy absorption. Furthermore, adipocyte differentiation and cholesterol homeostasis were unaffected. We found that the impaired lipid accumulation of mice was due to the imbalance between glycolysis and oxidative phosphorylation (OXPHOS). Mechanistically, the mechanistic target of rapamycin complex 1 (mTORC1)/ eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) pathway was down-regulated in Scarb2 deficient adipocytes, leading to impaired mitochondrial respiration and enhanced glycolysis. Altogether, we reveal the role of SCARB2 in metabolism regulation besides the nervous system, which provides a theoretical basis for weight loss treatment of patients with neurodegenerative diseases.
scavenger receptor class B, member 2 (SCARB2) 缺乏与戈谢病 (Gaucher disease, GD) 和帕金森病 (Parkinson's disease, PD) 有关，这两种疾病都是神经退行性疾病，尚无治愈方法。尽管这两种疾病都会导致体重减轻，从而影响生活质量和疾病进展，但潜在的分子机制仍不清楚。在本研究中，我们发现与 WT 小鼠相比，SCARB2 缺陷小鼠在正常饮食时白色脂肪组织（white fat tissues, WAT）中的脂质储存明显减少。然而，这种表型与产热、活动、食物摄入或能量吸收无关。此外，脂肪细胞分化和胆固醇稳态不受影响。我们发现， 小鼠脂质积累受损是由于糖酵解和氧化磷酸化（oxidative phosphorylation, OXPHOS）之间的失衡所致。在机制上，SCARB2 缺陷脂肪细胞中雷帕霉素复合物 1（mechanistic target of rapamycin complex 1, mTORC1）/真核翻译起始因子 4E 结合蛋白 1（eukaryotic translation initiation factor 4E binding protein 1, 4E-BP1）通路被下调，导致线粒体呼吸受损和糖酵解增强。总之，我们揭示了 SCARB2 在代谢调节中的作用，除了神经系统之外，这为治疗神经退行性疾病患者的体重减轻提供了理论依据。
