Zhang Pengcheng, Konja Daniels, Zhang Yiwei, Xu Aimin, Lee In-Kyu, Jeon Jae-Han, Bashiri Ghader, Mitra Alok, Wang Yu
The State Key Laboratory of Pharmaceutical Biotechnology, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
Department of Pharmacology and Pharmacy, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
iScience. 2021 Dec 29;25(1):103709. doi: 10.1016/j.isci.2021.103709. eCollection 2022 Jan 21.
SIRT1 is a metabolic sensor regulating energy homeostasis. The present study revealed that mice with selective overexpression of human SIRT1 in adipose tissue (Adipo-SIRT1) were protected from high-fat diet (HFD)-induced metabolic abnormalities. Adipose SIRT1 was enriched at mitochondria-ER contacts (MERCs) to trigger mitohormesis and unfolded protein response (UPR), in turn preventing ER stress. As a downstream target of UPR, clusterin was significantly upregulated and acted together with SIRT1 to regulate the protein and lipid compositions at MERCs of adipose tissue. In mice lacking clusterin, HFD-induced metabolic abnormalities were significantly enhanced and could not be prevented by overexpression of SIRT1 in adipose tissue. Treatment with ER stress inhibitors restored adipose SIRT1-mediated beneficial effects on systemic energy metabolism. In summary, adipose SIRT1 facilitated the dynamic interactions and communications between mitochondria and ER, via MERCs, in turn triggering a mild mitochondrial stress to instigate the defense responses against dietary obesity-induced metabolic dysfunctions.
SIRT1是一种调节能量平衡的代谢传感器。本研究表明，在脂肪组织中选择性过表达人SIRT1的小鼠（Adipo-SIRT1）可免受高脂饮食（HFD）诱导的代谢异常影响。脂肪组织中的SIRT1在线粒体-内质网接触位点（MERCs）富集，以触发线粒体应激反应和未折叠蛋白反应（UPR），进而预防内质网应激。作为UPR的下游靶点，簇集蛋白显著上调，并与SIRT1共同作用，调节脂肪组织MERCs处的蛋白质和脂质组成。在缺乏簇集蛋白的小鼠中，HFD诱导的代谢异常显著增强，脂肪组织中SIRT1的过表达无法预防这种异常。内质网应激抑制剂处理可恢复脂肪组织SIRT1对全身能量代谢的有益作用。总之，脂肪组织中的SIRT1通过MERCs促进线粒体与内质网之间的动态相互作用和通讯，进而引发轻度线粒体应激，以激发针对饮食性肥胖诱导的代谢功能障碍的防御反应。
