Clusterin is involved in mediating the metabolic function of adipose SIRT1

초록

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 (UPRmt), in turn preventing ER stress. As a downstream target of UPRmt, clusterin was significantly upregulatedand 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 meta-bolic dysfunctions.

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