SIRT1 deacetylates mitochondrial trifunctional enzyme ? subunit to inhibit ubiquitylation and decrease insulin resistance.

ABSTRACT: Dysregulation of free acid metabolism is a major contributor to the development of insulin resistance and diabetes. Mitochondrial trifunctional enzyme subunit (MTP?) has a critical role in fatty acid ?-oxidation. However, the association between MTP? and insulin resistance is not definitively known. Here, we aimed to determine how MTP? affects insulin resistance. We tested how MTP? affected glucose uptake in insulin-resistant 3T3-L1 adipocytes and white adipose tissue (WAT) of db/db diabetic mice. We also measured how acetylation and ubiquitylation modifications regulated MTP? activation and stability, using quantitative real-time polymerase chain reactions, immunoblotting, and immunoprecipitation. We found that MTP? overexpression promoted glucose uptake via Glut4 translocation to the plasma membrane in 3T3-L1 adipocytes. Moreover, MTP? upregulation decreased glycemia in db/db mice. Deacetylation increased MTP? protein stability and its ability to reduce insulin resistance. The activation of SIRT1, a major deacetylase, prevented MTP? degradation by decreasing its acetylation in adipocytes. Our study demonstrates a new role for MTP? in reducing insulin resistance. Acetylation and ubiquitylation modifications of MTP? were crucial to regulating its function in glucose metabolism.

SUBMITTER: Wang YM 

PROVIDER: S-EPMC7532168 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature