Intracellular endotrophin facilitates autophagosome accumulation and interferes with autophagic flux in adipocytes in obesity

Abstract

Endotrophin, a cleavage product of type VI collagen alpha 3 chain (Col6a3), causes systemic insulin resistance by increasing chronic inflammation and fibrosis in adipose tissues (AT) in obesity. Here, we report that endotrophin is internalized partly through caveolin-1-linked endocytosis and trafficked to lysosomes through late endosomes for degradation in AT of lean control. In contrast, the majority of endosomal endotrophin escapes lysosomal degradation in obese AT, where it is released into cytosol via direct interaction with SEC13, a major component of coat protein complex II (COPII) vesicles. Endotrophin facilitates the interaction between SEC13 and autophagy-related 7 (ATG7), leading to autophagosome accumulation and impaired autophagic flux. Mechanically, distinctive trafficking of intracellular endotrophin in obese AT compared to lean control is associated with autophagosome formation and autophagic flux through mediating supply of COPII vesicles to autophagosomes. Thus, accumulation of intracellular endotrophin in adipocytes contributes to autophagic flux disruption, leading to metabolic dysfunction in obesity.