Derlin-1 ameliorates nonalcoholic hepatic steatosis by promoting ubiquitylation and degradation of FABP1

Abstract Background The functions of liver fatty acid binding protein (FABP1) in the regulation of nonalcoholic fatty liver disease (NAFLD) have been demonstrated. However, it is not fully understood how FABP1 expression is dynamically regulated in metabolic disorders. Previous studies have reported that ubiquitin proteasome-mediated degradation of FABP1 is involved, but the mechanism remains unknown. Methods Dysregulated expression of hepatic FABP1 and Derlin-1 was observed in NAFLD patients. We performed mice hepatic tissue co-immunoprecipitation (IP)-based mass spectrum (MS) assays. Derlin-1 interacts with FABP1 and modifies its ubiquitin status, as confirmed by co-IP. The role of Derlin-1 in lipid deposition was tested using adenovirus-mediated overexpression in C57 mice, Derlin-1 overexpression (Derlin-1-OE), or Derlin-1 knockdown (Derlin-1-KO) HepG2 cells. Results As a subunit of the endoplasmic reticulum-associated degradation complex (ERAD), Derlin-1 is negatively associated with NAFLD patients and interacts with and ubiquitinates FABP1. Derlin-1 suppresses FABP1 protein levels and inhibits lipid deposition through a FABP1-dependent pathway. Additionally, Trim25, an E3 ubiquitin ligase present in the endoplasmic reticulum (ER), is recruited to promote Derlin-1-related polyubiquitylation of FABP1, thereby creating a ubiquitin-associated network for FABP1. Overexpression of Derlin-1 ameliorates hepatic steatosis in both C57 mice and HepG2 cells, and contributes to attenuated weight gain, lower liver weight, and visceral fat mass. Conclusions FABP1, a master enzyme that maintains fatty acid metabolism, undergoes degradation by Derlin-1 through ubiquitin modification. The activation of Derlin-1 in vivo may represent a potential therapeutic strategy for NAFLD. Trial registration: Clinical Trials. gov ID: NCT02118376.