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

BACKGROUND AND AIMS:The functions of liver fatty acid binding protein 1 (FABP1) in the regulation of nonalcoholic fatty liver disease (NAFLD) have been previously established. However, how FABP1 expression is dynamically regulated in metabolic disorders is unclear. 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 coimmunoprecipitation based mass spectrum assays. Interaction between Derlin-1 and FABP1, and its impact on FABP1 ubiquitination status was evaluated by coimmunoprecipitation. The role of Derlin-1 in lipid deposition was tested using adenovirus-mediated overexpression in C57BL/6 mice, as well as by Derlin-1 overexpression or knockdown in HepG2 cells. RESULTS:As a subunit of the endoplasmic reticulum-associated degradation complex, Derlin-1 was negatively associated with NAFLD patients, interacted with and ubiquitinated FABP1. Derlin-1 suppressed FABP1 levels and inhibited lipid deposition through a FABP1-dependent pathway. Additionally, Trim25, an E3 ubiquitin ligase present in the endoplasmic reticulum, was recruited to promote Derlin-1-related polyubiquitylation of FABP1, thereby creating a ubiquitin-associated network for FABP1 regulation. Derlin-1 overexpression ameliorated hepatic steatosis in both C57BL/6 mice and HepG2 cells, and contributed to attenuated weight gain, lower liver weight, and visceral fat mass. CONCLUSIONS:FABP1 was degraded by Derlin-1 through ubiquitin modification. Negative regulation of FABP1 by Derlin-1 overexpression, suppressed lipid metabolism and alleviated lipid deposition in vivo and in vitro. Hence, Derlin-1 activation in hepatocytes may represent a potential therapeutic strategy for NAFLD.