FBXL5 promotes lipid accumulation in alcoholic fatty liver disease by promoting the ubiquitination and degradation of TFEB.

Abstract

BACKGROUND:

Alcoholic fatty liver disease (AFLD) is characterized by abnormal lipid droplet accumulation in liver. Epigenetic regulation plays an important role in the pathogenesis of AFLD. Comprehensive bioinformatics analysis revealed that an E3 ubiquitin ligase, F-box and leucine-rich repeats protein 5 (FBXL5), was significantly upregulated in AFLD mice.

METHODS:

The mouse model of AFLD was established by feeding Lieber-DeCarli liquid diet containing ethanol. An in vitro model of AFLD was established by treating HepG2 cells with ethanol (EtOH). The FBXL5 expression was assessed by quantitative real-time PCR (qRT-PCR) and western blotting assays. The levels of triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipid accumulation were analyzed by enzyme-linked immunosorbent assay (ELISA) and Nile red staining.

RESULTS:

The FBXL5 expression was markedly up-regulated in in vivo and in vitro models of AFLD compared with controls. Functionally, FBXL5 knockdown alleviated lipid accumulation in EtOH-treated HepG2 cells. Mechanistically, FBXL5 directly interacted with transcription factor EB (TFEB) and accelerated its ubiquitination-mediated degradation. TFEB knockdown reversed the effect of FBXL5 inhibition on decreasing EtOH-induced lipid accumulation.

CONCLUSION:

Our data suggest that FBXL5 promotes lipid accumulation in AFLD by promoting the ubiquitination and degradation of TFEB.

• Authors: Shuo Zhang, Bing Ji, Jing Li, Wenjing Ji, Changqing Yang, Li Yang
• Journal: Cellular signalling (Cell Signal) Vol. 112 Pg. 110905 (Dec 2023) ISSN: 1873-3913 [Electronic] England
• PMID: 37743009 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Inc.

Chemical References

• Ethanol
• F-Box Proteins
• FBXL5 protein, mouse
• Lipids
• TFEB protein, human
• FBXL5 protein, human
• Tcfeb protein, mouse

Topics

• Animals
• Mice
• Epigenesis, Genetic
• Ethanol (toxicity, metabolism)
• F-Box Proteins (metabolism)
• Fatty Liver, Alcoholic (metabolism, pathology)
• Lipids
• Liver (metabolism)
• Ubiquitination
• Humans