ALS-associated P56S-VAPB mutation restrains 3T3-L1 preadipocyte differentiation

Yukako Tokutake, Kazunari Gushima, Honami Miyazaki, Takeshi Shimosato, Shinichi Yonekura

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Abstract Amyotrophic lateral sclerosis (ALS), which is the most common motor neuron disease in adults, is a neurodegenerative disease that involves the selective and systematic death of upper and lower motor neurons. In addition to the motor neuron death, altered metabolic functions, such as dyslipidemia, have also been reported for ALS patients; however, the underlying mechanism remains unknown. In the present study, we investigated the effects of ALS-associated P56S-vesicle-associated membrane proteinassociated protein B (VAPB), P56S-VAPB on 3T3-L1 preadipocyte differentiation and on the expression of differentiation-associated genes and unfolded protein response (UPR)-related genes. Experiments with 3T3-L1 cells transfected with wild-type (Wt)-VAPB and P56S-VAPB expression vectors showed that the size of lipid droplets was markedly smaller in P56S-VAPB-expressing cells, although fat accumulated intracellularly. In P56S-VAPB-expressing cells, increased the expression of PPARγ2, aP2, and C/EBPα, the genes deeply involved in adipocyte differentiation, was not observed. Furthermore, the expression levels of the UPR-related ATF4 and CHOP genes were found to be enhanced in the P56S-VAPB-expressing cells. From these results, P56S-VAPB was found to suppress adipocyte differentiation by promoting the activation of the ATF4-CHOP pathway. Given previous reports showing increased ATF4 and CHOP expression levels in neurons of ALS patients, results from the present study suggest that dyslipidemia is caused by enhanced ATF4-CHOP pathway in the adipose tissue of ALS patients.

Original languageEnglish
Article number33680
Pages (from-to)831-837
Number of pages7
JournalBiochemical and biophysical research communications
Volume460
Issue number3
DOIs
Publication statusPublished - 2015 May 8
Externally publishedYes

Keywords

  • ALS
  • Adipocyte
  • Differentiation
  • UPR
  • VAPB

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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