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TNF‐α downregulates CIDEC via MEK/ERK pathway in human adipocytes
Author(s) -
Tan Xinrui,
Cao Zhenzhen,
Li Min,
Xu Erdi,
Wang Jingjing,
Xiao Yanfeng
Publication year - 2016
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1002/oby.21436
Subject(s) - mapk/erk pathway , adipose tissue , 3t3 l1 , downregulation and upregulation , adipocyte , adipose triglyceride lipase , lipolysis , tumor necrosis factor alpha , microbiology and biotechnology , chemistry , endocrinology , cancer research , medicine , phosphorylation , biology , biochemistry , gene
Objective Cell death‐inducing DFF45‐like effector C (CIDEC) is a lipid droplet‐coating protein that promotes triglyceride accumulation and inhibits lipolysis. TNF‐α downregulates CIDEC levels to enhance basal lipolysis, whereas CIDEC overexpression could block this effect. This study aimed to investigate the signaling pathway of TNF‐α‐mediated CIDEC downregulation in human adipocytes. Methods First CIDEC expression was detected in adipose tissue of lean and human subjects with obesity. Next, the temporal‐ and dose‐dependent effects of TNF‐α on CIDEC expression in human SW872 adipocytes were investigated. Selective inhibitors or RNAi or constitutively active MEK1 mutant was used to suppress or stimulate MEK/ERK cascade. Immunofluorescence and subcellular fractionation technique were used to study PPARγ redistribution after TNF‐α treatment. Reporter assay was performed to confirm the direct effects of TNF‐α on CIDEC transcription. Results CIDEC expression decreased in adipose tissue of subjects with obesity and negatively correlated with adipose TNF‐α levels and systemic lipolysis. TNF‐α reduced CIDEC expression in vitro , but suppression of MEK/ERK cascade prevented TNF‐α‐mediated CIDEC downregulation. PPARγ, the transcription factor of CIDEC, was phosphorylated and redistributed by TNF‐α in a MEK/ERK‐dependent manner. Reporter assay confirmed that TNF‐α reduced CIDEC transcription. Conclusions TNF‐α downregulates CIDEC expression through phosphorylation and nuclear export of PPARγ by MEK/ERK cascade.