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Alleviation of palmitic acid‐induced endoplasmic reticulum stress by augmenter of liver regeneration through IP3R‐controlled Ca 2+ release
Author(s) -
Xiao Weichun,
Zhang Jing,
Chen Sili,
Shi Yijun,
Xiao Fan,
An Wei
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26463
Subject(s) - endoplasmic reticulum , unfolded protein response , lipotoxicity , transfection , microbiology and biotechnology , palmitic acid , chemistry , gene knockdown , downregulation and upregulation , mitochondrion , liver regeneration , apoptosis , biology , regeneration (biology) , endocrinology , biochemistry , fatty acid , insulin , insulin resistance , gene
The aberrant release of Ca 2+ from the endoplasmic reticulum (ER) contributes to the onset of ER stress, which is closely related to the pathogenesis of non‐alcoholic fatty liver disease. We previously reported that augmenter of liver regeneration (ALR) alleviates ER stress and protects hepatocytes from lipotoxicity. However, the link between ALR protection and the suppression of ER stress remains unclear. In this study, we investigated whether the protection against liver steatosis afforded by ALR is related to its inhibition of calcium overflow from the ER to the mitochondria. The treatment of HepG2 cells with palmitic acid (PA) upregulated IP3R expression, triggering ER‐luminal Ca 2+ release and inducing ER stress. However, in ALR ‐transfected ( ALR ‐Tx) HepG2 cells, PA‐induced cell injury was clearly alleviated compared with that in vector‐Tx cells. After exposure to PA, IP3R expression was downregulated and ER stress was effectively inhibited in the ALR ‐Tx cells, and ER‐Ca 2+ release and simultaneous mitochondrial Ca 2+ uptake were lower than those in vector‐Tx cells. The knockdown of ALR expression with shRNA abolished the protective effects afforded by ALR transfection. PA treatment also suppressed the interaction between BCL‐2 and IP3R in HepG2 cells, whereas this interaction was massively enhanced in the ALR ‐Tx cells, effectively reducing the IP3R‐mediated ER‐Ca 2+ release and thus mitochondrial Ca 2+ influx. Our results suggest that the inhibition of ER stress by ALR is related to the interruption of the interaction between BCL2 and IP3R, demonstrating a novel mechanism of ER stress resistance in ALR ‐Tx cells.