Alleviation of palmitic acid‐induced endoplasmic reticulum stress by augmenter of liver regeneration through IP3R‐controlled Ca2+ release

The aberrant release of Ca2+ 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 Ca2+ 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‐Ca2+ release and simultaneous mitochondrial Ca2+ 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‐Ca2+ release and thus mitochondrial Ca2+ 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. ALR reduces IP3R‐mediated Ca2+ release by decreasing the expression of IP3R and increasing the expression of Bcl‐2. And this leads to the attenuating ER stress and mitochondrial Ca2+ uptake, thus protecting liver cells from hepatic steatosis and cell apoptosis.