A wide range of biochemical, physiological and pathological stimuli have been associated to dysregulation of protein folding process which causes accumulation of unfolded or misfolded proteins in lumen of endoplasmic reticulum (ER), a condition referred to as ER stress. Among the responses raised by the ER stress, an induction of lipogenic genes expression has been observed. Activation of lipid synthesis in hepatocytes upon ER-stress contributes to the development of some liver disease such as steatosis. Acetyl- CoA carboxylase 1 (ACC1), encoded by ACACA gene, catalyzes the ATP-dependent carboxylation of acetyl- CoA to form malonyl-CoA. This reaction is the rate limiting step in the de novo fatty acid biosynthesis. The expression of ACC1 is dysregulated in metabolic disorders associated to obesity, diabetes, insulin resistance, and metabolic syndrome. The aim of this work was to deepen the regulation of ACC1 expression at translational level, characterizing the leader region of ACC1 mRNA. By using several approaches, in HepG2 cells treated with an ER stressor, such as tunicamycin or thapsigargin, we observed an increment of ACC1 expression, at transcriptional and translational level. An internal ribosome entry site (IRES), identified in the leader region of ACC1 mRNA, allows its translation through a cap-independent mechanism. Cellular stress conditions, such as serum starvation and hypoxia, caused an increase in the level of ACC1 protein in HepG2 cells, through the cap-independent translation mediated by IRES. All together, these findings indicate that the presence of IRES in the ACC1 5'-UTR allows translation of ACC1 mRNA under conditions that inhibit the cap-dependent translation.
Human acetyl-CoA carboxylase 1 mRNA translation is enhanced in HepG2 cells under endoplasmic reticulum stress, serum deprivation or hypoxia
MARIANGELA TESTINI;STEFANO TACCONI;GABRIELE V. GNONI;LUISA SICULELLA;FABRIZIO DAMIANO
2017-01-01
Abstract
A wide range of biochemical, physiological and pathological stimuli have been associated to dysregulation of protein folding process which causes accumulation of unfolded or misfolded proteins in lumen of endoplasmic reticulum (ER), a condition referred to as ER stress. Among the responses raised by the ER stress, an induction of lipogenic genes expression has been observed. Activation of lipid synthesis in hepatocytes upon ER-stress contributes to the development of some liver disease such as steatosis. Acetyl- CoA carboxylase 1 (ACC1), encoded by ACACA gene, catalyzes the ATP-dependent carboxylation of acetyl- CoA to form malonyl-CoA. This reaction is the rate limiting step in the de novo fatty acid biosynthesis. The expression of ACC1 is dysregulated in metabolic disorders associated to obesity, diabetes, insulin resistance, and metabolic syndrome. The aim of this work was to deepen the regulation of ACC1 expression at translational level, characterizing the leader region of ACC1 mRNA. By using several approaches, in HepG2 cells treated with an ER stressor, such as tunicamycin or thapsigargin, we observed an increment of ACC1 expression, at transcriptional and translational level. An internal ribosome entry site (IRES), identified in the leader region of ACC1 mRNA, allows its translation through a cap-independent mechanism. Cellular stress conditions, such as serum starvation and hypoxia, caused an increase in the level of ACC1 protein in HepG2 cells, through the cap-independent translation mediated by IRES. All together, these findings indicate that the presence of IRES in the ACC1 5'-UTR allows translation of ACC1 mRNA under conditions that inhibit the cap-dependent translation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
