Several 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. As part of a complex intracellular signaling pathway, a reduction of global and CAP-dependent protein synthesis is observed in ERstressed cells. Induction of lipogenic genes expression has been observed in cells under ER and contributes to the development of liver diseases such as steatosis. ATP citrate lyase (ACLY) catalyzes the ATP-dependent production of oxaloacetate and acetyl-CoA, the last representing the starter molecule for fatty acids and cholesterol synthesis. Considering that acetyl-CoA is also used in the protein acetylation, ACLY could influence different cellular processes. The expression of ACLY is dysregulated in metabolic disorders associated to obesity, diabetes, insulin resistance, and metabolic syndrome. By using several approaches, we deepened the regulation of ACLY expression in HepG2 cells treated with an ER stressor, such as tunicamycin or thapsigargin. We observed an increment of ACLY expression, at transcriptional and translational level. An internal ribosome entry site (IRES), identified in the leader region of ACLY mRNA, allows its translation through a capindependent mechanism. All together, these findings indicate that the presence of an IRES in the ACLY 5'-UTR allows translation of ACLY mRNA under conditions that inhibit the cap-dependent translation.
Enhanced ATP-citrate lyase expression triggered by endoplasmic reticulum stress is linked to the lipogenesis stimulation and lipid droplets accumulation in HepG2 cells
Fabrizio Damiano;Laura Giannotti;Mariangela Testini;Gabriele V. Gnoni;Luisa Siculella
2019-01-01
Abstract
Several 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. As part of a complex intracellular signaling pathway, a reduction of global and CAP-dependent protein synthesis is observed in ERstressed cells. Induction of lipogenic genes expression has been observed in cells under ER and contributes to the development of liver diseases such as steatosis. ATP citrate lyase (ACLY) catalyzes the ATP-dependent production of oxaloacetate and acetyl-CoA, the last representing the starter molecule for fatty acids and cholesterol synthesis. Considering that acetyl-CoA is also used in the protein acetylation, ACLY could influence different cellular processes. The expression of ACLY is dysregulated in metabolic disorders associated to obesity, diabetes, insulin resistance, and metabolic syndrome. By using several approaches, we deepened the regulation of ACLY expression in HepG2 cells treated with an ER stressor, such as tunicamycin or thapsigargin. We observed an increment of ACLY expression, at transcriptional and translational level. An internal ribosome entry site (IRES), identified in the leader region of ACLY mRNA, allows its translation through a capindependent mechanism. All together, these findings indicate that the presence of an IRES in the ACLY 5'-UTR allows translation of ACLY 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.
