Zalma Brian A, Ibrahim Maria, Rodriguez-Polanco Flavio C, Bhavsar Chintan T, Rodriguez Esther M, Cararo-Lopes Eduardo, Farooq Saad A, Levy Jordan L, Wek Ronald C, White Eileen, Anthony Tracy G
Nutritional Sciences Graduate Program, Rutgers University, New Brunswick, New Jersey, United States.
Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, United States.
J Biol Chem. 2025 Feb;301(2):108171. doi: 10.1016/j.jbc.2025.108171. Epub 2025 Jan 10.
Amino acid starvation by the chemotherapy agent asparaginase is a potent activator of the integrated stress response (ISR) in the liver and can upregulate autophagy in some cell types. We hypothesized that autophagy-related 7 (ATG7), a protein that is essential for autophagy and an ISR target gene, was necessary during exposure to asparaginase to maintain liver health. We knocked down Atg7 systemically (Atg7) or in hepatocytes only (ls-Atg7KO) in mice before exposure to pegylated asparaginase for 5 days. Intact mice injected with asparaginase lost body weight due to reduced food intake and increased energy expenditure. Systemic Atg7 ablation reduced liver protein synthesis and increased liver injury in vehicle-injected mice but did not further reduce liver protein synthesis, exacerbate steatosis or liver injury, or alter energy expenditure following 5 days of asparaginase exposure. Atg7 mice were unexpectantly protected from asparaginase-induced anorexia and weight loss. This protection corresponded with reduced phosphorylation of hepatic GCN2 and blunted increases in ISR gene targets including growth differentiation factor 15 (GDF15), a negative regulator of food intake. Interestingly, asparaginase elevated serum GDF15 and reduced food intake in ls-Atg7KO mice, similar to intact mice. Liver triglycerides and production of the hepatokine fibroblast growth factor 21, another ISR gene target, were suppressed in asparaginase-exposed Atg7 and ls-Atg7KO mice. This work identifies a bidirectional relationship between autophagy and the ISR in the liver during asparaginase, affecting food intake and liver health.
化疗药物天冬酰胺酶引起的氨基酸饥饿是肝脏中整合应激反应（ISR）的有效激活剂，并且可以上调某些细胞类型中的自噬。我们假设自噬相关蛋白7（ATG7），一种自噬所必需的蛋白质且是ISR的靶基因，在暴露于天冬酰胺酶期间对于维持肝脏健康是必需的。在小鼠暴露于聚乙二醇化天冬酰胺酶5天之前，我们全身性敲低Atg7（Atg7）或仅在肝细胞中敲低（ls-Atg7KO）。注射了天冬酰胺酶的正常小鼠由于食物摄入量减少和能量消耗增加而体重减轻。全身性Atg7缺失降低了注射赋形剂小鼠的肝脏蛋白质合成并增加了肝损伤，但在天冬酰胺酶暴露5天后并没有进一步降低肝脏蛋白质合成、加重脂肪变性或肝损伤，也没有改变能量消耗。Atg7小鼠意外地免受天冬酰胺酶诱导的厌食和体重减轻。这种保护作用与肝脏中GCN2磷酸化减少以及ISR基因靶点（包括食物摄入的负调节因子生长分化因子15（GDF15））的增加减弱相对应。有趣的是，天冬酰胺酶升高了ls-Atg7KO小鼠的血清GDF15并减少了食物摄入量，这与正常小鼠相似。在暴露于天冬酰胺酶的Atg7和ls-Atg7KO小鼠中，肝脏甘油三酯和肝因子成纤维细胞生长因子21（另一个ISR基因靶点）的产生受到抑制。这项工作确定了在天冬酰胺酶作用期间肝脏中自噬与ISR之间的双向关系，影响食物摄入和肝脏健康。
