Weight Loss During Obesity Provokes Asparaginase‐Associated Liver Steatosis and Endoplasmic Reticulum Stress

Asparaginase is an anti-leukemic agent that triggers severe adverse metabolic events. Obesity is a known risk factor for asparaginase-associated liver steatosis. To better understand why, we first compared the liver metabolome of lean versus diet-induced obese (DIO) mice exposed to native asparaginase and observed a substantially altered liver metabolome in DIO mice only. To explore the basis for the altered liver metabolome in DIO mice, we designed experiments to clarify the relative contributions of obesity versus feeding excessive fat during asparaginase on liver triglycerides. Lean mice and DIO mice were fed a high-fat, obesogenic diet (OD) or low fat, maintenance diet (MD) during exposure to pegylated (PEG)-asparaginase. In lean mice, feeding OD during PEG-asparaginase modestly (2-fold) increased liver steatosis. Obese mice fed OD during PEG-asparaginase showed the lowest food intake alongside the lowest liver triglyceride secretion rates, resulting in the largest (6-fold) increase in liver triglycerides and emergent endoplasmic reticulum (ER) stress. Switching obese mice to a MD during PEG-asparaginase did not rescue liver steatosis nor alleviate ER stress. In a separate study, DIO mice globally lacking albumin (AlbKO) were fed OD during exposure to PEG-asparaginase to examine if loss of the major plasma free fatty acid carrier could lessen liver steatosis, but loss of circulating albumin did not mitigate elevated liver triglycerides. In total, the results revealed that body weight loss enables asparaginase-associated liver steatosis and ER stress. Mitigating asparaginase-induced weight loss may be a meaningful strategy in preventing liver stress during treatment.