A subgroup of patients with alpha-1-antitrypsin (-1-AT) deficiency develops severe liver injury and/or hepatocellular carcinoma. Liver injury is thought to be caused by the retention of a polymerized mutant -1-ATZ molecule in the endoplasmic reticulum (ER) of hepatocytes and recent studies have indicated that ER retention of -1-ATZ is associated with an intense autophagic response. There is limited information about the genetic/environmental mechanisms that determine susceptibility to liver disease among -1-AT-deficient patients and little information about how physiologic stressors affect the liver in these patients. In this study we examined the effect of fasting on the liver of a transgenic mouse model of -1-AT deficiency because fasting is a well-characterized physiological stressor and a known stimulus for autophagy in the liver. The results show that there is a marked increase in fat accumulation and in -1-AT-containing, ER-derived globules in the liver of the PiZ mouse induced by fasting 18 hours. These changes were particularly exaggerated at 3 to 6 months of age. Although fasting 18 hours induced a marked autophagic response in wild type mice, the autophagic response was already activated in PiZ mice to levels more than 50% higher than those in the liver of fasted wild type mice, and did not increase further during fasting. Three-month-old PiZ mice also had a significantly decreased tolerance for fasting compared to nontransgenic C57 black mice (PiZ mice 0% survival of 72 hour fast, C57BL 100% survival). These results demonstrate an altered response to stress in the -1-AT-deficient liver, including inability to mount an increased autophagic response because autophagy is already constitutively activated, a developmental state-specific increase in -1-AT-containing ER-derived globules, and increased mortality.