TY - JOUR
T1 - Fasting in α1-antitrypsin deficient liver
T2 - Consultative activation of autophagy
AU - Teckman, Jeffrey H.
AU - An, Jae Koo
AU - Loethen, Scott
AU - Perlmutter, David H.
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2002/11
Y1 - 2002/11
N2 - α1-Antitrypsin (α1-AT) deficiency causes severe liver injury in a subgroup of patients. Liver injury is thought to be caused by retention of a polymerized mutant α1-ATZ molecule in the endoplasmic reticulum (ER) of hepatocytes and is associated with an intense autophagic response. However, there is limited information about what physiologic stressors might influence liver injury. In this study, we examined the effect of fasting in the PiZ mouse model of α1-AT deficiency, because fasting is a well-characterized physiological stressor and a known stimulus for autophagy. Results show that there is a marked increase in fat accumulation and in α1-AT-containing globules in the liver of the PiZ mouse induced by fasting. Although fasting induced a marked autophagic response in wild-type mice the autophagic response was already activated in PiZ mice and did not further increase with fasting. PiZ mice also had a significantly decreased tolerance for prolonged fasting compared with wild-type mice (PiZ mice 0% survival of 72-h fast; wild-type 100% survivial). These results demonstrate an altered response to stress in the α1-AT-deficient liver, including inability to further increase an activated autophagic response, a developmental state-specific increase in α1-AT-containing globules, and increased mortality.
AB - α1-Antitrypsin (α1-AT) deficiency causes severe liver injury in a subgroup of patients. Liver injury is thought to be caused by retention of a polymerized mutant α1-ATZ molecule in the endoplasmic reticulum (ER) of hepatocytes and is associated with an intense autophagic response. However, there is limited information about what physiologic stressors might influence liver injury. In this study, we examined the effect of fasting in the PiZ mouse model of α1-AT deficiency, because fasting is a well-characterized physiological stressor and a known stimulus for autophagy. Results show that there is a marked increase in fat accumulation and in α1-AT-containing globules in the liver of the PiZ mouse induced by fasting. Although fasting induced a marked autophagic response in wild-type mice the autophagic response was already activated in PiZ mice and did not further increase with fasting. PiZ mice also had a significantly decreased tolerance for prolonged fasting compared with wild-type mice (PiZ mice 0% survival of 72-h fast; wild-type 100% survivial). These results demonstrate an altered response to stress in the α1-AT-deficient liver, including inability to further increase an activated autophagic response, a developmental state-specific increase in α1-AT-containing globules, and increased mortality.
KW - Endoplasmic reticulum
KW - Protein degradation
UR - http://www.scopus.com/inward/record.url?scp=0036840471&partnerID=8YFLogxK
U2 - 10.1152/ajpgi.00041.2002
DO - 10.1152/ajpgi.00041.2002
M3 - Article
C2 - 12381530
AN - SCOPUS:0036840471
SN - 0193-1857
VL - 283
SP - G1156-G1165
JO - American Journal of Physiology - Gastrointestinal and Liver Physiology
JF - American Journal of Physiology - Gastrointestinal and Liver Physiology
IS - 5 46-5
ER -