title: Dysfunctional glycogen storage in a mouse model of alpha1-antitrypsin deficiency.
abstract: Autophagy is an intracellular pathway that contributes to the degradation and recycling of unfolded proteins. Based on the knowledge that autophagy affects glycogen metabolism and that alpha(1)-antitrypsin (AAT) deficiency is associated with an autophagic response in the liver, we hypothesized that the conformational abnormalities of the Z-AAT protein interfere with hepatocyte glycogen storage and/or metabolism. Compared with wild-type mice (WT), the Z-AAT mice had lower liver glycogen stores (P < 0.001) and abnormal activities of glycogen-related enzymes, including acid alpha-glucosidase (P < 0.05) and the total glycogen synthase (P < 0.05). As metabolic consequences, PiZ mice demonstrated lower blood glucose levels (P < 0.05), lower body weights (P < 0.001), and lower fat pad weights (P < 0.001) compared with WT. After the stress of fasting or partial hepatectomy, PiZ mice had further reduced liver glycogen and lower blood glucose levels (both P < 0.05 compared WT). Finally, PiZ mice exhibited decreased survival after partial hepatectomy (P < 0.01 compared with WT), but this was normalized with postoperative dextrose supplementation. In conclusion, these observations are consistent with the general concept that abnormal protein conformation and degradation affects other cellular functions, suggesting that diseases in the liver might benefit from metabolic compensation if glycogen metabolism is affected.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10021, USA.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Hubner
authors.forename: Philip L
authors.initials: PL
authors.lastname: Leopold
authors.forename: Maija
authors.initials: M
authors.lastname: Kiuru
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: De
authors.forename: Anja
authors.initials: A
authors.lastname: Krause
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006003:Glycogen / Q000235:genetics / Q000378:metabolism*; D006008:Glycogen Storage Disease / Q000235:genetics / Q000378:metabolism*; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011656:Pulmonary Emphysema / Q000235:genetics / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics; D000520:alpha-Glucosidases / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D000515:alpha 1-Antitrypsin; D006003:Glycogen; D006006:Glycogen Synthase; D000520:alpha-Glucosidases