Dietary Zinc Regulates Apoptosis through the Phosphorylated Eukaryotic Initiation Factor 2α/Activating Transcription Factor-4/C/EBP-Homologous Protein Pathway during Pharmacologically Induced Endoplasmic Reticulum Stress in Livers of Mice.
BACKGROUND
Several in vitro studies have shown that zinc deficiency could induce endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response.


OBJECTIVE
We aimed to determine whether consumption of a zinc-deficient diet (ZnD) triggers ER stress and to understand the impact of dietary zinc intake on ER stress-induced apoptosis using a mouse model.


METHODS
Young adult (8-16 wk of age) male mice of strain C57BL/6 were fed either a ZnD (<1 mg/kg diet), or a zinc-adequate diet (ZnA; 30 mg/kg diet). After 2 wk, liver, pancreas, and serum samples were collected and analyzed for indexes of ER stress. In another experiment, mice were fed either a ZnD, a ZnA, or a zinc-supplementation diet (ZnS; 180 mg/kg diet). After 2 wk, vehicle or tunicamycin (TM; 2 mg/kg body weight) was administered to mice to model ER stress. Liver and serum were analyzed for indexes of ER stress to evaluate the effects of zinc status.


RESULTS
Mice fed a ZnD did not activate the apoptotic and ER stress markers in the liver or pancreas. During the TM challenge, mice fed a ZnD showed greater C/EBP-homologous protein expression in the liver (3.8-fold, P < 0.01) than did ZnA-fed mice. TM-treated mice fed a ZnD also had greater terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells in the liver (2.2-fold, P < 0.05), greater hepatic triglyceride accumulation (1.5-fold, P < 0.05), greater serum alanine aminotransferase activity (1.6-fold, P < 0.05), and greater protein-tyrosine phosphatase 1B activity (1.5-fold, P < 0.05), respectively, than did those fed a ZnA. No significant differences were observed in these parameters between mice fed ZnAs and ZnSs.


CONCLUSIONS
Consumption of a ZnD per se is not a critical factor for induction of ER stress in mice; however, once ER stress is triggered, adequate dietary zinc intake is required for suppressing apoptotic cell death and further insults in the liver of mice.
Food Science and Human Nutrition, and Center for Nutritional Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL.
Min-Hyun
MH
Kim
Food Science and Human Nutrition, and Center for Nutritional Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL.
Tolunay B
TB
Aydemir
Food Science and Human Nutrition, and Center for Nutritional Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL cousins@ufl.edu.
Robert J
RJ
Cousins
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000008:administration & dosage / Q000494:pharmacology*
C081452:Atf4 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D015032:Zinc
apoptosis; endoplasmic reticulum stress; protein tyrosine phosphatase 1B; unfolded protein response; zinc-deficient diet