title: Scurvy leads to endoplasmic reticulum stress and apoptosis in the liver of Guinea pigs.
abstract: Insufficient ascorbate intake causes scurvy in certain species. Beyond its known functions, it has been suggested that ascorbate participates in oxidative protein folding in the endoplasmic reticulum (ER). Because redox imbalance in this organelle might cause ER stress and apoptosis, we hypothesized that this might contribute to the pathology of scurvy. Guinea pigs were divided into 7 groups: the control group was fed a commercial guinea pig food containing 0.1 g/100 g ascorbate for 4 wk, 5 groups consumed an ascorbate-free food for 0, 1, 2, 3, or 4 wk and 1 group was fed this scorbutic diet for 2 wk and then the commercial food plus 1 g/L ascorbate in drinking water for 2 wk. TBARS generation and the expression of some ER chaperones and foldases were determined in hepatic microsomes. The apoptotic index was assessed in histological sections. Although ascorbate, measured by HPLC, was undetectable in the livers of the guinea pigs after they had consumed the scorbutic diet for 2 wk, the microsomal TBARS level was elevated relative to the initial value only at wk 4. Western blot revealed the induction of GRP78, GRP94, and protein disulfide isomerase at wk 3 and 4. Apoptosis was greater than in the control, beginning at wk 3. None of the alterations occurred in the groups fed the commercial guinea pig food or ascorbate-free food followed by ascorbate supplementation. Therefore, persistent ascorbate deficiency leads to ER stress, unfolded protein response, and apoptosis in the liver, suggesting that insufficient protein processing participates in the pathology of scurvy.
authors.affiliation: Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Endoplasmic Reticulum Research Group of The Hungarian Academy of Science, Budapest, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Margittai
authors.forename: Gábor
authors.initials: G
authors.lastname: Bánhegyi
authors.forename: András
authors.initials: A
authors.lastname: Kiss
authors.forename: Gábor
authors.initials: G
authors.lastname: Nagy
authors.forename: József
authors.initials: J
authors.lastname: Mandl
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Schaff
authors.forename: Miklós
authors.initials: M
authors.lastname: Csala
mesh_terms: D000818:Animals; D017209:Apoptosis; D001205:Ascorbic Acid / Q000032:analysis; D015153:Blotting, Western; D001835:Body Weight; D004721:Endoplasmic Reticulum / Q000473:pathology* / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D006168:Guinea Pigs; D006360:Heat-Shock Proteins / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008862:Microsomes, Liver / Q000737:chemistry; D018832:Molecular Chaperones / Q000032:analysis; D009929:Organ Size; D011506:Proteins / Q000032:analysis; D012614:Scurvy / Q000473:pathology*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D011506:Proteins; D017392:Thiobarbituric Acid Reactive Substances; C053387:endoplasmin; D001205:Ascorbic Acid