title: Endoplasmic Reticulum Stress in Mice Increases Hepatic Expression of Genes Carrying a Premature Termination Codon via a Nutritional Status-Independent GRP78-Dependent Mechanism.
abstract: Nonsense-mediated mRNA decay (NMD) degrades mRNAs carrying a premature termination codon (PTC) in eukaryotes. Cellular stresses, including endoplasmic reticulum (ER) stress, inhibit NMD, and up-regulate PTC-containing mRNA (PTC-mRNA) levels in several cell lines. However, whether similar effects exist under in vivo conditions that involve systemic nutritional status is unclear. Here, we compared the effects of pharmacological induction of ER stress with those of nutritional interventions on hepatic PTC-mRNA levels in mice. In mouse livers, the ER stress inducer tunicamycin increased PTC-mRNA levels of endogenous marker genes. Tunicamycin decreased body weight and perturbed nutrient metabolism in mice. Food restriction or deprivation mimicked the effect of tunicamycin on weight loss and metabolism, but did not increase PTC-mRNA levels. Hyperphagia-induced obesity also had little effect on hepatic PTC-mRNA levels. Meanwhile, in mouse liver phosphorylation of eIF2α, a factor that regulates NMD, was increased by both tunicamycin and nutritional interventions. Hepatic expression of GRP78, a central chaperone in ER stress responses, was increased by tunicamycin but not by the nutritional interventions. In cultured liver cells (Hepa), exogenous overexpression of a phosphomimetic eIF2α failed to increase PTC-mRNA levels. However, GRP78 overexpression in Hepa cells increased PTC-mRNA and PTC-mRNA-derived protein levels. ER stress promoted localization of GRP78 to mitochondria, and exogenous expression of a GRP78 fusion protein targeted to mitochondria mimicked the effect of wild type GRP78. These results indicate that GRP78, but not nutritional status, is a potent up-regulator of hepatic PTC-mRNA levels during induction of ER stress in vivo. J. Cell. Biochem. 118: 3810-3824, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Nagakatsu
authors.identifier: 0000-0001-8206-833X
authors.initials: N
authors.lastname: Harada
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Okuyama
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshikatsu
authors.affiliation: Faculty of Human Life, Department of Health and Nutrition, Jin-ai University, 3-1-1 Ohde-cho, Echizen City, 915-8586, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Ishiwata
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Chikako
authors.initials: C
authors.lastname: Hamada
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Hirose
authors.affiliation: Support Center for Advanced Medical Sciences, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shono
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kuroda
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Tsutsumi
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.|Central Research Laboratory, Nippon Suisan Kaisha, 32-3 Nanakuni 1 Chome, Hachioji, Tokyo, 192-0991, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Takeo
authors.affiliation: Department of Clinical Nutrition and Food Management, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Taketani
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
authors.affiliation: Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakaue
mesh_terms: D000818:Animals; D018388:Codon, Terminator; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006963:Hyperphagia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D041681:NIH 3T3 Cells; D059365:Nonsense Mediated mRNA Decay; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014415:Tunicamycin / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D018388:Codon, Terminator; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D014415:Tunicamycin
keywords: ENDOPLASMIC RETICULUM STRESS; GRP78; LIVER; NONSENSE-MEDIATED mRNA DECAY; NUTRITIONAL STATUS