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. Pharmacological induction of ER stress augmented premature termination codon‐containing mRNA (PTC‐mRNA) levels in mouse liver. Neither food restriction nor hyperphagia increased hepatic PTC‐mRNA levels. Hepatic expression of GRP78 was induced by ER stress and GRP78 increased PTC‐mRNA and PTC‐mRNA‐derived protein levels in liver cells.