ArticleNutrition & metabolism2017
eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet.
Article in Nutrition & metabolism, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 33 citations in OpenAlex.
- Title: Resveratrol ameliorates liver fibrosis by inhibiting ATF4 to regulate glutamine metabolism in hepatic stellate cells.Archives of pharmacal research · 2025Article
- Integrated stress response signaling acts as a metabolic sensor in fat tissues to regulate oocyte maturation and ovulation.Cell reports · 2024Article
- A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure-Associated Liver Disease in Preterm Yorkshire Piglets.Gastroenterology · 2023Article
- Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD.Metabolism: clinical and experimental · 2023Article
- Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.bioRxiv : the preprint server for biology · 2023Article
- Regulation and function of elF2B in neurological and metabolic disorders.Bioscience reports · 2022Review
- [Activation of endoplasmic reticulum stress sensors by metabolic disease-associated diets and COVID-19].Revista medica del Instituto Mexicano del Seguro Social · 2022Review
- Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphoethanolamine.Scientific reports · 2022Article
- Translation Inhibitors Activate Autophagy Master Regulators TFEB and TFE3.International journal of molecular sciences · 2021Article
- Rumen epithelial transcriptome and microbiome profiles of rumen epithelium and contents of beef cattle with and without liver abscesses.Journal of animal science · 2020Article
- Article
- Phosphorylation of eIF2α Promotes Schwann Cell Differentiation and Myelination in CMT1B Mice with Activated UPR.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Proteomics provides insights into the inhibition of Chinese hamster V79 cell proliferation in the deep underground environment.Scientific reports · 2020Article
- Fructose and hepatic insulin resistance.Critical reviews in clinical laboratory sciences · 2020Review
- Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs).International journal of molecular sciences · 2020Review
- Roles of the Translation Initiation Factor eIF2α Phosphorylation in Cell Structure and Function.Cell structure and function · 2020Article
- Reduced EGFR Level in eIF2α PhosphorylationDeficient Hepatocytes Is Responsible for Susceptibility to Oxidative Stress.Molecules and cells · 2020Article
- FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases.Frontiers in endocrinology · 2020Review
- Inhibition of eIF2BioMed research international · 2020Article
- Inhibiting alpha subunit of eukaryotic initiation factor 2 dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation in acute liver injury.Croatian medical journal · 2019Article
Corrections and comments
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Authors and funding
16 authors at 8 institutions in 2 countries.
Funding
Abstract
backgroundDietary fructose can rapidly cause fatty liver in animals through de novo lipogenesis (DNL) and contribute to the development and severity of nonalcoholic fatty liver disease (NAFLD). In response to diverse cellular insults including endoplasmic reticulum (ER) and oxidative stress, phosphorylation of the eukaryotic translation initiation factor 2 alpha subunit (eIF2α) attenuates general translation initiation, allowing cells to conserve resources and initiate adaptive gene expression to restore homeostasis. The present study aimed to investigate the role of eIF2α phosphorylation in protecting against NAFLD induced by high fructose ingestion in a hepatocyte-specific eIF2α-phosphorylation-deficient mouse model.
methodsHepatocyte-specific non-phosphorylatable (S51A) eIF2α knock-in (
resultsProlonged fructose feeding to mice caused dysregulation of the unfolded protein response (UPR) sensor activation and UPR gene expression, and then led to decreased expression of several ROS defense genes including glutathione biogenesis genes. Nonetheless, these changes were not sufficient to induce the death of eIF2α phosphorylation-sufficient hepatocytes. However, there was a substantial increase in hepatocyte death and liver fibrosis in fructose-fed middle-aged mice deficient in hepatocyte-specific eIF2α phosphorylation because of diminished antioxidant capacity due to reduced expression of antioxidant enzymes (GPX1 and HO-1) and lower NADPH and glutathione levels, as well as a possible increase in ROS-induced damage from infiltrating NOX2-expressing leukocytes; all this led to a vicious cycle of hepatocyte death and leukocyte infiltration.
conclusionOur findings suggest that eIF2α phosphorylation maintains NADPH and GSH levels and controls the expression of ROS-defense genes, thereby protecting hepatocytes from oxidative stresses induced by fructose metabolism.
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