eIF2 alpha phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet
DC Field | Value | Language |
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dc.contributor.author | Choi, Woo-Gyun | - |
dc.contributor.author | Han, Jaeseok | - |
dc.contributor.author | Kim, Ji-Hyeon | - |
dc.contributor.author | Kim, Mi-Jeong | - |
dc.contributor.author | Park, Jae-Woo | - |
dc.contributor.author | Song, Benbo | - |
dc.contributor.author | Cha, Hee-Jeong | - |
dc.contributor.author | Choi, Hye-Seon | - |
dc.contributor.author | Chung, Hun-Taeg | - |
dc.contributor.author | Lee, In-Kyu | - |
dc.contributor.author | Park, Tae-Sik | - |
dc.contributor.author | Hatzoglou, Maria | - |
dc.contributor.author | Choi, Hueng-Sik | - |
dc.contributor.author | Yoo, Hyun Ju | - |
dc.contributor.author | Kaufman, Randal J. | - |
dc.contributor.author | Back, Sung Hoon | - |
dc.date.available | 2020-02-27T17:43:50Z | - |
dc.date.created | 2020-02-06 | - |
dc.date.issued | 2017-08-01 | - |
dc.identifier.issn | 1743-7075 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/5839 | - |
dc.description.abstract | Background: Dietary 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 (eIF2 alpha) 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 eIF2 alpha phosphorylation in protecting against NAFLD induced by high fructose ingestion in a hepatocyte-specific eIF2 alpha-phosphorylation-deficient mouse model. Methods: Hepatocyte-specific non-phosphorylatable (S51A) eIF2 alpha knock-in (A/A;fTg/0;Cre(Hep)/0, A/A(Hep)) mice were generated by crossing A/A;fTg/fTg mice with the floxed WT eIF2 alpha transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre(Hep)/0 (S/A-Cre(Hep)) mice. Hepatocyte-specific eIF2 alpha-phosphorylation-deficient 3-month-old mice or 12-month-old mice were fed a 60% high fructose diet (HFrD) for 16 or 5 wks, and the effects of eIF2 alpha-phosphorylation deficiency on NADP/NADPH and GSSG/GSH levels, ROS-defense gene expression, oxidative damage, cell death, and fibrosis were observed. Results: Prolonged 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 eIF2 alpha 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 eIF2 alpha 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. Conclusion: Our findings suggest that eIF2 alpha phosphorylation maintains NADPH and GSH levels and controls the expression of ROS-defense genes, thereby protecting hepatocytes from oxidative stresses induced by fructose metabolism. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | BIOMED CENTRAL LTD | - |
dc.relation.isPartOf | NUTRITION & METABOLISM | - |
dc.subject | ENDOPLASMIC-RETICULUM STRESS | - |
dc.subject | UNFOLDED PROTEIN RESPONSE | - |
dc.subject | HEPATIC INSULIN-RESISTANCE | - |
dc.subject | OXIDATIVE STRESS | - |
dc.subject | TRANSLATIONAL CONTROL | - |
dc.subject | CELL-DEATH | - |
dc.subject | ER-STRESS | - |
dc.subject | MESSENGER-RNA | - |
dc.subject | GLUTATHIONE SYNTHESIS | - |
dc.subject | LIPID-ACCUMULATION | - |
dc.title | eIF2 alpha phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000406955900001 | - |
dc.identifier.doi | 10.1186/s12986-017-0202-6 | - |
dc.identifier.bibliographicCitation | NUTRITION & METABOLISM, v.14 | - |
dc.identifier.scopusid | 2-s2.0-85026530271 | - |
dc.citation.title | NUTRITION & METABOLISM | - |
dc.citation.volume | 14 | - |
dc.contributor.affiliatedAuthor | Park, Tae-Sik | - |
dc.type.docType | Article | - |
dc.subject.keywordAuthor | Nonalcoholic fatty liver disease | - |
dc.subject.keywordAuthor | Fibrosis | - |
dc.subject.keywordAuthor | High fructose diet | - |
dc.subject.keywordAuthor | eIF2 alpha phosphorylation | - |
dc.subject.keywordAuthor | Aging | - |
dc.subject.keywordAuthor | Oxidative stress | - |
dc.subject.keywordAuthor | Antioxidant enzymes | - |
dc.subject.keywordAuthor | NADPH | - |
dc.subject.keywordAuthor | Glutathione | - |
dc.subject.keywordPlus | ENDOPLASMIC-RETICULUM STRESS | - |
dc.subject.keywordPlus | UNFOLDED PROTEIN RESPONSE | - |
dc.subject.keywordPlus | HEPATIC INSULIN-RESISTANCE | - |
dc.subject.keywordPlus | OXIDATIVE STRESS | - |
dc.subject.keywordPlus | TRANSLATIONAL CONTROL | - |
dc.subject.keywordPlus | CELL-DEATH | - |
dc.subject.keywordPlus | ER-STRESS | - |
dc.subject.keywordPlus | MESSENGER-RNA | - |
dc.subject.keywordPlus | GLUTATHIONE SYNTHESIS | - |
dc.subject.keywordPlus | LIPID-ACCUMULATION | - |
dc.relation.journalResearchArea | Nutrition & Dietetics | - |
dc.relation.journalWebOfScienceCategory | Nutrition & Dietetics | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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