eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet
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 stres...
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| Autor*in: |
Woo-Gyun Choi [verfasserIn] Jaeseok Han [verfasserIn] Ji-Hyeon Kim [verfasserIn] Mi-Jeong Kim [verfasserIn] Jae-Woo Park [verfasserIn] Benbo Song [verfasserIn] Hee-Jeong Cha [verfasserIn] Hye-Seon Choi [verfasserIn] Hun-Taeg Chung [verfasserIn] In-Kyu Lee [verfasserIn] Tae-Sik Park [verfasserIn] Maria Hatzoglou [verfasserIn] Hueng-Sik Choi [verfasserIn] Hyun Ju Yoo [verfasserIn] Randal J. Kaufman [verfasserIn] Sung Hoon Back [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
In: Nutrition & Metabolism - BMC, 2004, 14(2017), 1, Seite 21 |
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| Übergeordnetes Werk: |
volume:14 ; year:2017 ; number:1 ; pages:21 |
| Links: |
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| DOI / URN: |
10.1186/s12986-017-0202-6 |
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| Katalog-ID: |
DOAJ075835053 |
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| 520 | |a 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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. | ||
| 650 | 4 | |a Nonalcoholic fatty liver disease | |
| 650 | 4 | |a Fibrosis | |
| 650 | 4 | |a High fructose diet | |
| 650 | 4 | |a eIF2α phosphorylation | |
| 650 | 4 | |a Aging | |
| 650 | 4 | |a Oxidative stress | |
| 653 | 0 | |a Nutrition. Foods and food supply | |
| 653 | 0 | |a Nutritional diseases. Deficiency diseases | |
| 700 | 0 | |a Jaeseok Han |e verfasserin |4 aut | |
| 700 | 0 | |a Ji-Hyeon Kim |e verfasserin |4 aut | |
| 700 | 0 | |a Mi-Jeong Kim |e verfasserin |4 aut | |
| 700 | 0 | |a Jae-Woo Park |e verfasserin |4 aut | |
| 700 | 0 | |a Benbo Song |e verfasserin |4 aut | |
| 700 | 0 | |a Hee-Jeong Cha |e verfasserin |4 aut | |
| 700 | 0 | |a Hye-Seon Choi |e verfasserin |4 aut | |
| 700 | 0 | |a Hun-Taeg Chung |e verfasserin |4 aut | |
| 700 | 0 | |a In-Kyu Lee |e verfasserin |4 aut | |
| 700 | 0 | |a Tae-Sik Park |e verfasserin |4 aut | |
| 700 | 0 | |a Maria Hatzoglou |e verfasserin |4 aut | |
| 700 | 0 | |a Hueng-Sik Choi |e verfasserin |4 aut | |
| 700 | 0 | |a Hyun Ju Yoo |e verfasserin |4 aut | |
| 700 | 0 | |a Randal J. Kaufman |e verfasserin |4 aut | |
| 700 | 0 | |a Sung Hoon Back |e verfasserin |4 aut | |
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10.1186/s12986-017-0202-6 doi (DE-627)DOAJ075835053 (DE-599)DOAJ622f68c66e374394b6921639e0484074 DE-627 ger DE-627 rakwb eng TX341-641 RC620-627 Woo-Gyun Choi verfasserin aut eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. Nonalcoholic fatty liver disease Fibrosis High fructose diet eIF2α phosphorylation Aging Oxidative stress Nutrition. Foods and food supply Nutritional diseases. Deficiency diseases Jaeseok Han verfasserin aut Ji-Hyeon Kim verfasserin aut Mi-Jeong Kim verfasserin aut Jae-Woo Park verfasserin aut Benbo Song verfasserin aut Hee-Jeong Cha verfasserin aut Hye-Seon Choi verfasserin aut Hun-Taeg Chung verfasserin aut In-Kyu Lee verfasserin aut Tae-Sik Park verfasserin aut Maria Hatzoglou verfasserin aut Hueng-Sik Choi verfasserin aut Hyun Ju Yoo verfasserin aut Randal J. Kaufman verfasserin aut Sung Hoon Back verfasserin aut In Nutrition & Metabolism BMC, 2004 14(2017), 1, Seite 21 (DE-627)394163419 (DE-600)2160376-5 17437075 nnns volume:14 year:2017 number:1 pages:21 https://doi.org/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/article/622f68c66e374394b6921639e0484074 kostenfrei http://link.springer.com/article/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/toc/1743-7075 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2017 1 21 |
| spelling |
10.1186/s12986-017-0202-6 doi (DE-627)DOAJ075835053 (DE-599)DOAJ622f68c66e374394b6921639e0484074 DE-627 ger DE-627 rakwb eng TX341-641 RC620-627 Woo-Gyun Choi verfasserin aut eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. Nonalcoholic fatty liver disease Fibrosis High fructose diet eIF2α phosphorylation Aging Oxidative stress Nutrition. Foods and food supply Nutritional diseases. Deficiency diseases Jaeseok Han verfasserin aut Ji-Hyeon Kim verfasserin aut Mi-Jeong Kim verfasserin aut Jae-Woo Park verfasserin aut Benbo Song verfasserin aut Hee-Jeong Cha verfasserin aut Hye-Seon Choi verfasserin aut Hun-Taeg Chung verfasserin aut In-Kyu Lee verfasserin aut Tae-Sik Park verfasserin aut Maria Hatzoglou verfasserin aut Hueng-Sik Choi verfasserin aut Hyun Ju Yoo verfasserin aut Randal J. Kaufman verfasserin aut Sung Hoon Back verfasserin aut In Nutrition & Metabolism BMC, 2004 14(2017), 1, Seite 21 (DE-627)394163419 (DE-600)2160376-5 17437075 nnns volume:14 year:2017 number:1 pages:21 https://doi.org/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/article/622f68c66e374394b6921639e0484074 kostenfrei http://link.springer.com/article/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/toc/1743-7075 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2017 1 21 |
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10.1186/s12986-017-0202-6 doi (DE-627)DOAJ075835053 (DE-599)DOAJ622f68c66e374394b6921639e0484074 DE-627 ger DE-627 rakwb eng TX341-641 RC620-627 Woo-Gyun Choi verfasserin aut eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. Nonalcoholic fatty liver disease Fibrosis High fructose diet eIF2α phosphorylation Aging Oxidative stress Nutrition. Foods and food supply Nutritional diseases. Deficiency diseases Jaeseok Han verfasserin aut Ji-Hyeon Kim verfasserin aut Mi-Jeong Kim verfasserin aut Jae-Woo Park verfasserin aut Benbo Song verfasserin aut Hee-Jeong Cha verfasserin aut Hye-Seon Choi verfasserin aut Hun-Taeg Chung verfasserin aut In-Kyu Lee verfasserin aut Tae-Sik Park verfasserin aut Maria Hatzoglou verfasserin aut Hueng-Sik Choi verfasserin aut Hyun Ju Yoo verfasserin aut Randal J. Kaufman verfasserin aut Sung Hoon Back verfasserin aut In Nutrition & Metabolism BMC, 2004 14(2017), 1, Seite 21 (DE-627)394163419 (DE-600)2160376-5 17437075 nnns volume:14 year:2017 number:1 pages:21 https://doi.org/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/article/622f68c66e374394b6921639e0484074 kostenfrei http://link.springer.com/article/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/toc/1743-7075 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2017 1 21 |
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10.1186/s12986-017-0202-6 doi (DE-627)DOAJ075835053 (DE-599)DOAJ622f68c66e374394b6921639e0484074 DE-627 ger DE-627 rakwb eng TX341-641 RC620-627 Woo-Gyun Choi verfasserin aut eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. Nonalcoholic fatty liver disease Fibrosis High fructose diet eIF2α phosphorylation Aging Oxidative stress Nutrition. Foods and food supply Nutritional diseases. Deficiency diseases Jaeseok Han verfasserin aut Ji-Hyeon Kim verfasserin aut Mi-Jeong Kim verfasserin aut Jae-Woo Park verfasserin aut Benbo Song verfasserin aut Hee-Jeong Cha verfasserin aut Hye-Seon Choi verfasserin aut Hun-Taeg Chung verfasserin aut In-Kyu Lee verfasserin aut Tae-Sik Park verfasserin aut Maria Hatzoglou verfasserin aut Hueng-Sik Choi verfasserin aut Hyun Ju Yoo verfasserin aut Randal J. Kaufman verfasserin aut Sung Hoon Back verfasserin aut In Nutrition & Metabolism BMC, 2004 14(2017), 1, Seite 21 (DE-627)394163419 (DE-600)2160376-5 17437075 nnns volume:14 year:2017 number:1 pages:21 https://doi.org/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/article/622f68c66e374394b6921639e0484074 kostenfrei http://link.springer.com/article/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/toc/1743-7075 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2017 1 21 |
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10.1186/s12986-017-0202-6 doi (DE-627)DOAJ075835053 (DE-599)DOAJ622f68c66e374394b6921639e0484074 DE-627 ger DE-627 rakwb eng TX341-641 RC620-627 Woo-Gyun Choi verfasserin aut eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. Nonalcoholic fatty liver disease Fibrosis High fructose diet eIF2α phosphorylation Aging Oxidative stress Nutrition. Foods and food supply Nutritional diseases. Deficiency diseases Jaeseok Han verfasserin aut Ji-Hyeon Kim verfasserin aut Mi-Jeong Kim verfasserin aut Jae-Woo Park verfasserin aut Benbo Song verfasserin aut Hee-Jeong Cha verfasserin aut Hye-Seon Choi verfasserin aut Hun-Taeg Chung verfasserin aut In-Kyu Lee verfasserin aut Tae-Sik Park verfasserin aut Maria Hatzoglou verfasserin aut Hueng-Sik Choi verfasserin aut Hyun Ju Yoo verfasserin aut Randal J. Kaufman verfasserin aut Sung Hoon Back verfasserin aut In Nutrition & Metabolism BMC, 2004 14(2017), 1, Seite 21 (DE-627)394163419 (DE-600)2160376-5 17437075 nnns volume:14 year:2017 number:1 pages:21 https://doi.org/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/article/622f68c66e374394b6921639e0484074 kostenfrei http://link.springer.com/article/10.1186/s12986-017-0202-6 kostenfrei https://doaj.org/toc/1743-7075 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2106 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2017 1 21 |
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Woo-Gyun Choi @@aut@@ Jaeseok Han @@aut@@ Ji-Hyeon Kim @@aut@@ Mi-Jeong Kim @@aut@@ Jae-Woo Park @@aut@@ Benbo Song @@aut@@ Hee-Jeong Cha @@aut@@ Hye-Seon Choi @@aut@@ Hun-Taeg Chung @@aut@@ In-Kyu Lee @@aut@@ Tae-Sik Park @@aut@@ Maria Hatzoglou @@aut@@ Hueng-Sik Choi @@aut@@ Hyun Ju Yoo @@aut@@ Randal J. Kaufman @@aut@@ Sung Hoon Back @@aut@@ |
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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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. 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Woo-Gyun Choi |
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Woo-Gyun Choi misc TX341-641 misc RC620-627 misc Nonalcoholic fatty liver disease misc Fibrosis misc High fructose diet misc eIF2α phosphorylation misc Aging misc Oxidative stress misc Nutrition. Foods and food supply misc Nutritional diseases. Deficiency diseases eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet |
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TX341-641 RC620-627 eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet Nonalcoholic fatty liver disease Fibrosis High fructose diet eIF2α phosphorylation Aging Oxidative stress |
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misc TX341-641 misc RC620-627 misc Nonalcoholic fatty liver disease misc Fibrosis misc High fructose diet misc eIF2α phosphorylation misc Aging misc Oxidative stress misc Nutrition. Foods and food supply misc Nutritional diseases. Deficiency diseases |
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misc TX341-641 misc RC620-627 misc Nonalcoholic fatty liver disease misc Fibrosis misc High fructose diet misc eIF2α phosphorylation misc Aging misc Oxidative stress misc Nutrition. Foods and food supply misc Nutritional diseases. Deficiency diseases |
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misc TX341-641 misc RC620-627 misc Nonalcoholic fatty liver disease misc Fibrosis misc High fructose diet misc eIF2α phosphorylation misc Aging misc Oxidative stress misc Nutrition. Foods and food supply misc Nutritional diseases. Deficiency diseases |
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eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet |
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Woo-Gyun Choi Jaeseok Han Ji-Hyeon Kim Mi-Jeong Kim Jae-Woo Park Benbo Song Hee-Jeong Cha Hye-Seon Choi Hun-Taeg Chung In-Kyu Lee Tae-Sik Park Maria Hatzoglou Hueng-Sik Choi Hyun Ju Yoo Randal J. Kaufman Sung Hoon Back |
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eif2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet |
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TX341-641 |
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eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet |
| abstract |
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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. |
| abstractGer |
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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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. |
| abstract_unstemmed |
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 (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. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α 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 eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-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 eIF2α-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 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. Conclusion Our 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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eIF2α phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet |
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https://doi.org/10.1186/s12986-017-0202-6 https://doaj.org/article/622f68c66e374394b6921639e0484074 http://link.springer.com/article/10.1186/s12986-017-0202-6 https://doaj.org/toc/1743-7075 |
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Jaeseok Han Ji-Hyeon Kim Mi-Jeong Kim Jae-Woo Park Benbo Song Hee-Jeong Cha Hye-Seon Choi Hun-Taeg Chung In-Kyu Lee Tae-Sik Park Maria Hatzoglou Hueng-Sik Choi Hyun Ju Yoo Randal J. Kaufman Sung Hoon Back |
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Jaeseok Han Ji-Hyeon Kim Mi-Jeong Kim Jae-Woo Park Benbo Song Hee-Jeong Cha Hye-Seon Choi Hun-Taeg Chung In-Kyu Lee Tae-Sik Park Maria Hatzoglou Hueng-Sik Choi Hyun Ju Yoo Randal J. Kaufman Sung Hoon Back |
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2024-07-03T17:05:41.105Z |
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