5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction
Endoplasmic reticulum (ER) stress plays a pivotal role in the progression of steatohepatitis. 5-aminolevulinic acid (5-ALA), a precursor in the heme biosynthetic pathway, has recently been reported to induce heme oxygenase (HO)-1. HO-1 exerts important cytoprotective actions. In this study, we aimed...
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/11405 |
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| author | Takaaki Hashimoto Takaaki Sugihara Tsutomu Kanda Tomoaki Takata Hajime Isomoto |
| author_facet | Takaaki Hashimoto Takaaki Sugihara Tsutomu Kanda Tomoaki Takata Hajime Isomoto |
| author_sort | Takaaki Hashimoto |
| collection | DOAJ |
| description | Endoplasmic reticulum (ER) stress plays a pivotal role in the progression of steatohepatitis. 5-aminolevulinic acid (5-ALA), a precursor in the heme biosynthetic pathway, has recently been reported to induce heme oxygenase (HO)-1. HO-1 exerts important cytoprotective actions. In this study, we aimed to explore the therapeutic potential of 5-ALA on palmitate-induced ER stress and lipoapoptosis. Huh-7 cells were treated with palmitic acid (PA) (800 μM) to induce steatosis for eight hours. Steatosis was evaluated by Lipi-green staining. 5-ALA (200 μM) was added with PA. The gene expression levels of the nuclear factor erythroid 2–related factor 2 (<i>NRF2</i>), <i>HO-1</i>, Glucose-regulated protein 78 (<i>GRP78</i>), activating transcription factor 6 (<i>ATF6</i>), PKR-like endoplasmic reticulum kinase (<i>PERK</i>), inositol-requiring enzyme 1 (<i>IRE1</i>), C/EBP homologous protein (<i>CHOP</i>), and B-cell lymphoma 2 (<i>BCL-2</i>) were evaluated by RT-PCR. Caspase-3/7 activity was evaluated by fluorescein active Caspase-3/7 staining. Cell death was evaluated by Annexin V/SYTOX green staining. PA significantly induced steatosis and increased <i>GRP78</i> expression in Huh-7 cells. 5-ALA significantly induced <i>HO-1</i> and decreased <i>GRP78</i> expression. <i>ATF6</i> was subsequently decreased. However, <i>NRF2</i> and <i>CHOP</i> expression were not altered. Anti-apoptotic <i>BCL-2</i> expression significantly increased, and Caspase 3/7 activity and cell death also decreased. 5-ALA has a therapeutic potential on hepatic steatosis by suppressing ER stress and lipoapoptosis by attenuating <i>GRP78</i> via <i>HO-1</i> induction. |
| first_indexed | 2024-03-10T06:03:00Z |
| format | Article |
| id | doaj.art-c3eb87c5c69749b9baa075e6366c62ae |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:03:00Z |
| publishDate | 2021-10-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c3eb87c5c69749b9baa075e6366c62ae2023-11-22T20:51:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211140510.3390/ijms2221114055-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 InductionTakaaki Hashimoto0Takaaki Sugihara1Tsutomu Kanda2Tomoaki Takata3Hajime Isomoto4Faculty of Medicine, School of Medicine, Tottori University, Yonago 683-8503, JapanDivision of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanDivision of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, Faculty of Medicine, Tottori University, Yonago 683-8504, JapanEndoplasmic reticulum (ER) stress plays a pivotal role in the progression of steatohepatitis. 5-aminolevulinic acid (5-ALA), a precursor in the heme biosynthetic pathway, has recently been reported to induce heme oxygenase (HO)-1. HO-1 exerts important cytoprotective actions. In this study, we aimed to explore the therapeutic potential of 5-ALA on palmitate-induced ER stress and lipoapoptosis. Huh-7 cells were treated with palmitic acid (PA) (800 μM) to induce steatosis for eight hours. Steatosis was evaluated by Lipi-green staining. 5-ALA (200 μM) was added with PA. The gene expression levels of the nuclear factor erythroid 2–related factor 2 (<i>NRF2</i>), <i>HO-1</i>, Glucose-regulated protein 78 (<i>GRP78</i>), activating transcription factor 6 (<i>ATF6</i>), PKR-like endoplasmic reticulum kinase (<i>PERK</i>), inositol-requiring enzyme 1 (<i>IRE1</i>), C/EBP homologous protein (<i>CHOP</i>), and B-cell lymphoma 2 (<i>BCL-2</i>) were evaluated by RT-PCR. Caspase-3/7 activity was evaluated by fluorescein active Caspase-3/7 staining. Cell death was evaluated by Annexin V/SYTOX green staining. PA significantly induced steatosis and increased <i>GRP78</i> expression in Huh-7 cells. 5-ALA significantly induced <i>HO-1</i> and decreased <i>GRP78</i> expression. <i>ATF6</i> was subsequently decreased. However, <i>NRF2</i> and <i>CHOP</i> expression were not altered. Anti-apoptotic <i>BCL-2</i> expression significantly increased, and Caspase 3/7 activity and cell death also decreased. 5-ALA has a therapeutic potential on hepatic steatosis by suppressing ER stress and lipoapoptosis by attenuating <i>GRP78</i> via <i>HO-1</i> induction.https://www.mdpi.com/1422-0067/22/21/11405endoplasmic reticulum stressheme oxygenase-1glucose-regulated protein 78steatohepatitis5-aminolevulinic acid |
| spellingShingle | Takaaki Hashimoto Takaaki Sugihara Tsutomu Kanda Tomoaki Takata Hajime Isomoto 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction International Journal of Molecular Sciences endoplasmic reticulum stress heme oxygenase-1 glucose-regulated protein 78 steatohepatitis 5-aminolevulinic acid |
| title | 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction |
| title_full | 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction |
| title_fullStr | 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction |
| title_full_unstemmed | 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction |
| title_short | 5-Aminolevulinic Acid Attenuates Glucose-Regulated Protein 78 Expression and Hepatocyte Lipoapoptosis via Heme Oxygenase-1 Induction |
| title_sort | 5 aminolevulinic acid attenuates glucose regulated protein 78 expression and hepatocyte lipoapoptosis via heme oxygenase 1 induction |
| topic | endoplasmic reticulum stress heme oxygenase-1 glucose-regulated protein 78 steatohepatitis 5-aminolevulinic acid |
| url | https://www.mdpi.com/1422-0067/22/21/11405 |
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