TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner
Objectives: Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, particip...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877824002114 |
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| author | Arun Chhetri Channy Park Hyunsoo Kim Laxman Manandhar Chagtsalmaa Chuluunbaatar Jaetaek Hwang Xiaofan Wei Gyuho Jang Batching Chinbold Hyug Moo Kwon Sang-wook Lee Raekil Park |
| author_facet | Arun Chhetri Channy Park Hyunsoo Kim Laxman Manandhar Chagtsalmaa Chuluunbaatar Jaetaek Hwang Xiaofan Wei Gyuho Jang Batching Chinbold Hyug Moo Kwon Sang-wook Lee Raekil Park |
| author_sort | Arun Chhetri |
| collection | DOAJ |
| description | Objectives: Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver. Methods: We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells. Results: TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD+/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels. Conclusions: TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis. |
| format | Article |
| id | doaj-art-855adc47393d4233a903ed8b4092b367 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-855adc47393d4233a903ed8b4092b3672025-02-01T04:11:56ZengElsevierMolecular Metabolism2212-87782025-02-0192102080TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent mannerArun Chhetri0Channy Park1Hyunsoo Kim2Laxman Manandhar3Chagtsalmaa Chuluunbaatar4Jaetaek Hwang5Xiaofan Wei6Gyuho Jang7Batching Chinbold8Hyug Moo Kwon9Sang-wook Lee10Raekil Park11Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of KoreaSchool of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of KoreaDepartment of Radiation Oncology Asan Medical Center, Seoul, Republic of KoreaDepartment of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; Corresponding author. Department of Biomedical Science & Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.Objectives: Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver. Methods: We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells. Results: TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD+/NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels. Conclusions: TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis.http://www.sciencedirect.com/science/article/pii/S2212877824002114TMEM135Lipid accumulationCD36SIRT1 |
| spellingShingle | Arun Chhetri Channy Park Hyunsoo Kim Laxman Manandhar Chagtsalmaa Chuluunbaatar Jaetaek Hwang Xiaofan Wei Gyuho Jang Batching Chinbold Hyug Moo Kwon Sang-wook Lee Raekil Park TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner Molecular Metabolism TMEM135 Lipid accumulation CD36 SIRT1 |
| title | TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner |
| title_full | TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner |
| title_fullStr | TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner |
| title_full_unstemmed | TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner |
| title_short | TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner |
| title_sort | tmem135 deficiency improves hepatic steatosis by suppressing cd36 in a sirt1 dependent manner |
| topic | TMEM135 Lipid accumulation CD36 SIRT1 |
| url | http://www.sciencedirect.com/science/article/pii/S2212877824002114 |
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