Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon
Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/5/4570 |
| _version_ | 1797615189877587968 |
|---|---|
| author | Weicang Wang Karen M. Wagner Yuxin Wang Nalin Singh Jun Yang Qiyi He Christophe Morisseau Bruce D. Hammock |
| author_facet | Weicang Wang Karen M. Wagner Yuxin Wang Nalin Singh Jun Yang Qiyi He Christophe Morisseau Bruce D. Hammock |
| author_sort | Weicang Wang |
| collection | DOAJ |
| description | Aging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers <i>p21</i>, <i>p16</i>, <i>Tp53</i>, and <i>β-galactosidase</i> in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators <i>Perk</i> and <i>Ire1</i> as well as the downstream pro-apoptotic effectors <i>Chop</i> and <i>Gadd34</i>. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon. |
| first_indexed | 2024-03-11T07:22:52Z |
| format | Article |
| id | doaj.art-afcb9d1b3a4248e7820fc42189a44435 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T07:22:52Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-afcb9d1b3a4248e7820fc42189a444352023-11-17T07:50:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01245457010.3390/ijms24054570Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice ColonWeicang Wang0Karen M. Wagner1Yuxin Wang2Nalin Singh3Jun Yang4Qiyi He5Christophe Morisseau6Bruce D. Hammock7Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USADepartment of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USAAging, which is characterized by enhanced cell senescence and functional decline of tissues, is a major risk factor for many chronic diseases. Accumulating evidence shows that age-related dysfunction in the colon leads to disorders in multiple organs and systemic inflammation. However, the detailed pathological mechanisms and endogenous regulators underlying colon aging are still largely unknown. Here, we report that the expression and activity of the soluble epoxide hydrolase (sEH) enzyme are increased in the colon of aged mice. Importantly, genetic knockout of sEH attenuated the age-related upregulation of senescent markers <i>p21</i>, <i>p16</i>, <i>Tp53</i>, and <i>β-galactosidase</i> in the colon. Moreover, sEH deficiency alleviated aging-associated endoplasmic reticulum (ER) stress in the colon by reducing both the upstream regulators <i>Perk</i> and <i>Ire1</i> as well as the downstream pro-apoptotic effectors <i>Chop</i> and <i>Gadd34</i>. Furthermore, treatment with sEH-derived linoleic acid metabolites, dihydroxy-octadecenoic acids (DiHOMEs), decreased cell viability and increased ER stress in human colon CCD-18Co cells in vitro. Together, these results support that the sEH is a key regulator of the aging colon, which highlights its potential application as a therapeutic target for reducing or treating age-related diseases in the colon.https://www.mdpi.com/1422-0067/24/5/4570colon agingsoluble epoxide hydrolasecell senescenceER stress |
| spellingShingle | Weicang Wang Karen M. Wagner Yuxin Wang Nalin Singh Jun Yang Qiyi He Christophe Morisseau Bruce D. Hammock Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon International Journal of Molecular Sciences colon aging soluble epoxide hydrolase cell senescence ER stress |
| title | Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon |
| title_full | Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon |
| title_fullStr | Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon |
| title_full_unstemmed | Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon |
| title_short | Soluble Epoxide Hydrolase Contributes to Cell Senescence and ER Stress in Aging Mice Colon |
| title_sort | soluble epoxide hydrolase contributes to cell senescence and er stress in aging mice colon |
| topic | colon aging soluble epoxide hydrolase cell senescence ER stress |
| url | https://www.mdpi.com/1422-0067/24/5/4570 |
| work_keys_str_mv | AT weicangwang solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT karenmwagner solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT yuxinwang solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT nalinsingh solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT junyang solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT qiyihe solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT christophemorisseau solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon AT brucedhammock solubleepoxidehydrolasecontributestocellsenescenceanderstressinagingmicecolon |