Palmitate induces integrated stress response and lipoapoptosis in trophoblasts
Abstract Maternal obesity increases the risk of childhood obesity and programs the offspring to develop metabolic syndrome later in their life. Palmitate is the predominant saturated free fatty acid (FFA) that is transported across the placenta to the fetus. We have recently shown that saturated FFA...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06415-6 |
| _version_ | 1827381932412895232 |
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| author | Prakash Kumar Sahoo Chandan Krishnamoorthy Jennifer R. Wood Corrine Hanson Ann Anderson-Berry Justin L. Mott Sathish Kumar Natarajan |
| author_facet | Prakash Kumar Sahoo Chandan Krishnamoorthy Jennifer R. Wood Corrine Hanson Ann Anderson-Berry Justin L. Mott Sathish Kumar Natarajan |
| author_sort | Prakash Kumar Sahoo |
| collection | DOAJ |
| description | Abstract Maternal obesity increases the risk of childhood obesity and programs the offspring to develop metabolic syndrome later in their life. Palmitate is the predominant saturated free fatty acid (FFA) that is transported across the placenta to the fetus. We have recently shown that saturated FFA in the maternal circulation as a result of increased adipose tissue lipolysis in third trimester of pregnancy induces trophoblast lipoapoptosis. Here, we hypothesized that palmitate induces integrated stress response by activating mitogen-activated protein kinases (MAPKs), endoplasmic reticulum (ER) stress and granular stress and lipoapoptosis in trophoblasts. Choriocarcinoma-derived third-trimester placental trophoblast-like cells (JEG-3 and JAR) referred as trophoblasts were exposed to various concentrations of palmitate (PA). Apoptosis was assessed by nuclear morphological changes and caspase 3/7 activity. Immunoblot and immunofluorescence analysis was performed to measure the activation of MAPKs, ER stress and granular stress response pathways. Trophoblasts exposed to pathophysiological concentrations of PA showed a concentration-dependent increase in trophoblast lipoapoptosis. PA induces a caspase-dependent trophoblast lipoapoptosis. Further, PA induces MAPK activation (JNK and ERK) via phosphorylation, and activation of ER stress as evidenced by an increased phosphorylation eIF2α & IRE1α. PA also induces the activation of stress granules formation. Two pro-apoptotic transcriptional mediators of PA-induced trophoblast lipoapoptosis, CHOP and FoxO3 have increased nuclear translocation. Mechanistically, PA-induced JNK is critical for trophoblast lipoapoptosis. However, PA-induced activation of ERK and stress granule formation were shown to be cell survival signals to combat subcellular stress due to PA exposure. In conclusion, PA induces the activation of integrated stress responses, among which small molecule inhibition of JNK demonstrated that activation of JNK is critical for PA-induced trophoblast lipoapoptosis and small molecule activation of stress granule formation significantly prevents PA-induced trophoblast lipoapoptosis. |
| first_indexed | 2024-03-08T14:12:07Z |
| format | Article |
| id | doaj.art-5e1116ec305248fb8409170fac7a6dda |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-08T14:12:07Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-5e1116ec305248fb8409170fac7a6dda2024-01-14T12:38:18ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111210.1038/s41419-023-06415-6Palmitate induces integrated stress response and lipoapoptosis in trophoblastsPrakash Kumar Sahoo0Chandan Krishnamoorthy1Jennifer R. Wood2Corrine Hanson3Ann Anderson-Berry4Justin L. Mott5Sathish Kumar Natarajan6Department of Nutrition and Health Sciences, University of Nebraska-LincolnDepartment of Nutrition and Health Sciences, University of Nebraska-LincolnDepartment of Animal Sciences, University of Nebraska-LincolnCollege of Allied Health Professions Medical Nutrition Education, University of Nebraska Medical CenterDepartment of Pediatrics, University of Nebraska Medical CenterDepartment of Biochemistry and Molecular Biology, University of Nebraska Medical CenterDepartment of Nutrition and Health Sciences, University of Nebraska-LincolnAbstract Maternal obesity increases the risk of childhood obesity and programs the offspring to develop metabolic syndrome later in their life. Palmitate is the predominant saturated free fatty acid (FFA) that is transported across the placenta to the fetus. We have recently shown that saturated FFA in the maternal circulation as a result of increased adipose tissue lipolysis in third trimester of pregnancy induces trophoblast lipoapoptosis. Here, we hypothesized that palmitate induces integrated stress response by activating mitogen-activated protein kinases (MAPKs), endoplasmic reticulum (ER) stress and granular stress and lipoapoptosis in trophoblasts. Choriocarcinoma-derived third-trimester placental trophoblast-like cells (JEG-3 and JAR) referred as trophoblasts were exposed to various concentrations of palmitate (PA). Apoptosis was assessed by nuclear morphological changes and caspase 3/7 activity. Immunoblot and immunofluorescence analysis was performed to measure the activation of MAPKs, ER stress and granular stress response pathways. Trophoblasts exposed to pathophysiological concentrations of PA showed a concentration-dependent increase in trophoblast lipoapoptosis. PA induces a caspase-dependent trophoblast lipoapoptosis. Further, PA induces MAPK activation (JNK and ERK) via phosphorylation, and activation of ER stress as evidenced by an increased phosphorylation eIF2α & IRE1α. PA also induces the activation of stress granules formation. Two pro-apoptotic transcriptional mediators of PA-induced trophoblast lipoapoptosis, CHOP and FoxO3 have increased nuclear translocation. Mechanistically, PA-induced JNK is critical for trophoblast lipoapoptosis. However, PA-induced activation of ERK and stress granule formation were shown to be cell survival signals to combat subcellular stress due to PA exposure. In conclusion, PA induces the activation of integrated stress responses, among which small molecule inhibition of JNK demonstrated that activation of JNK is critical for PA-induced trophoblast lipoapoptosis and small molecule activation of stress granule formation significantly prevents PA-induced trophoblast lipoapoptosis.https://doi.org/10.1038/s41419-023-06415-6 |
| spellingShingle | Prakash Kumar Sahoo Chandan Krishnamoorthy Jennifer R. Wood Corrine Hanson Ann Anderson-Berry Justin L. Mott Sathish Kumar Natarajan Palmitate induces integrated stress response and lipoapoptosis in trophoblasts Cell Death and Disease |
| title | Palmitate induces integrated stress response and lipoapoptosis in trophoblasts |
| title_full | Palmitate induces integrated stress response and lipoapoptosis in trophoblasts |
| title_fullStr | Palmitate induces integrated stress response and lipoapoptosis in trophoblasts |
| title_full_unstemmed | Palmitate induces integrated stress response and lipoapoptosis in trophoblasts |
| title_short | Palmitate induces integrated stress response and lipoapoptosis in trophoblasts |
| title_sort | palmitate induces integrated stress response and lipoapoptosis in trophoblasts |
| url | https://doi.org/10.1038/s41419-023-06415-6 |
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