Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways
High levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by <i>Fkbp5</i> is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. <i>Fkb...
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MDPI AG
2023-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/1/89 |
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| author | Kent E. Williams Yi Zou Bin Qiu Tatsuyoshi Kono Changyong Guo Dawn Garcia Hanying Chen Tamara Graves Zhao Lai Carmella Evans-Molina Yao-Ying Ma Suthat Liangpunsakul Weidong Yong Tiebing Liang |
| author_facet | Kent E. Williams Yi Zou Bin Qiu Tatsuyoshi Kono Changyong Guo Dawn Garcia Hanying Chen Tamara Graves Zhao Lai Carmella Evans-Molina Yao-Ying Ma Suthat Liangpunsakul Weidong Yong Tiebing Liang |
| author_sort | Kent E. Williams |
| collection | DOAJ |
| description | High levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by <i>Fkbp5</i> is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. <i>Fkbp5</i> has been previously linked to neurite outgrowth and hippocampal morphology, sex differences in stress response, and epigenetic modification. Presently, primary cultured <i>Fkbp5</i> KO and WT mouse neurons were examined for neurite outgrowth and mitochondrial signal with and without alcohol. We found neurite specification differences between KO and WT; particularly, mesh-like morphology was observed after alcohol treatment and confirmed higher MitoTracker signal in cultured neurons of <i>Fkbp5</i> KO compared to WT at both naive and alcohol-treated conditions. Brain regions that express FKBP51 protein were identified, and hippocampus was confirmed to possess a high level of expression. RNA-seq profiling was performed using the hippocampus of naïve or alcohol-injected (2 mg EtOH/Kg) male and female <i>Fkbp5</i> KO and WT mice. Differentially expressed genes (DEGs) were identified between <i>Fkbp5</i> KO and WT at baseline and following alcohol treatment, with female comparisons possessing a higher number of DEGs than male comparisons. Pathway analysis suggested that genes affecting calcium signaling, lipid metabolism, and axon guidance were differentially expressed at naïve condition between KO and WT. Alcohol treatment significantly affected pathways and enzymes involved in biosynthesis (Keto, serine, and glycine) and signaling (dopamine and insulin receptor), and neuroprotective role. Functions related to cell morphology, cell-to-cell signaling, lipid metabolism, injury response, and post-translational modification were significantly altered due to alcohol. In summary, <i>Fkbp5</i> plays a critical role in the response to acute alcohol treatment by altering metabolism and signaling-related genes. |
| first_indexed | 2024-03-08T15:09:41Z |
| format | Article |
| id | doaj.art-bd9ba3e9865a4a2db1ec431a34823b1f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T15:09:41Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-bd9ba3e9865a4a2db1ec431a34823b1f2024-01-10T14:53:30ZengMDPI AGCells2073-44092023-12-011318910.3390/cells13010089Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related PathwaysKent E. Williams0Yi Zou1Bin Qiu2Tatsuyoshi Kono3Changyong Guo4Dawn Garcia5Hanying Chen6Tamara Graves7Zhao Lai8Carmella Evans-Molina9Yao-Ying Ma10Suthat Liangpunsakul11Weidong Yong12Tiebing Liang13Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USADiabetes Research Center, Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADepartment Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USADivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USAGreehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USADiabetes Research Center, Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USADivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USADepartment of Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USADivision of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USAHigh levels of alcohol intake alter brain gene expression and can produce long-lasting effects. FK506-binding protein 51 (FKBP51) encoded by <i>Fkbp5</i> is a physical and cellular stress response gene and has been associated with alcohol consumption and withdrawal severity. <i>Fkbp5</i> has been previously linked to neurite outgrowth and hippocampal morphology, sex differences in stress response, and epigenetic modification. Presently, primary cultured <i>Fkbp5</i> KO and WT mouse neurons were examined for neurite outgrowth and mitochondrial signal with and without alcohol. We found neurite specification differences between KO and WT; particularly, mesh-like morphology was observed after alcohol treatment and confirmed higher MitoTracker signal in cultured neurons of <i>Fkbp5</i> KO compared to WT at both naive and alcohol-treated conditions. Brain regions that express FKBP51 protein were identified, and hippocampus was confirmed to possess a high level of expression. RNA-seq profiling was performed using the hippocampus of naïve or alcohol-injected (2 mg EtOH/Kg) male and female <i>Fkbp5</i> KO and WT mice. Differentially expressed genes (DEGs) were identified between <i>Fkbp5</i> KO and WT at baseline and following alcohol treatment, with female comparisons possessing a higher number of DEGs than male comparisons. Pathway analysis suggested that genes affecting calcium signaling, lipid metabolism, and axon guidance were differentially expressed at naïve condition between KO and WT. Alcohol treatment significantly affected pathways and enzymes involved in biosynthesis (Keto, serine, and glycine) and signaling (dopamine and insulin receptor), and neuroprotective role. Functions related to cell morphology, cell-to-cell signaling, lipid metabolism, injury response, and post-translational modification were significantly altered due to alcohol. In summary, <i>Fkbp5</i> plays a critical role in the response to acute alcohol treatment by altering metabolism and signaling-related genes.https://www.mdpi.com/2073-4409/13/1/89RNA-seqhippocampusFkbp5mitochondrialipid metabolism |
| spellingShingle | Kent E. Williams Yi Zou Bin Qiu Tatsuyoshi Kono Changyong Guo Dawn Garcia Hanying Chen Tamara Graves Zhao Lai Carmella Evans-Molina Yao-Ying Ma Suthat Liangpunsakul Weidong Yong Tiebing Liang Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways Cells RNA-seq hippocampus Fkbp5 mitochondria lipid metabolism |
| title | Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways |
| title_full | Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways |
| title_fullStr | Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways |
| title_full_unstemmed | Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways |
| title_short | Sex-Specific Impact of Fkbp5 on Hippocampal Response to Acute Alcohol Injection: Involvement in Alterations of Metabolism-Related Pathways |
| title_sort | sex specific impact of fkbp5 on hippocampal response to acute alcohol injection involvement in alterations of metabolism related pathways |
| topic | RNA-seq hippocampus Fkbp5 mitochondria lipid metabolism |
| url | https://www.mdpi.com/2073-4409/13/1/89 |
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