Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1
Abstract Background Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulating T2DM related lipid metabolism and the effect of ketogenic diet (KD) on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effec...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-021-00429-6 |
| _version_ | 1818941777110892544 |
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| author | Jielin Zhou Yao Lu Yajing Jia Jing Lu Zhengxuan Jiang Keyang Chen |
| author_facet | Jielin Zhou Yao Lu Yajing Jia Jing Lu Zhengxuan Jiang Keyang Chen |
| author_sort | Jielin Zhou |
| collection | DOAJ |
| description | Abstract Background Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulating T2DM related lipid metabolism and the effect of ketogenic diet (KD) on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of KD on diabetic mice and its mediated mechanism. Methods Male C57BL/6J and KKA y mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo was applied. Results Hepatic PES1 expression in diabetic mice was markedly increased, which was suppressed by KD feeding with an accompanying reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, Caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar outcomes were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which were, however reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and Caspase1 promoters. The inhibition of p300 and Caspase1 expression elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of Caspase1 also alleviated the TG levels in cultured hepatocytes. Conclusion KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression. |
| first_indexed | 2024-12-20T07:00:55Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-20T07:00:55Z |
| publishDate | 2022-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-bd31020eb47d4148a3a5979a5b331a822022-12-21T19:49:13ZengBMCMolecular Medicine1076-15511528-36582022-01-0128111610.1186/s10020-021-00429-6Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1Jielin Zhou0Yao Lu1Yajing Jia2Jing Lu3Zhengxuan Jiang4Keyang Chen5Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical UniversityDepartment of Anesthesiology, The First Affiliated Hospital, Anhui Medical UniversityDepartment of Health Inspection and Quarantine, School of Public Health, Anhui Medical UniversityDepartment of Nutrition and Food Hygiene, School of Public Health, Anhui Medical UniversityDepartment of Ophthalmology, The Second Affiliated Hospital, Anhui Medical UniversityDepartment of Nutrition and Food Hygiene, School of Public Health, Anhui Medical UniversityAbstract Background Previous reports implied a possible link between PES1 and lipid metabolism. However, the role of PES1 in regulating T2DM related lipid metabolism and the effect of ketogenic diet (KD) on PES1 have not been reported. The aim of present study is to explore the role of PES1 in effects of KD on diabetic mice and its mediated mechanism. Methods Male C57BL/6J and KKA y mice were fed with standard diet (SD) and KD, respectively. Simultaneously, McArdle 7777 cells were treated by β-hydroxybutyric acid (β-HB), Pes1 siRNA or Pes1 overexpression plasmid, respectively. Additionally, liver-conditional knockout (CKO) of Pes1 in vivo was applied. Results Hepatic PES1 expression in diabetic mice was markedly increased, which was suppressed by KD feeding with an accompanying reduction of hepatic and plasma triglycerides (TG). In mice with CKO of Pes1, the protein levels of p300, SREBP1c, FASN, SCD1, Caspase1, NLRP3 and GSDMD were dramatically downregulated in livers, and the plasma and hepatic TG, IL-1β and IL-18 were decreased as well. The similar outcomes were also observed in β-HB and Pes1 knockdown treated hepatocytes. By contrast, Pes1 overexpression in cultured hepatocytes showed that these levels were significantly enhanced, which were, however reduced under β-HB treatment. Mechanistically, we discovered that β-HB decreased CHOP binding to the Pes1 promoters, resulting in the downregulation of PES1, thereby reducing PES1 binding to p300 and Caspase1 promoters. The inhibition of p300 and Caspase1 expression elicited the dramatic suppression of acetylation of SREBP1c via its interaction with p300, and the decreased GSDMD levels. Besides, knockdown of Caspase1 also alleviated the TG levels in cultured hepatocytes. Conclusion KD may improve lipid dysregulation in type 2 diabetic mice by downregulating hepatic PES1 expression.https://doi.org/10.1186/s10020-021-00429-6Ketogenic diet (KD)β-Hydroxybutyrate (β-HB)PES1Lipid metabolismInflammation |
| spellingShingle | Jielin Zhou Yao Lu Yajing Jia Jing Lu Zhengxuan Jiang Keyang Chen Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 Molecular Medicine Ketogenic diet (KD) β-Hydroxybutyrate (β-HB) PES1 Lipid metabolism Inflammation |
| title | Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 |
| title_full | Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 |
| title_fullStr | Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 |
| title_full_unstemmed | Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 |
| title_short | Ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 |
| title_sort | ketogenic diet ameliorates lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1 |
| topic | Ketogenic diet (KD) β-Hydroxybutyrate (β-HB) PES1 Lipid metabolism Inflammation |
| url | https://doi.org/10.1186/s10020-021-00429-6 |
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