Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway
Non-alcoholic fatty liver disease (NAFLD)is accompanied by typical inflammatory damage and cell death. As a pro-inflammatory form of cell death, pyroptosis participates in important pathological processes involved in NAFLD. Regulatory roles of both CCCTC-binding factor (CTCF) and dipeptidyl peptidas...
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.669202/full |
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| author | Tian Shen Tao Lei Lin Chen Bing-Bing Zhu Bi-Lin Xu Cui-Ping Zhang Hong-Ping Wang |
| author_facet | Tian Shen Tao Lei Lin Chen Bing-Bing Zhu Bi-Lin Xu Cui-Ping Zhang Hong-Ping Wang |
| author_sort | Tian Shen |
| collection | DOAJ |
| description | Non-alcoholic fatty liver disease (NAFLD)is accompanied by typical inflammatory damage and cell death. As a pro-inflammatory form of cell death, pyroptosis participates in important pathological processes involved in NAFLD. Regulatory roles of both CCCTC-binding factor (CTCF) and dipeptidyl peptidase-4 (DPP4) have been reported in NAFLD, but it is still unclear whether the mechanism of action of gardenoside, a potential therapeutic for NAFLD, can be driven via these proteins. In this study, the direct interaction between CTCF and DPP4 was first confirmed by a dual-luciferase reporter assay system. Then, a cell model of NAFLD was established by induction with palmitic acid (PA) and lipopolysaccharide (LPS). A mouse NAFLD model was established, and the effect of gardenoside on both the cell and mouse models of NAFLD was also investigated. Increased lipid accumulation, NLRP3 inflammasome activation, and hepatocyte pyroptosis were recorded in NAFLD in vitro and in vivo. Gardenoside treatment effectively reduced the lipid accumulation, increased cell viability, reduced reactive oxygen species (ROS) generation, and attenuated pyroptosis and apoptosis in NAFLD in the in vitro and in vivo models. Alterations in these biological processes were evidenced by the decreased expression levels of several pro-pyroptotic markers including the NLR family, pyrin domain-containing 3 (NLRP3), apoptosis-related speckle-like protein (ASC), caspase-1 p20, Gasdermin D N-terminal domain (GSDMD-N), and IL-1β, along with simultaneously decreased CTCF and DPP4 levels. Importantly, CTCF silencing or DPP4 silencing exhibited effects similar to gardenoside treatment, while CTCF overexpression counteracted this trend, which indicated that CTCF might be a target responsible for gardenoside-induced alleviation of NAFLD, such therapeutic effects might be achieved through controlling the expression of the direct target of CTCF (DPP4) and several downstream molecules. In general, the current study provides a promising strategy for NAFLD treatment. |
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| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-19T19:33:54Z |
| publishDate | 2021-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-d7ef8e3dbf094aa2bc0b1cf0ee6dd5f82022-12-21T20:08:31ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-09-011210.3389/fphys.2021.669202669202Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling PathwayTian Shen0Tao Lei1Lin Chen2Bing-Bing Zhu3Bi-Lin Xu4Cui-Ping Zhang5Hong-Ping Wang6Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Nephrology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaNon-alcoholic fatty liver disease (NAFLD)is accompanied by typical inflammatory damage and cell death. As a pro-inflammatory form of cell death, pyroptosis participates in important pathological processes involved in NAFLD. Regulatory roles of both CCCTC-binding factor (CTCF) and dipeptidyl peptidase-4 (DPP4) have been reported in NAFLD, but it is still unclear whether the mechanism of action of gardenoside, a potential therapeutic for NAFLD, can be driven via these proteins. In this study, the direct interaction between CTCF and DPP4 was first confirmed by a dual-luciferase reporter assay system. Then, a cell model of NAFLD was established by induction with palmitic acid (PA) and lipopolysaccharide (LPS). A mouse NAFLD model was established, and the effect of gardenoside on both the cell and mouse models of NAFLD was also investigated. Increased lipid accumulation, NLRP3 inflammasome activation, and hepatocyte pyroptosis were recorded in NAFLD in vitro and in vivo. Gardenoside treatment effectively reduced the lipid accumulation, increased cell viability, reduced reactive oxygen species (ROS) generation, and attenuated pyroptosis and apoptosis in NAFLD in the in vitro and in vivo models. Alterations in these biological processes were evidenced by the decreased expression levels of several pro-pyroptotic markers including the NLR family, pyrin domain-containing 3 (NLRP3), apoptosis-related speckle-like protein (ASC), caspase-1 p20, Gasdermin D N-terminal domain (GSDMD-N), and IL-1β, along with simultaneously decreased CTCF and DPP4 levels. Importantly, CTCF silencing or DPP4 silencing exhibited effects similar to gardenoside treatment, while CTCF overexpression counteracted this trend, which indicated that CTCF might be a target responsible for gardenoside-induced alleviation of NAFLD, such therapeutic effects might be achieved through controlling the expression of the direct target of CTCF (DPP4) and several downstream molecules. In general, the current study provides a promising strategy for NAFLD treatment.https://www.frontiersin.org/articles/10.3389/fphys.2021.669202/fullgardenosideNAFLDinflammasomecaspase-1pyroptosisCTCF |
| spellingShingle | Tian Shen Tao Lei Lin Chen Bing-Bing Zhu Bi-Lin Xu Cui-Ping Zhang Hong-Ping Wang Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway Frontiers in Physiology gardenoside NAFLD inflammasome caspase-1 pyroptosis CTCF |
| title | Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway |
| title_full | Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway |
| title_fullStr | Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway |
| title_full_unstemmed | Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway |
| title_short | Gardenoside Hinders Caspase-1-Mediated Hepatocyte Pyroptosis Through the CTCF/DPP4 Signaling Pathway |
| title_sort | gardenoside hinders caspase 1 mediated hepatocyte pyroptosis through the ctcf dpp4 signaling pathway |
| topic | gardenoside NAFLD inflammasome caspase-1 pyroptosis CTCF |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.669202/full |
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