Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization
Abstract Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disorders, has become a serious public health issue. Although the Smad4 signaling pathway has been implicated in the progression of NAFLD, the specific role of Smad4 in hepatocytes in NAFLD pathogenesis remains unclear...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07376-8 |
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| author | Wei Yang Xuanxuan Yan Rui Chen Xin Xin Shuang Ge Yongxiang Zhao Xinlong Yan Jinhua Zhang |
| author_facet | Wei Yang Xuanxuan Yan Rui Chen Xin Xin Shuang Ge Yongxiang Zhao Xinlong Yan Jinhua Zhang |
| author_sort | Wei Yang |
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| description | Abstract Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disorders, has become a serious public health issue. Although the Smad4 signaling pathway has been implicated in the progression of NAFLD, the specific role of Smad4 in hepatocytes in NAFLD pathogenesis remains unclear. Hepatocyte-specific knockout Smad4 mice (AlbSmad4−/−) were first constructed using the Cre-Loxp recombinant system to establish a high-fat diet induced NAFLD model. The role of Smad4 in the occurrence and development of NAFLD was determined by monitoring the body weight of mice, detecting triglycerides and free fatty acids in serum and liver tissue homogenates, staining the tissue sections to observe the accumulation of liver fat, and RT-qPCR detecting the expression of genes related to lipogenesis, fatty acid intake, and fatty acid β oxidation. The molecular mechanism of Smad4 in hepatocytes affecting NAFLD was therefore investigated through combining in vitro and in vivo experiments. Smad4 deficiency in hepatocytes mitigated NAFLD progression and decreased inflammatory cell infiltration. Moreover, Smad4 deficiency inhibited CXCL1 secretion by suppressing the activation of the ASK1/P38/JNK signaling pathway. Furthermore, targeting CXCL1 using CXCR2 inhibitors diminished hepatocyte lipogenesis and inhibited the polarization of M1-type macrophages. Collectively, these results suggested that Smad4 plays a vital role in exacerbating NAFLD and may be a promising candidate for anti-NAFLD therapy. |
| format | Article |
| id | doaj-art-9b32dda884c0406086ac9b100a5e86fc |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death and Disease |
| spelling | doaj-art-9b32dda884c0406086ac9b100a5e86fc2025-02-02T12:44:46ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111110.1038/s41419-025-07376-8Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarizationWei Yang0Xuanxuan Yan1Rui Chen2Xin Xin3Shuang Ge4Yongxiang Zhao5Xinlong Yan6Jinhua Zhang7The College of Life Science and Bioengineering, Beijing Jiaotong UniversityThe College of Life Science and Bioengineering, Beijing Jiaotong UniversityThe College of Life Science and Bioengineering, Beijing Jiaotong UniversityThe College of Life Science and Bioengineering, Beijing Jiaotong UniversityNational Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targetubg Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical UniversityNational Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targetubg Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-Targeting Theranostics, Guangxi Medical UniversityFaculty of Environmental and Life Sciences, Beijing University of TechnologyThe College of Life Science and Bioengineering, Beijing Jiaotong UniversityAbstract Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disorders, has become a serious public health issue. Although the Smad4 signaling pathway has been implicated in the progression of NAFLD, the specific role of Smad4 in hepatocytes in NAFLD pathogenesis remains unclear. Hepatocyte-specific knockout Smad4 mice (AlbSmad4−/−) were first constructed using the Cre-Loxp recombinant system to establish a high-fat diet induced NAFLD model. The role of Smad4 in the occurrence and development of NAFLD was determined by monitoring the body weight of mice, detecting triglycerides and free fatty acids in serum and liver tissue homogenates, staining the tissue sections to observe the accumulation of liver fat, and RT-qPCR detecting the expression of genes related to lipogenesis, fatty acid intake, and fatty acid β oxidation. The molecular mechanism of Smad4 in hepatocytes affecting NAFLD was therefore investigated through combining in vitro and in vivo experiments. Smad4 deficiency in hepatocytes mitigated NAFLD progression and decreased inflammatory cell infiltration. Moreover, Smad4 deficiency inhibited CXCL1 secretion by suppressing the activation of the ASK1/P38/JNK signaling pathway. Furthermore, targeting CXCL1 using CXCR2 inhibitors diminished hepatocyte lipogenesis and inhibited the polarization of M1-type macrophages. Collectively, these results suggested that Smad4 plays a vital role in exacerbating NAFLD and may be a promising candidate for anti-NAFLD therapy.https://doi.org/10.1038/s41419-025-07376-8 |
| spellingShingle | Wei Yang Xuanxuan Yan Rui Chen Xin Xin Shuang Ge Yongxiang Zhao Xinlong Yan Jinhua Zhang Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization Cell Death and Disease |
| title | Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization |
| title_full | Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization |
| title_fullStr | Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization |
| title_full_unstemmed | Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization |
| title_short | Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization |
| title_sort | smad4 deficiency in hepatocytes attenuates nafld progression via inhibition of lipogenesis and macrophage polarization |
| url | https://doi.org/10.1038/s41419-025-07376-8 |
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