STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes
Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poor...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Health/LWW
2021-07-01
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| Series: | Hepatology Communications |
| Online Access: | https://doi.org/10.1002/hep4.1702 |
| _version_ | 1811173719741038592 |
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| author | Mara Caputo Emmelie Cansby Sima Kumari Yeshwant Kurhe Syam Nair Marcus Ståhlman Nagaraj M. Kulkarni Jan Borén Hanns‐Ulrich Marschall Matthias Blüher Margit Mahlapuu |
| author_facet | Mara Caputo Emmelie Cansby Sima Kumari Yeshwant Kurhe Syam Nair Marcus Ståhlman Nagaraj M. Kulkarni Jan Borén Hanns‐Ulrich Marschall Matthias Blüher Margit Mahlapuu |
| author_sort | Mara Caputo |
| collection | DOAJ |
| description | Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20‐type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating β‐oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposition by suppressing mitochondrial fatty acid oxidation and triacylglycerol efflux, while enhancing lipogenesis. In parallel to these reciprocal alterations in lipid storage, we detected substantially decreased or aggravated oxidative/endoplasmic reticulum stress in human hepatocytes with reduced or increased MST4 levels, respectively. Interestingly, MST4 protein was predominantly associated with intracellular lipid droplets in both human and rodent hepatocytes. Conclusion: Together, our results suggest that hepatic lipid droplet–decorating protein MST4 is a critical regulatory node governing susceptibility to NAFLD and warrant future investigations to address the therapeutic potential of MST4 antagonism as a strategy to prevent or mitigate the development and aggravation of this disease. |
| first_indexed | 2024-04-10T17:52:50Z |
| format | Article |
| id | doaj.art-4e024d45939a4d848075e192c67e1a5a |
| institution | Directory Open Access Journal |
| issn | 2471-254X |
| language | English |
| last_indexed | 2024-04-10T17:52:50Z |
| publishDate | 2021-07-01 |
| publisher | Wolters Kluwer Health/LWW |
| record_format | Article |
| series | Hepatology Communications |
| spelling | doaj.art-4e024d45939a4d848075e192c67e1a5a2023-02-02T20:04:18ZengWolters Kluwer Health/LWWHepatology Communications2471-254X2021-07-01571183120010.1002/hep4.1702STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in HepatocytesMara Caputo0Emmelie Cansby1Sima Kumari2Yeshwant Kurhe3Syam Nair4Marcus Ståhlman5Nagaraj M. Kulkarni6Jan Borén7Hanns‐Ulrich Marschall8Matthias Blüher9Margit Mahlapuu10Department of Chemistry and Molecular Biology University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Chemistry and Molecular Biology University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Chemistry and Molecular Biology University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Chemistry and Molecular Biology University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenInstitute of Neuroscience and Physiology, and Institute of Clinical Sciences Sahlgrenska AcademyUniversity of Gothenburg Gothenburg SwedenDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory Institute of Medicine University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Chemistry and Molecular Biology University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory Institute of Medicine University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory Institute of Medicine University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenDepartment of Medicine University of Leipzig Leipzig GermanyDepartment of Chemistry and Molecular Biology University of Gothenburg and Sahlgrenska University Hospital Gothenburg SwedenNonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20‐type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating β‐oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposition by suppressing mitochondrial fatty acid oxidation and triacylglycerol efflux, while enhancing lipogenesis. In parallel to these reciprocal alterations in lipid storage, we detected substantially decreased or aggravated oxidative/endoplasmic reticulum stress in human hepatocytes with reduced or increased MST4 levels, respectively. Interestingly, MST4 protein was predominantly associated with intracellular lipid droplets in both human and rodent hepatocytes. Conclusion: Together, our results suggest that hepatic lipid droplet–decorating protein MST4 is a critical regulatory node governing susceptibility to NAFLD and warrant future investigations to address the therapeutic potential of MST4 antagonism as a strategy to prevent or mitigate the development and aggravation of this disease.https://doi.org/10.1002/hep4.1702 |
| spellingShingle | Mara Caputo Emmelie Cansby Sima Kumari Yeshwant Kurhe Syam Nair Marcus Ståhlman Nagaraj M. Kulkarni Jan Borén Hanns‐Ulrich Marschall Matthias Blüher Margit Mahlapuu STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes Hepatology Communications |
| title | STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes |
| title_full | STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes |
| title_fullStr | STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes |
| title_full_unstemmed | STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes |
| title_short | STE20‐Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes |
| title_sort | ste20 type protein kinase mst4 controls nafld progression by regulating lipid droplet dynamics and metabolic stress in hepatocytes |
| url | https://doi.org/10.1002/hep4.1702 |
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