Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage
The primary hepatic consequence of obesity is non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global adult population. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD characterized by liver lipid accumulation, inflammation, and hepatocyte ballooning, with a diffe...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227522000712 |
| _version_ | 1818465928275296256 |
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| author | Sumit Kumar Anand Mara Caputo Ying Xia Emma Andersson Emmelie Cansby Sima Kumari Marcus Henricsson Rando Porosk Katharina Susanne Keuenhof Johanna Louise Höög Syam Nair Hanns-Ulrich Marschall Matthias Blüher Margit Mahlapuu |
| author_facet | Sumit Kumar Anand Mara Caputo Ying Xia Emma Andersson Emmelie Cansby Sima Kumari Marcus Henricsson Rando Porosk Katharina Susanne Keuenhof Johanna Louise Höög Syam Nair Hanns-Ulrich Marschall Matthias Blüher Margit Mahlapuu |
| author_sort | Sumit Kumar Anand |
| collection | DOAJ |
| description | The primary hepatic consequence of obesity is non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global adult population. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD characterized by liver lipid accumulation, inflammation, and hepatocyte ballooning, with a different degree of hepatic fibrosis. In the light of rapidly increasing prevalence of NAFLD and NASH, there is an urgent need for improved understanding of the molecular pathogenesis of these diseases. The aim of this study was to decipher the possible role of STE20-type kinase MAP4K4 in the regulation of hepatocellular lipotoxicity and susceptibility to NAFLD. We found that MAP4K4 mRNA expression in human liver biopsies was positively correlated with key hallmarks of NAFLD (i.e., liver steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis). We also found that the silencing of MAP4K4 suppressed lipid deposition in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while attenuating fatty acid influx and lipid synthesis. Furthermore, downregulation of MAP4K4 markedly reduced the glycolysis rate and lowered incidences of oxidative/endoplasmic reticulum stress. In parallel, we observed suppressed JNK and ERK and increased AKT phosphorylation in MAP4K4-deficient hepatocytes. Together, these results provide the first experimental evidence supporting the potential involvement of STE20-type kinase MAP4K4 as a component of the hepatocellular lipotoxic milieu promoting NAFLD susceptibility. |
| first_indexed | 2024-04-13T20:51:29Z |
| format | Article |
| id | doaj.art-27fa9e174f6b494d9c0fcdb5a2bacb3c |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-13T20:51:29Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-27fa9e174f6b494d9c0fcdb5a2bacb3c2022-12-22T02:30:28ZengElsevierJournal of Lipid Research0022-22752022-07-01637100238Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damageSumit Kumar Anand0Mara Caputo1Ying Xia2Emma Andersson3Emmelie Cansby4Sima Kumari5Marcus Henricsson6Rando Porosk7Katharina Susanne Keuenhof8Johanna Louise Höög9Syam Nair10Hanns-Ulrich Marschall11Matthias Blüher12Margit Mahlapuu13Department 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, 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, SwedenBiomarker Discovery and Development, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, SwedenDepartment of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, EstoniaDepartment 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 Academy, University of Gothenburg, Gothenburg, SwedenDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, SwedenHelmholtz Institute for Metabolic, Obesity, and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, GermanyDepartment of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; For correspondence: Margit MahlapuuThe primary hepatic consequence of obesity is non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global adult population. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD characterized by liver lipid accumulation, inflammation, and hepatocyte ballooning, with a different degree of hepatic fibrosis. In the light of rapidly increasing prevalence of NAFLD and NASH, there is an urgent need for improved understanding of the molecular pathogenesis of these diseases. The aim of this study was to decipher the possible role of STE20-type kinase MAP4K4 in the regulation of hepatocellular lipotoxicity and susceptibility to NAFLD. We found that MAP4K4 mRNA expression in human liver biopsies was positively correlated with key hallmarks of NAFLD (i.e., liver steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis). We also found that the silencing of MAP4K4 suppressed lipid deposition in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while attenuating fatty acid influx and lipid synthesis. Furthermore, downregulation of MAP4K4 markedly reduced the glycolysis rate and lowered incidences of oxidative/endoplasmic reticulum stress. In parallel, we observed suppressed JNK and ERK and increased AKT phosphorylation in MAP4K4-deficient hepatocytes. Together, these results provide the first experimental evidence supporting the potential involvement of STE20-type kinase MAP4K4 as a component of the hepatocellular lipotoxic milieu promoting NAFLD susceptibility.http://www.sciencedirect.com/science/article/pii/S0022227522000712MAP4K4non-alcoholic fatty liver diseasenon-alcoholic steatohepatitisliver steatosishepatic lipid metabolismhepatic glycolysis |
| spellingShingle | Sumit Kumar Anand Mara Caputo Ying Xia Emma Andersson Emmelie Cansby Sima Kumari Marcus Henricsson Rando Porosk Katharina Susanne Keuenhof Johanna Louise Höög Syam Nair Hanns-Ulrich Marschall Matthias Blüher Margit Mahlapuu Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage Journal of Lipid Research MAP4K4 non-alcoholic fatty liver disease non-alcoholic steatohepatitis liver steatosis hepatic lipid metabolism hepatic glycolysis |
| title | Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage |
| title_full | Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage |
| title_fullStr | Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage |
| title_full_unstemmed | Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage |
| title_short | Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage |
| title_sort | inhibition of map4k4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage |
| topic | MAP4K4 non-alcoholic fatty liver disease non-alcoholic steatohepatitis liver steatosis hepatic lipid metabolism hepatic glycolysis |
| url | http://www.sciencedirect.com/science/article/pii/S0022227522000712 |
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