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  • Kumar Anand, SumitGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology (author)

Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • Elsevier BV,2022

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/317600
  • https://gup.ub.gu.se/publication/317600URI
  • https://doi.org/10.1016/j.jlr.2022.100238DOI

Supplementary language notes

  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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 he-patocellular 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 he-patocytes by stimulating beta-oxidation and tri-acylglycerol secretion, while attenuating fatty acid influx and lipid synthesis. Furthermore, down -regulation 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 hep-atocytes. 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.

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  • Caputo, MaraGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xcapma (author)
  • Xia, YingGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xxiayi (author)
  • Andersson, Emma,1994Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xaemmi (author)
  • Cansby, Emmelie,1984Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xcanem (author)
  • Kumari, SimaGothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xkumsi (author)
  • Henricsson, Marcus,1975Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory(Swepub:gu)xstahm (author)
  • Porosk, R. (author)
  • Keuenhof, Katharina,1994Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xkeuka (author)
  • Höög, Johanna L,1979Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xhoojo (author)
  • Nair, SyamGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institutionen för neurovetenskap och fysiologi,Institute of Clinical Sciences,Institute of Neuroscience and Physiology(Swepub:gu)xnaisy (author)
  • Marschall, Hanns-Ulrich,1954Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory(Swepub:gu)xmarsh (author)
  • Bluher, M. (author)
  • Mahlapuu, Margit,1972Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology(Swepub:gu)xmahma (author)
  • Göteborgs universitetInstitutionen för kemi och molekylärbiologi (creator_code:org_t)

Related titles

  • In:Journal of Lipid Research: Elsevier BV63:70022-2275

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