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Xia, Y.* ; Andersson, E.* ; Caputo, M.* ; Cansby, E.* ; Sedda, F.* ; Font-Gironès, F.* ; Ruud, J.* ; Kurhe, Y.* ; Hallberg, B.* ; Marschall, H.U.* ; Asterholm, I.W.* ; Romeo, S.* ; Blüher, M. ; Mahlapuu, M.*

Knockout of STE20-type kinase TAOK3 does not attenuate diet-induced NAFLD development in mice.

Mol. Med. 29:138 (2023)
Verlagsversion DOI PMC
Creative Commons Lizenzvertrag
OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD), the primary hepatic consequence of obesity, is affecting about 25% of the global adult population. The aim of this study was to examine the in vivo role of STE20-type protein kinase TAOK3, which has been previously reported to regulate hepatocellular lipotoxicity in vitro, in the development of NAFLD and systemic insulin resistance in the context of obesity. METHODS: Taok3 knockout mice and wild-type littermates were challenged with a high-fat diet. Various in vivo tests were performed to characterize the whole-body metabolism. NAFLD progression in the liver, and lipotoxic damage in adipose tissue, kidney, and skeletal muscle were compared between the genotypes by histological assessment, immunofluorescence microscopy, protein and gene expression profiling, and biochemical assays. Intracellular lipid accumulation and oxidative/ER stress were analyzed in cultured human and mouse hepatocytes where TAOK3 was knocked down by small interfering RNA. The expression of TAOK3-related STE20-type kinases was quantified in different organs from high-fat diet-fed Taok3-/- and wild-type mice. RESULTS: TAOK3 deficiency had no impact on body weight or composition, food consumption, locomotor activity, or systemic glucose or insulin homeostasis in obese mice. Consistently, Taok3-/- mice and wild-type littermates developed a similar degree of high-fat diet-induced liver steatosis, inflammation, and fibrosis, and we detected no difference in lipotoxic damage of adipose tissue, kidney, or skeletal muscle when comparing the two genotypes. In contrast, the silencing of TAOK3 in vitro markedly suppressed ectopic lipid accumulation and metabolic stress in mouse and human hepatocytes. Interestingly, the hepatic mRNA abundance of several TAOK3-related kinases, which have been previously implicated to increase the risk of NAFLD susceptibility, was significantly elevated in Taok3-/- vs. wild-type mice. CONCLUSIONS: In contrast to the in vitro observations, genetic deficiency of TAOK3 in mice failed to mitigate the detrimental metabolic consequences of chronic exposure to dietary lipids, which may be partly attributable to the activation of liver-specific compensation response for the genetic loss of TAOK3 by related STE20-type kinases.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Genetic Compensation ; Non-alcoholic Fatty Liver Disease ; Non-alcoholic Steatohepatitis ; Systemic Glucose And Insulin Homeostasis ; Taok3; Insulin-resistance; Stk25; Expression; Disease; Nash
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 1076-1551
e-ISSN 1435-8123
Zeitschrift Molecular Medicine
Quellenangaben Band: 29, Heft: 1, Seiten: , Artikelnummer: 138 Supplement: ,
Verlag Feinstein Inst. for Medical Research
Verlagsort One New York Plaza, Suite 4600, New York, Ny, United States
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-506501-001
Förderungen Swedish Research Council
Swedish Cancer Society
Novo Nordisk Foundation
Swedish Heart-Lung Foundation
Swedish Diabetes Foundation
Adlerbert Research Foundation
I. Hultman Foundation
University of Gothenburg
M. Bergvall Foundation
A. Gabrielsson Foundation
O.E. and E. Johansson Foundation
S. and E. Goljes Foundation
Erling-Persson Foundation
EFSD/European Research Programme on "New Targets for Diabetes or Obesity-related Metabolic Diseases" - MSD
Diabetes Wellness Sweden
Swedish Government
ALF-agreement
W. and M. Lundgren Foundation
DOI 10.1186/s10020-023-00738-y
WOS ID 001099668900002
Scopus ID 85174499806
PubMed ID 37864157
Erfassungsdatum 2023-11-28
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