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Xia, Y.* ; Andersson, E.* ; Anand, S.K.* ; Cansby, E.* ; Caputo, M.* ; Kumari, S.* ; Porosk, R.* ; Kilk, K.* ; Nair, S.* ; Marschall, H.U.* ; Blüher, M. ; Mahlapuu, M.*

Silencing of STE20-type kinase TAOK1 confers protection against hepatocellular lipotoxicity through metabolic rewiring.

Hepat. Commun. 7:17 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
BACKGROUND: NAFLD has become the leading cause of chronic liver disease worldwide afflicting about one quarter of the adult population. NASH is a severe subtype of NAFLD, which in addition to hepatic steatosis connotes liver inflammation and hepatocyte ballooning. In light of the exponentially increasing prevalence of NAFLD, it is imperative to gain a better understanding of its molecular pathogenesis. The aim of this study was to examine the potential role of STE20-type kinase TAOK1 -a hepatocellular lipid droplet-associated protein-in the regulation of liver lipotoxicity and NAFLD etiology. METHODS: The correlation between TAOK1 mRNA expression in liver biopsies and the severity of NAFLD was evaluated in a cohort of 62 participants. Immunofluorescence microscopy was applied to describe the subcellular localization of TAOK1 in human and mouse hepatocytes. Metabolic reprogramming and oxidative/endoplasmic reticulum stress were investigated in immortalized human hepatocytes, where TAOK1 was overexpressed or silenced by small interfering RNA, using functional assays, immunofluorescence microscopy, and colorimetric analysis. Migration, invasion, and epithelial-mesenchymal transition were examined in TAOK1-deficient human hepatoma-derived cells. Alterations in hepatocellular metabolic and pro-oncogenic signaling pathways were assessed by immunoblotting. RESULTS: We observed a positive correlation between the TAOK1 mRNA abundance in human liver biopsies and key hallmarks of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Furthermore, we found that TAOK1 protein fully colocalized with intracellular lipid droplets in human and mouse hepatocytes. The silencing of TAOK1 alleviated lipotoxicity in cultured human hepatocytes by accelerating lipid catabolism (mitochondrial β-oxidation and triacylglycerol secretion), suppressing lipid anabolism (fatty acid influx and lipogenesis), and mitigating oxidative/endoplasmic reticulum stress, and the opposite changes were detected in TAOK1-overexpressing cells. We also found decreased proliferative, migratory, and invasive capacity, as well as lower epithelial-mesenchymal transition in TAOK1-deficient human hepatoma-derived cells. Mechanistic studies revealed that TAOK1 knockdown inhibited ERK and JNK activation and repressed acetyl-CoA carboxylase (ACC) protein abundance in human hepatocytes. CONCLUSIONS: Together, we provide the first experimental evidence supporting the role of hepatic lipid droplet-decorating kinase TAOK1 in NAFLD development through mediating fatty acid partitioning between anabolic and catabolic pathways, regulating oxidative/endoplasmic reticulum stress, and modulating metabolic and pro-oncogenic signaling.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Protein-kinase; Hepatic Inflammation; Insulin Sensitivity; Fatty-acids; Stk25; Lipase; Overexpression; Activation; Disease
ISSN (print) / ISBN 2471-254X
e-ISSN 2471-254X
Zeitschrift Hepatology communications
Quellenangaben Band: 7, Heft: 4, Seiten: , Artikelnummer: 17 Supplement: ,
Verlag Wiley
Verlagsort Hoboken, NJ
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen Swedish Cancer Society
Novo Nordisk Foundation
Swedish Heart-Lung Foundation
Swedish Diabetes Foundation
A. Wiberg Foundation
Adlerbert Research Foundation
I. Hultman Foundation
Swedish Research Council
Prof. N. Svartz Foundation
L. and J. Gronberg Foundation
W. and M. Lundgren Foundation
I.-B. and A. Lundberg Research Foundation
Erling-Persson Foundation
Wenner-Gren Foundation
Swedish Government
Swedish county councils, the ALF-agreement
F. Neubergh Foundation