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STE20-type kinase TAOK3 regulates hepatic lipid partitioning

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid storage in hepatocytes, has recently emerged as a leading global cause of chronic liver disease. The aim of this study was to examine the role of STE20-type protein kinase TAOK3, which has previously been shown to associ...

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Autores principales: Xia, Ying, Caputo, Mara, Cansby, Emmelie, Anand, Sumit Kumar, Sütt, Silva, Henricsson, Marcus, Porosk, Rando, Marschall, Hanns-Ulrich, Blüher, Matthias, Mahlapuu, Margit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567304/
https://www.ncbi.nlm.nih.gov/pubmed/34634521
http://dx.doi.org/10.1016/j.molmet.2021.101353
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author Xia, Ying
Caputo, Mara
Cansby, Emmelie
Anand, Sumit Kumar
Sütt, Silva
Henricsson, Marcus
Porosk, Rando
Marschall, Hanns-Ulrich
Blüher, Matthias
Mahlapuu, Margit
author_facet Xia, Ying
Caputo, Mara
Cansby, Emmelie
Anand, Sumit Kumar
Sütt, Silva
Henricsson, Marcus
Porosk, Rando
Marschall, Hanns-Ulrich
Blüher, Matthias
Mahlapuu, Margit
author_sort Xia, Ying
collection PubMed
description OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid storage in hepatocytes, has recently emerged as a leading global cause of chronic liver disease. The aim of this study was to examine the role of STE20-type protein kinase TAOK3, which has previously been shown to associate with hepatic lipid droplets, in the initiation and aggravation of human NAFLD. METHODS: The correlation between TAOK3 mRNA expression and the severity of NAFLD was investigated in liver biopsies from 62 individuals. In immortalized human hepatocytes, intracellular fat deposition, lipid metabolism, and oxidative and endoplasmic reticulum stress were analyzed when TAOK3 was overexpressed or knocked down by small interfering RNA. Subcellular localization of TAOK3 was characterized in human and mouse hepatocytes by immunofluorescence microscopy. RESULTS: We found that the TAOK3 transcript levels in human liver biopsies were positively correlated with the key lesions of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Overexpression of TAOK3 in cultured human hepatocytes exacerbated lipid storage by inhibiting β-oxidation and triacylglycerol secretion while enhancing lipid synthesis. Conversely, silencing of TAOK3 attenuated lipid deposition in human hepatocytes by stimulating mitochondrial fatty acid oxidation and triacylglycerol efflux while suppressing lipogenesis. We also found aggravated or decreased oxidative/endoplasmic reticulum stress in human hepatocytes with increased or reduced TAOK3 levels, respectively. The subcellular localization of TAOK3 in human and mouse hepatocytes was confined to intracellular lipid droplets. CONCLUSIONS: This study provides the first evidence that hepatic lipid droplet-coating kinase TAOK3 is a critical regulatory node controlling liver lipotoxicity and susceptibility to NAFLD.
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spelling pubmed-85673042021-11-09 STE20-type kinase TAOK3 regulates hepatic lipid partitioning Xia, Ying Caputo, Mara Cansby, Emmelie Anand, Sumit Kumar Sütt, Silva Henricsson, Marcus Porosk, Rando Marschall, Hanns-Ulrich Blüher, Matthias Mahlapuu, Margit Mol Metab Original Article OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid storage in hepatocytes, has recently emerged as a leading global cause of chronic liver disease. The aim of this study was to examine the role of STE20-type protein kinase TAOK3, which has previously been shown to associate with hepatic lipid droplets, in the initiation and aggravation of human NAFLD. METHODS: The correlation between TAOK3 mRNA expression and the severity of NAFLD was investigated in liver biopsies from 62 individuals. In immortalized human hepatocytes, intracellular fat deposition, lipid metabolism, and oxidative and endoplasmic reticulum stress were analyzed when TAOK3 was overexpressed or knocked down by small interfering RNA. Subcellular localization of TAOK3 was characterized in human and mouse hepatocytes by immunofluorescence microscopy. RESULTS: We found that the TAOK3 transcript levels in human liver biopsies were positively correlated with the key lesions of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Overexpression of TAOK3 in cultured human hepatocytes exacerbated lipid storage by inhibiting β-oxidation and triacylglycerol secretion while enhancing lipid synthesis. Conversely, silencing of TAOK3 attenuated lipid deposition in human hepatocytes by stimulating mitochondrial fatty acid oxidation and triacylglycerol efflux while suppressing lipogenesis. We also found aggravated or decreased oxidative/endoplasmic reticulum stress in human hepatocytes with increased or reduced TAOK3 levels, respectively. The subcellular localization of TAOK3 in human and mouse hepatocytes was confined to intracellular lipid droplets. CONCLUSIONS: This study provides the first evidence that hepatic lipid droplet-coating kinase TAOK3 is a critical regulatory node controlling liver lipotoxicity and susceptibility to NAFLD. Elsevier 2021-10-08 /pmc/articles/PMC8567304/ /pubmed/34634521 http://dx.doi.org/10.1016/j.molmet.2021.101353 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Xia, Ying
Caputo, Mara
Cansby, Emmelie
Anand, Sumit Kumar
Sütt, Silva
Henricsson, Marcus
Porosk, Rando
Marschall, Hanns-Ulrich
Blüher, Matthias
Mahlapuu, Margit
STE20-type kinase TAOK3 regulates hepatic lipid partitioning
title STE20-type kinase TAOK3 regulates hepatic lipid partitioning
title_full STE20-type kinase TAOK3 regulates hepatic lipid partitioning
title_fullStr STE20-type kinase TAOK3 regulates hepatic lipid partitioning
title_full_unstemmed STE20-type kinase TAOK3 regulates hepatic lipid partitioning
title_short STE20-type kinase TAOK3 regulates hepatic lipid partitioning
title_sort ste20-type kinase taok3 regulates hepatic lipid partitioning
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567304/
https://www.ncbi.nlm.nih.gov/pubmed/34634521
http://dx.doi.org/10.1016/j.molmet.2021.101353
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