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Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2

BACKGROUND: Hepatic stellate cell (HSC) activation is a central event during hepatic fibrosis. Aerobic glycolysis is one of its metabolic hallmarks. Blocking glycolysis is a novel therapeutic option for liver fibrosis. This study investigated the effects of costunolide, a natural product demonstrate...

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Autores principales: Ban, Dujing, Hua, Shangbo, Zhang, Wen, Shen, Chao, Miao, Xuehua, Liu, Wensheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694499/
https://www.ncbi.nlm.nih.gov/pubmed/31428167
http://dx.doi.org/10.1186/s11658-019-0179-4
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author Ban, Dujing
Hua, Shangbo
Zhang, Wen
Shen, Chao
Miao, Xuehua
Liu, Wensheng
author_facet Ban, Dujing
Hua, Shangbo
Zhang, Wen
Shen, Chao
Miao, Xuehua
Liu, Wensheng
author_sort Ban, Dujing
collection PubMed
description BACKGROUND: Hepatic stellate cell (HSC) activation is a central event during hepatic fibrosis. Aerobic glycolysis is one of its metabolic hallmarks. Blocking glycolysis is a novel therapeutic option for liver fibrosis. This study investigated the effects of costunolide, a natural product demonstrated to have hepatoprotective effects, on HSC activation and glycolysis. METHODS: Primary HSCs were isolated from rats and cultured through 5 to 6 passages. Cell viability, activation markers, and glycolytic metabolism were examined in primary HSCs using various cellular and molecular approaches. RESULTS: At 30 μM, costunolide reduced the viability of HSCs and inhibited the expression of α-smooth muscle actin and collagen I, two key markers of HSC activation. It also decreased glucose uptake and consumption, and reduced the intracellular levels of lactate in HSCs. At 10 mM, the glycolysis inhibitor 2-DG had a similar impact to costunolide at 30 μM: it significantly downregulated the expression of HSC activation markers. The combination of the two compounds produced more remarkable effects. Furthermore, costunolide repressed the expression and activity of hexokinase 2 (HK2), a pivotal rate-limiting enzyme that regulates glycolysis. However, overexpression of HK2 via plasmid transfection significantly reversed the costunolide-mediated downregulation of activation markers in HSCs, indicating that suppression of HK2 was required for costunolide to inhibit glycolysis-associated HSC activation. CONCLUSIONS: Our results show that costunolide can suppress HSC activation, and this is associated with inhibition of HK2, which blocks aerobic glycolysis. This suggests that costunolide is an antifibrotic candidate with potential for further development.
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spelling pubmed-66944992019-08-19 Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2 Ban, Dujing Hua, Shangbo Zhang, Wen Shen, Chao Miao, Xuehua Liu, Wensheng Cell Mol Biol Lett Research Letter BACKGROUND: Hepatic stellate cell (HSC) activation is a central event during hepatic fibrosis. Aerobic glycolysis is one of its metabolic hallmarks. Blocking glycolysis is a novel therapeutic option for liver fibrosis. This study investigated the effects of costunolide, a natural product demonstrated to have hepatoprotective effects, on HSC activation and glycolysis. METHODS: Primary HSCs were isolated from rats and cultured through 5 to 6 passages. Cell viability, activation markers, and glycolytic metabolism were examined in primary HSCs using various cellular and molecular approaches. RESULTS: At 30 μM, costunolide reduced the viability of HSCs and inhibited the expression of α-smooth muscle actin and collagen I, two key markers of HSC activation. It also decreased glucose uptake and consumption, and reduced the intracellular levels of lactate in HSCs. At 10 mM, the glycolysis inhibitor 2-DG had a similar impact to costunolide at 30 μM: it significantly downregulated the expression of HSC activation markers. The combination of the two compounds produced more remarkable effects. Furthermore, costunolide repressed the expression and activity of hexokinase 2 (HK2), a pivotal rate-limiting enzyme that regulates glycolysis. However, overexpression of HK2 via plasmid transfection significantly reversed the costunolide-mediated downregulation of activation markers in HSCs, indicating that suppression of HK2 was required for costunolide to inhibit glycolysis-associated HSC activation. CONCLUSIONS: Our results show that costunolide can suppress HSC activation, and this is associated with inhibition of HK2, which blocks aerobic glycolysis. This suggests that costunolide is an antifibrotic candidate with potential for further development. BioMed Central 2019-08-14 /pmc/articles/PMC6694499/ /pubmed/31428167 http://dx.doi.org/10.1186/s11658-019-0179-4 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Letter
Ban, Dujing
Hua, Shangbo
Zhang, Wen
Shen, Chao
Miao, Xuehua
Liu, Wensheng
Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
title Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
title_full Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
title_fullStr Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
title_full_unstemmed Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
title_short Costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
title_sort costunolide reduces glycolysis-associated activation of hepatic stellate cells via inhibition of hexokinase-2
topic Research Letter
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694499/
https://www.ncbi.nlm.nih.gov/pubmed/31428167
http://dx.doi.org/10.1186/s11658-019-0179-4
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