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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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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. |
format | Online Article Text |
id | pubmed-6694499 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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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