Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells
Abstract Background Contraction of hepatic stellate cells (HSCs) plays an important role in the pathogenesis of liver fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Here, we investigated how HSC contraction was affected by the natural compound oroxylin A, and eluci...
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doaj-61600781abee479694324aa9ac2029242020-11-25T02:05:34ZengBMCCell Communication and Signaling1478-811X2019-02-0117111310.1186/s12964-019-0324-8Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cellsFeixia Wang0Yan Jia1Mengmeng Li2Ling Wang3Jiangjuan Shao4Qinglong Guo5Shanzhong Tan6Hai Ding7Anping Chen8Feng Zhang9Shizhong Zheng10Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineJiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese MedicineJiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical UniversityThe Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineThe Nanjing Hospital Affiliated to Nanjing University of Chinese MedicineDepartment of Pathology, School of Medicine, Saint Louis UniversityJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineJiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese MedicineAbstract Background Contraction of hepatic stellate cells (HSCs) plays an important role in the pathogenesis of liver fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Here, we investigated how HSC contraction was affected by the natural compound oroxylin A, and elucidated the underlying mechanism. Methods Cell contraction and glycolysis were examined in cultured human HSCs and mouse liver fibrosis model upon oroxylin A intervention using diversified cellular and molecular assays, as well as genetic approaches. Results Oroxylin A limited HSC contraction associated with inhibiting myosin light chain 2 phosphorylation. Oroxylin A blocked aerobic glycolysis in HSCs evidenced by reduction in glucose uptake and consumption and lactate production. Oroxylin A also decreased extracellular acidification rate and inhibited the expression and activity of glycolysis rate-limiting enzymes (hexose kinase 2, phosphofructokinase 1 and pyruvate kinas type M2) in HSCs. Then, we identified that oroxylin A blockade of aerobic glycolysis contributed to inhibition of HSC contraction. Furthermore, oroxylin A inhibited the expression and activity of lactate dehydrogenase-A (LDH-A) in HSCs, which was required for oroxylin A blockade of glycolysis and suppression of contraction. Oral administration of oroxylin A at 40 mg/kg reduced liver injury and fibrosis, and inhibited HSC glycolysis and contraction in mice with carbon tetrachloride-induced hepatic fibrosis. However, adenovirus-mediated overexpression of LDH-A significantly counteracted the oroxylin A’s effects in fibrotic mice. Conclusions Blockade of aerobic glycolysis by oroxylin A via inhibition of LDH-A reduced HSC contraction and attenuated liver fibrosis, suggesting LDH-A as a promising target for intervention of hepatic fibrosis.http://link.springer.com/article/10.1186/s12964-019-0324-8Liver fibrosisOroxylin aHepatic stellate cellAerobic glycolysisContractionLactate dehydrogenase-a |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Feixia Wang Yan Jia Mengmeng Li Ling Wang Jiangjuan Shao Qinglong Guo Shanzhong Tan Hai Ding Anping Chen Feng Zhang Shizhong Zheng |
spellingShingle |
Feixia Wang Yan Jia Mengmeng Li Ling Wang Jiangjuan Shao Qinglong Guo Shanzhong Tan Hai Ding Anping Chen Feng Zhang Shizhong Zheng Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells Cell Communication and Signaling Liver fibrosis Oroxylin a Hepatic stellate cell Aerobic glycolysis Contraction Lactate dehydrogenase-a |
author_facet |
Feixia Wang Yan Jia Mengmeng Li Ling Wang Jiangjuan Shao Qinglong Guo Shanzhong Tan Hai Ding Anping Chen Feng Zhang Shizhong Zheng |
author_sort |
Feixia Wang |
title |
Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells |
title_short |
Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells |
title_full |
Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells |
title_fullStr |
Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells |
title_full_unstemmed |
Blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells |
title_sort |
blockade of glycolysis-dependent contraction by oroxylin a via inhibition of lactate dehydrogenase-a in hepatic stellate cells |
publisher |
BMC |
series |
Cell Communication and Signaling |
issn |
1478-811X |
publishDate |
2019-02-01 |
description |
Abstract Background Contraction of hepatic stellate cells (HSCs) plays an important role in the pathogenesis of liver fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Here, we investigated how HSC contraction was affected by the natural compound oroxylin A, and elucidated the underlying mechanism. Methods Cell contraction and glycolysis were examined in cultured human HSCs and mouse liver fibrosis model upon oroxylin A intervention using diversified cellular and molecular assays, as well as genetic approaches. Results Oroxylin A limited HSC contraction associated with inhibiting myosin light chain 2 phosphorylation. Oroxylin A blocked aerobic glycolysis in HSCs evidenced by reduction in glucose uptake and consumption and lactate production. Oroxylin A also decreased extracellular acidification rate and inhibited the expression and activity of glycolysis rate-limiting enzymes (hexose kinase 2, phosphofructokinase 1 and pyruvate kinas type M2) in HSCs. Then, we identified that oroxylin A blockade of aerobic glycolysis contributed to inhibition of HSC contraction. Furthermore, oroxylin A inhibited the expression and activity of lactate dehydrogenase-A (LDH-A) in HSCs, which was required for oroxylin A blockade of glycolysis and suppression of contraction. Oral administration of oroxylin A at 40 mg/kg reduced liver injury and fibrosis, and inhibited HSC glycolysis and contraction in mice with carbon tetrachloride-induced hepatic fibrosis. However, adenovirus-mediated overexpression of LDH-A significantly counteracted the oroxylin A’s effects in fibrotic mice. Conclusions Blockade of aerobic glycolysis by oroxylin A via inhibition of LDH-A reduced HSC contraction and attenuated liver fibrosis, suggesting LDH-A as a promising target for intervention of hepatic fibrosis. |
topic |
Liver fibrosis Oroxylin a Hepatic stellate cell Aerobic glycolysis Contraction Lactate dehydrogenase-a |
url |
http://link.springer.com/article/10.1186/s12964-019-0324-8 |
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