Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression

Lin An; Mi Zhang; Yuefang Lin; Ting Jiang; Keyang Xu; Shilin Xiao; Liming Cai; Hiu Yee Kwan; Zhongqiu Liu; Tao Su

doi:10.1016/j.phymed.2022.154199

Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression

Lin An, Mi Zhang, Yuefang Lin, Ting Jiang, Keyang Xu, Shilin Xiao, Liming Cai, Hiu Yee Kwan^*, Zhongqiu Liu^*, Tao Su^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › peer-review

11 Citations (Scopus)

Abstract

Background

Liver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated.

Purpose

To explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models.

Methods

LAL expression was examined in the liver tissues of CCl₄ and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction.

Results

We found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression.

Conclusions

This study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.

Original language	English
Article number	154199
Number of pages	10
Journal	Phytomedicine
Volume	103
Early online date	24 May 2022
DOIs	https://doi.org/10.1016/j.phymed.2022.154199
Publication status	Published - Aug 2022

User-Defined Keywords

GATA3
Liver fibrosis
Lysosomal acid lipase
Morroniside

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.phymed.2022.154199

Cite this

@article{fca15467e21e4d0792ebdd37368c9d63,

title = "Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression",

abstract = "BackgroundLiver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated. PurposeTo explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models. MethodsLAL expression was examined in the liver tissues of CCl4 and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction. ResultsWe found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression. ConclusionsThis study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.",

keywords = "GATA3, Liver fibrosis, Lysosomal acid lipase, Morroniside",

author = "Lin An and Mi Zhang and Yuefang Lin and Ting Jiang and Keyang Xu and Shilin Xiao and Liming Cai and Kwan, {Hiu Yee} and Zhongqiu Liu and Tao Su",

note = "Funding Information: This work was supported by The National Natural Science Foundation of China ( 82104687 , 82074019 ), The Basic and Applied Basic Research Fund Project of Guangdong Province ( 2019A1515110202 ), The China Postdoctoral Science Foundation ( 2021T140145 , 2020M672604 ), the open project of State Key Laboratory of Quality Research in Chinese Medicine ( Macau University of Science and Technology , MUST-SKL-2021-003 , 2R2103 ), Administration of Traditional Chinese Medicine of Guangdong Province ( 20222042 ), Guangdong Basic and Applied Basic Research Foundation (2020B1515130005), Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine (2020B1212030006), Key-Area Research and Development Program of Guangdong Province (2020B1111100004), Research Grant Council of HKSAR (HKBU-22103017-ECS), Innovation & Technology Commission (PRP/015/19FX), National Natural Science Foundation of China ( SCM-2016-NSFC-003 ) and Natural Science Foundation of Guangdong Province ( 2018A0303130122 ). Publisher Copyright: {\textcopyright} 2022 Elsevier GmbH. All rights reserved. ",

year = "2022",

month = aug,

doi = "10.1016/j.phymed.2022.154199",

language = "English",

volume = "103",

journal = "Phytomedicine",

issn = "0944-7113",

publisher = "Elsevier GmbH",

}

TY - JOUR

T1 - Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression

AU - An, Lin

AU - Zhang, Mi

AU - Lin, Yuefang

AU - Jiang, Ting

AU - Xu, Keyang

AU - Xiao, Shilin

AU - Cai, Liming

AU - Kwan, Hiu Yee

AU - Liu, Zhongqiu

AU - Su, Tao

N1 - Funding Information: This work was supported by The National Natural Science Foundation of China ( 82104687 , 82074019 ), The Basic and Applied Basic Research Fund Project of Guangdong Province ( 2019A1515110202 ), The China Postdoctoral Science Foundation ( 2021T140145 , 2020M672604 ), the open project of State Key Laboratory of Quality Research in Chinese Medicine ( Macau University of Science and Technology , MUST-SKL-2021-003 , 2R2103 ), Administration of Traditional Chinese Medicine of Guangdong Province ( 20222042 ), Guangdong Basic and Applied Basic Research Foundation (2020B1515130005), Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine (2020B1212030006), Key-Area Research and Development Program of Guangdong Province (2020B1111100004), Research Grant Council of HKSAR (HKBU-22103017-ECS), Innovation & Technology Commission (PRP/015/19FX), National Natural Science Foundation of China ( SCM-2016-NSFC-003 ) and Natural Science Foundation of Guangdong Province ( 2018A0303130122 ). Publisher Copyright: © 2022 Elsevier GmbH. All rights reserved.

PY - 2022/8

Y1 - 2022/8

N2 - BackgroundLiver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated. PurposeTo explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models. MethodsLAL expression was examined in the liver tissues of CCl4 and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction. ResultsWe found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression. ConclusionsThis study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.

AB - BackgroundLiver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated. PurposeTo explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models. MethodsLAL expression was examined in the liver tissues of CCl4 and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction. ResultsWe found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression. ConclusionsThis study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.

KW - GATA3

KW - Liver fibrosis

KW - Lysosomal acid lipase

KW - Morroniside

UR - http://www.scopus.com/inward/record.url?scp=85131752697&partnerID=8YFLogxK

U2 - 10.1016/j.phymed.2022.154199

DO - 10.1016/j.phymed.2022.154199

M3 - Journal article

C2 - 35679793

SN - 0944-7113

VL - 103

JO - Phytomedicine

JF - Phytomedicine

M1 - 154199

ER -

Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression

Abstract

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